2542 PART V  Prevention of Infectious Diseases
245  Active Immunizing Agents
Penelope H. Dennehy • Ian C. Michelow • Michael P. Koster •
Michael A. Smit • Jerome Larkin
Prevention of infectious diseases in children by immunization is one
of the outstanding accomplishments of medical science. Children enjoy
better health today because of effective immunization programs, which
in many countries have markedly diminished the morbidity and mortality
of previously common contagious diseases. The striking decline in the
United States in vaccine-preventable childhood diseases is demonstrated
in Table 245.1.4 Immunization programs have led to the global eradication
of smallpox, elimination of measles and poliomyelitis in some regions
of the world, and substantial reductions in the morbidity and mortality
attributed to diphtheria, tetanus, and pertussis. The World Health
Organization (WHO) estimates that 2 to 3 million child deaths are
prevented by vaccinations annually (http://www.who.int/mediacentre/
factsheets/fs378/en/).
To achieve this progress in child health, scientific technology and
medical practice have combined efforts to (1) understand the biology
of causal infectious agents, (2) purify these agents and some of their
components, (3) develop and test safe and effective vaccines, (4) manu-
facture and administer the vaccines to appropriate segments of the
population, (5) develop appropriate indications and implement schedules
for immunizations, and (6) identify necessary contraindications.
Infectious diseases can be prevented through immunization by
stimulating an active immunologic defense (e.g., from humoral antibody)
through the administration of antigens, usually before natural exposure
to an infectious agent (i.e., active immunization) or by temporarily
supplying preformed human or animal antibody to persons before or
soon after exposure to certain infectious agents (i.e., passive immuniza-
tion). Active immunizations, including the currently available vaccines,
are discussed in this chapter. The composition of major vaccines and
their routes of administration are listed in Table 245.2.
ACTIVE IMMUNOPROPHYLAXIS:
CONSIDERATIONS AND RECOMMENDATIONS
Vaccines
An ideal immunizing agent should include several characteristics. The
agent should be easy to produce in well-standardized preparations that
are readily quantifiable and stable in immunobiologic potency. It should
be easy to administer and not produce disease in the recipient or
susceptible contacts. It should induce long-lasting (ideally permanent)
immunity that is measurable by available and inexpensive techniques.
It should be free of contaminating and potentially toxic substances,
and adverse reactions should be minimal and have minor consequences.
All of these objectives rarely, if ever, are met with the currently available
vaccines because they are neither completely safe nor completely effective.
Partial immunity or undesirable side effects or reactions, or both,
including rare severe reactions, can occur. Nonetheless, vaccines in
current use are highly effective and very safe.
All active immunizing agents (i.e., vaccines) contain one or more
antigens that stimulate a protective immunologic response. Some are
live attenuated viruses or bacteria; other vaccines consist of killed
microorganisms or contain inactivated components such as exotoxins
(i.e., toxoids). In some vaccines, the antigen is a highly defined, single
constituent, such as Haemophilus influenzae type b (Hib) polysaccharide,
whereas in others, the antigen component is less well defined, such as
live viruses or whole-cell pertussis vaccines composed of killed Bordetella
pertussis organisms.
Immunizing agents are administered in suspending fluids such as
sterile water, saline solution, or complex tissue culture fluid that can
contain proteins or other constituents from the medium from which
the vaccine was produced (e.g., serum proteins, egg antigens, other
tissue culture–derived antigens). Certain preservatives, stabilizers, or
antibiotics are added to some vaccines, and in some cases, the additives
can result in hypersensitivity reactions. To enhance immunogenicity,
particularly for vaccines containing inactivated microorganisms or
their extracted components, adjuvants such as aluminum compounds
are added.
Immunization Schedules
The vacinee’s age and timing of immunization are critical for the success
of vaccination. The vaccine schedule is based on many factors, including
the epidemiology of naturally occurring disease, age-specific risk of
complications caused by the natural disease, anticipated immunologic
 CHAPTER 245  Active Immunizing Agents 2543

TABLE 245.1  Reduction in Morbidity of Some Vaccine-Preventable Diseases in the United States
Disease Maximum No. of Cases (y) Cases in 2015 % Decrease
Diphtheria 206,939 (1921) 0 100
Pertussis 265,269 (1934) 20,762 92
Tetanus 1314 (1922–1926) 29 98
Poliomyelitis, paralytic 21,269 (1952) 0 100
Measles 894,134 (1941) 188 >99
Mumps 152,209 (1968) 1329 >99
Rubella 57,686 (1969) 5 >99
Congenital rubella syndrome 20,000 (1964–1965) 1 >99
Haemophilus influenzae type b 20,000 (before 1987) 29 >99
Invasive pneumococcal disease (>5 y) 15,933 (2000) 1177 93
Hepatitis B 21,102 (1990) 3370 84
Varicella 158,364 (1992) 9789 94
Modified from Centers for Disease Control and Prevention. Notice to readers: final 2015 reports of nationally notifiable infectious diseases and conditions. MMWR Morb Mortal Wkly Rep.
2016;651306–21.

TABLE 245.2  Vaccines Available in the United States for Pediatric Use and Routes of Administrationa
Vaccine Type Recommended Route
BCG Live bacteria ID (preferred) or SC
Diphtheria-tetanus (DT, Td) Toxoids IM
DTaP Toxoids and inactivated bacterial components IM
DTaP–hepatitis B–IPV (combination) Toxoids and inactivated bacterial components, recombinant viral IM
antigen, inactivated virus
DtaP-IPV/Hib (combination) Toxoids and inactivated bacterial components, polysaccharide-protein IM
conjugate, inactivated virus
DtaP-IPV (combination) Toxoids and inactivated bacterial components, inactivated virus IM
Hepatitis A Inactivated virus IM
Hepatitis B Recombinant viral antigen IM
Hepatitis A–hepatitis B (combination) Inactivated virus and recombinant viral antigen IM
Hib conjugate Bacterial polysaccharide-protein conjugate IM
Hib–hepatitis B (combination) Bacterial polysaccharide-protein conjugate and recombinant viral antigen IM
Hib conjugate–meningococcal conjugate CY Bacterial polysaccharide-protein conjugate combined with bacterial
(combination) polysaccharide
Human papilloma virus (HPV2, HPV4, and HPV9) Recombinant viral antigens IM
Influenza (IIV) Inactivated viral components IM
Influenza (LAIV) Live attenuated viruses Intranasal spray
Japanese encephalitis Inactivated virus SC
Meningococcal polysaccharide (MPSV4) Bacterial polysaccharide SC
Meningococcal conjugate (MCV4) Bacterial polysaccharide-protein conjugate IM
Meningococcal serogroup B (MenB) Bacterial lipoprotein IM
MMR Live attenuated viruses SC
MMRV Live attenuated viruses SC
Pneumococcal polysaccharide (PPSV23) Bacterial polysaccharide IM or SC
Pneumococcal conjugate (PCV13) Bacterial polysaccharide-protein conjugate IM
Poliovirus (IPV) Inactivated viruses IM or SC
Rabies Inactivated virus IM
Rotavirus (RV1 and RV5) Live attenuated viruses oral
Tdap Toxoids and inactivated bacterial components IM
Tetanus Toxoid IM
Typhoid Bacterial capsular polysaccharide IM
Typhoid Live attenuated bacteria Oral
Varicella Live attenuated virus SC
Yellow fever Live attenuated virus SC
a
Only major childhood vaccines and selected others are included.
BCG, Bacille Calmette-Guérin (tuberculosis); DT, diphtheria-tetanus toxoids (for children <7 y); DTaP, diphtheria-tetanus toxoids–acellular pertussis vaccine (for children <7 y); Hib,
Haemophilus influenzae type b conjugate vaccine; ID, intradermal; IM, intramuscular; IPV, inactivated poliovirus vaccine; MMR, live measles-mumps-rubella viruses vaccine; MMRV, live
measles-mumps-rubella-varicella viruses vaccine; SC, subcutaneous; Td, tetanus-diphtheria toxoid (for children ≥7 y and adults); Tdap, diphtheria–reduced tetanus toxoids–acellular pertussis
vaccine (for children ≥10 y and adults).
2544 PART V  Prevention of Infectious Diseases

response of the host to the antigens, duration of immunity that can be

induced, and recommended ages for routine health care visits. Vaccines TABLE 245.3  Site and Needle Length by Age
are recommended at the youngest age at which significant risk for the for Intramuscular Immunization
natural disease and its complications exist and at which a protective Needle Length, Suggested
immunologic response to the vaccine can occur. Age Group inches (mm) Injection Site
An example is measles vaccine, which in the United States is recom- 5
mended routinely at 12 to 15 months of age because in the first year Neonate (preterm 8 (16) Anterolateral
of life many children have residual, transplacentally acquired maternal and term) and thigh muscle
measles serum antibody that interferes with the antibody response. infants age <1 mo
However, during measles outbreaks or for travel of infants to measles- Term infant, age 1 (25) Anterolateral
endemic areas, measles vaccination is recommended for infants as young 1–12 mo thigh muscle
5
as 6 months because the risk of complications with measles is high Toddlers and children 8 –1 (16–25) Deltoid muscle
among children younger than 1 year.38,471 These infants should be of the arm
vaccinated again at 12 to 15 months of age. Similarly, in countries where 1– 1 14 (25–32) Anterolateral
measles causes significant morbidity and mortality for infants younger thigh muscle
than 9 months, the Global Advisory Group of the WHO’s Expanded Adolescents and
Programme on Immunization (EPI) has recommended giving measles young adults
vaccine to infants as young as 6 months of age.697 Female and male, 1 (25) Deltoid muscle
The recommended doses of vaccine are determined by the number <60 kg of the arm
necessary to achieve a uniform and predictable immunologic response Female, 60–70 kg 1 (25) Deltoid muscle
and to sustain protection. Some immunizing agents require the admin- of the arm
istration of more than one dose for development of an adequate antibody Female, 70–90 kg 1 (25) – 1 12 (38) Deltoid muscle
response and require a booster dose to maintain protection. Examples of the arm
are pertussis, diphtheria, and tetanus vaccines. Intervals between doses Female, >90 kg 1 12 (38) Deltoid muscle
are based on the kinetics of primary and secondary antibody responses. of the arm
Male, 70–118 kg 1 (25) – 1 12 (38) Deltoid muscle
Route of Administration of the arm
An example of the effect of the route of administration on immunologic Male, >118 kg 1 12 (38) Deltoid muscle
response is provided by poliomyelitis vaccines. Inactivated poliovirus of the arm
vaccines given intramuscularly induce systemic immunity through serum
antibody production, but they do not consistently evoke local secretory Modified from American Academy of Pediatrics. Active immunization. In: Kimberlin DW,
Brady MT, Jackson MA, Long SS, eds. Red Book: 2015 Report of the Committee on
immunoglobulin A (IgA) antibodies in the intestinal tract and thereby Infectious Diseases. 30th ed. Elk Grove Village, IL: American Academy of Pediatrics;
effectively prevent subsequent transmission of wild-type virus. Because 2015:1–56.
live attenuated oral polio vaccine (OPV) induces optimal intestinal and
systemic antibody, it was the preferred vaccine for routine immunization
of children in the United States against poliomyelitis for 3 decades and
remains the recommended vaccine by the WHO for global eradication.701 immunizing agents cannot replicate in the host, these vaccines must
Vaccines containing adjuvants must be injected deep into the muscle contain an adequate antigenic mass to stimulate the desired immunologic
mass because if they are administered subcutaneously or intradermally, response. Long-lasting immunity with these vaccines requires repeated
they can cause local irritation, inflammation, granuloma formation, or doses. Exceeding the recommended dose can be hazardous because of
necrosis.29,408 excessive local or systemic concentrations of immunizing agents, whereas
Injectable vaccines should be administered in areas unlikely to cause administration of doses smaller than those recommended may result
local neural, vascular, or tissue injury (Table 245.3).29,408 Although the in inadequate response and protection.29,408
upper, outer quadrant of the buttocks has been used as a frequent site
of immunization, this area ordinarily should not be used because the Lapsed Immunizations
gluteal region consists mostly of fat in young children and because of Intervals between multiple doses of an antigen longer than those recom-
potential injury to the sciatic nerve. Ideally, intramuscular injections mended do not affect the antibody responses achieved, provided the
should be given in the anterolateral aspect of the upper part of the thigh immunization series is completed. Restarting the series after interruption
or the deltoid muscle of the upper part of the arm. The anterolateral of the vaccine schedule or giving additional doses is not necessary.
aspect of the thigh is preferred for infants because of its muscle mass
relative to other sites. For older children, the deltoid muscle usually is Simultaneous Administration of Multiple Vaccines
sufficiently large for intramuscular injection. The incidence of significant Because most vaccines can be given simultaneously without impairing
pain in 18-month-old children injected intramuscularly in the thigh is effectiveness or safety, multiple vaccines are given to children concur-
greater than that after deltoid injections and can result in transient rently.392 Simultaneous administration of vaccines is particularly
limping.363 The deltoid is the preferred site for intramuscular administra- important for inadequately immunized children whose return for further
tion of vaccines in children 18 months of age or older, although some immunization is doubtful or for patients with imminent travel plans.
physicians prefer the anterolateral aspect of the thigh for toddlers.29,408 An inactivated vaccine and a live virus vaccine can be administered
Subcutaneous inoculations usually should be given in the thigh of simultaneously at different sites without interference with the immune
infants and the deltoid area of older children. Intradermal vaccines response. Exceptions are yellow fever and cholera vaccines because
should be administered on the volar aspect of the forearm. antibody responses are diminished if they are administered simultane-
Recommended routes for administration of vaccines are provided ously. If possible, administration of these vaccines should be
in their package inserts and are summarized in recommendations for separated by at least an interval of 3 weeks.408 In the case of live virus
immunizations by the Committee on Infectious Diseases of the American vaccines, the immune response to one live virus vaccine can be impaired
Academy of Pediatrics (AAP)29 and the Advisory Committee on if it is given within 4 weeks of another.408 Parenteral live virus vaccines
Immunization Practices (ACIP) of the Centers for Disease Control and not administered on the same day should be given at least 4 weeks
Prevention (CDC).408 apart. This consideration is the basis of the recommended minimal
interval of 1 month (i.e., 4 weeks) between doses of measles
Vaccine Dose vaccine, such as for a previously unimmunized person who is entering
The recommended dose of each immunizing agent is derived from college. Guidelines for spacing live and killed antigen vaccines are given
theoretical considerations and vaccine trials. Because inactivated in Table 245.4.

TABLE 245.4  Guidelines for Spacing the
Administration of Live and Inactivated Antigens
Antigen Recommended Minimum Interval
Combination Between Doses
Two or more None; can be administered simultaneously or
inactivateda at any interval between doses
Inactivated plus live None, can be administered simultaneously or
at any interval between doses
Two or more live 28-day minimum interval, if not administered
injectibleb simultaneously
a compensation program. Decisions on compensation are made by the
In people with functional or anatomic asplenia, quadrivalent meningococcal conjugate
vaccine (MCV4-D; Menactra) should not be given until at least 4 weeks after all doses of
13-valent pneumococcal conjugate vaccine (PCV13) have been administered because of
interference with the immune response to the PCV13 series because both vaccines are
conjugated to diphtheria toxin carrier protein. PCV13 and 23-valent pneumococcal
polysaccharide vaccine (PPSV23) should not be administered simultaneously and should be
spaced at least 8 weeks apart; when both vaccines are indicated, PCV13 should be
administered first, if possible.
b
An exception is made for some live oral vaccines (e.g., Ty21a typhoid vaccine, oral
poliovirus vaccine, oral rotavirus vaccine) that can be administered simultaneously or at
any interval before or after inactivated or live parenteral vaccines.
Modified from American Academy of Pediatrics. Active immunization. In: Kimberlin DW,
Brady MT, Jackson MA, Long SS, eds. Red Book: 2015 Report of the Committee on
Infectious Diseases. 30th ed. Elk Grove Village, IL: American Academy of Pediatrics;
2015:1–56.
Record Keeping, Patient Information, Informed
Consent, and Reporting
Accurate record keeping by physicians is required, and parents (or
patients) should keep up-to-date immunization records for their children.
The 1986 National Childhood Vaccine Injury Act (NCVIA) requires
that for routinely recommended childhood vaccines, health care providers
record in the child’s permanent medical record the date of administration
of the vaccine, manufacturer, lot number, and name of the health care
provider administering the vaccines.29
All children and their parents or caregivers should be informed
about the benefits and risks of the vaccines to be administered. For
vaccines currently specified in the NCVIA, Vaccine Information State-
ments (VISs) have been prepared by the CDC and must be used by
vaccine administrators.
Informed consent should be obtained before the administration of
vaccines. Some physicians and other health care providers may choose
to obtain the parent’s signature, but current law does not require written
consent. An appropriate alternative to written consent is to note in the
patient’s record that the VISs have been provided and discussed with
the parent, patient, or legal guardian.29
To increase knowledge about adverse reactions, all temporally associated
events severe enough to require the patient to seek medical attention should
be reported to the Vaccine Adverse Events Reporting System (VAERS);
VAERS forms can be obtained by calling 800-822-7967 or by accessing
the website (http://vaers.hhs.gov). Health care providers who administer
vaccines are required in the United States to report to the VAERS specific
adverse events in recipients of the vaccines covered by the NCVIA
(Health Resources and Services Administration: http://www.hrsa.gov/
vaccinecompensation/vaccinetable.html.). This system for reporting adverse
events associated with vaccination was established by the US Department
of Health and Human Services to foster recognition of vaccine-related
reactions and further study to establish possible causation.
Decreased occurrence of vaccine-preventable infectious diseases has
resulted in a greater number of adverse events temporally related to
immunization than cases of disease. Although in some cases, such as
vaccine-associated paralytic poliomyelitis, vaccine has been established
as the cause, in other circumstances, such as brain damage alleged to
be attributed to whole-cell pertussis vaccine, causation by vaccine has
not been proved.14
Increased public visibility of vaccine reactions contributed to a
marked increase in vaccine litigation in the 1980s as compensation was
CHAPTER 245  Active Immunizing Agents 2545
sought through the judicial system by those alleged to have suffered
serious vaccine-related sequelae. A marked increase in manufacturers’
actual and anticipated liability costs and subsequent escalating increases
in the price of vaccines occurred concomitantly. These and other
developments, such as threats to the vaccine supply, concerns by parents
about vaccine safety, and recognition of the benefits derived from
improved coordination and planning of vaccine programs, led to passage
of the 1986 NCVIA and the National Vaccine Injury Compensation
Program (https://www.hrsa.gov/vaccinecompensation/index.html), a
no-fault system to compensate victims of certain presumed vaccine-
related events.
The Department of Health and Human Services administers the
US Court of Federal Claims and are based on the Vaccine Injury Table,
which was revised since passage of the original legislation in response
to new findings and analysis by several Institute of Medicine (IOM)
committees. Compensation for injuries occurring after the program’s
effective date of October 1, 1988, is provided by excise taxes on each
vaccine. The program has been successful in reducing vaccine-related
litigation, stabilizing vaccine prices, and creating a favorable environment
for the introduction of new vaccines.262
Vaccine Recommendations and Schedules
In developing recommendations for immunization, many factors are
considered, including the vaccine’s characteristics, scientific knowledge
about the principles of immunization, assessment of the benefits of
the vaccine, the risk of the disease and its complications, vaccine costs,
and risk of adverse reactions. Changes in relative benefits and risks
necessitate continued review of recommendations.
In the United States, recommendations for immunization of infants
and children are made by the ACIP of the CDC and the AAP’s Committee
on Infectious Diseases. These committees work closely together, and
in most circumstances, their recommendations are similar. The two
committees and the American Academy of Family Practice (AAFP)
issue a single vaccine schedule each year. The 2016 schedule for
routine administration of childhood vaccines is given in Fig. 245.1 and
Table 245.5.
A major change in 1996 was the establishment of a routine preado-
lescent immunization visit at 11 to 12 years of age.125 The dose of adult
tetanus-diphtheria–acellular pertussis (Tdap) vaccine should be given
at that time, as should a dose of the meningococcal conjugate vaccine
and the first dose of human papillomavirus (HPV) vaccine. At this
preadolescent visit, children not previously vaccinated with hepatitis
B, varicella, or the second dose of measles-containing vaccine (or any
combination of these vaccines) should be given the necessary immuniza-
tions and scheduled for future visits to receive any vaccines not
administered during this visit.
Other countries have similar national mechanisms for formulating
immunization schedules and recommendations that are based on the
local epidemiology of diseases and available vaccines. In low-resource
countries, practices are guided by the WHO’s EPI. Current recom-
mendations are listed at the website (http://www.who.int/immunization/
policy/Immunization_routine_table2.pdf?ua=1).
As new vaccines and scientific knowledge become available, vaccine
recommendations and schedules are modified and changed. Examples
of changes in the past 2 decades include the use of pneumococcal
conjugate vaccine beginning at 2 months of age, universal toddler
hepatitis A immunization, and recommendations for administration
of a second dose of varicella vaccine, and the introduction of acellular
pertussis vaccines for adolescents and adults.
Implementation of Vaccine Programs
In addition to the availability of safe and effective vaccines and appropri-
ate schedules for their use, effective means of implementation and
delivery are necessary for the success of vaccine programs. In the United
States, high rates of immunization among school-aged children have
been achieved, in part because of public health programs for vaccine
administration, government support for vaccine purchase, and state
laws requiring immunization for school entry. In contrast to rates of
approximately 95% or higher among school-aged children, immunization
2546 PART V  Prevention of Infectious Diseases

19–23
Vaccine Birth 1 mo 2 mos 4 mos 6 mos 9 mos 12 mos 15 mos 18 mos 2–3 yrs 4–6 yrs 7–10 yrs 11–12 yrs 13–15 yrs 16–18 yrs
mos

Hepatitis B1 (HepB) 1st dose 2nd dose 3rd dose

Rotavirus2 (RV) RV1 (2-dose st nd See

1 dose 2 dose
series); RV5 (3-dose series) footnote 2

Diphtheria, tetanus, and acellular st nd

1 dose 2 dose 3rd dose 4th dose 5th dose
pertussis3 (DTaP: <7 yrs)

Haemophilus influenzae type b4 See 3rd or 4th dose

1st dose 2nd dose footnote 4
(Hib) See footnote 4

Pneumococcal conjugate5
1st dose 2nd dose 3rd dose 4th dose
(PCV13)

Inactivated poliovirus6
(IPV: <18 yrs) 1st dose 2nd dose 3rd dose 4th dose

Annual vaccination (LAIV or Annual vaccination (LAIV or IIV)

Influenza7 (IIV; LAIV) Annual vaccination (IIV only) 1 or 2 doses IIV) 1 or 2 doses 1 dose only

Measles, mumps, rubella8 (MMR) See footnote 8 1st dose 2nd dose

Varicella9 (VAR) 1st dose 2nd dose

Hepatitis A10 (HepA) 2-dose series, see footnote 10

Meningococcal11 (Hib-MenCY)
6 weeks; MenACWY-D 9 mos; See footnote 11 1st dose Booster

MenACWY-CRM 2 mos)
Tetanus, diphtheria, and acellular
(Tdap)
pertussis12 (Tdap: 7 yrs)

Human papillomavirus13 (2vHPV:

females only; 4vHPV, 9vHPV: (3-dose
males and females) series)

See footnote 11
Meningococcal B11

Pneumococcal polysaccharide5
See footnote 5
(PPSV23)

Range of recommended Range of recommended ages Range of recommended ages Range of recommended ages for non-high-risk No recommendation
ages for all children for catch-up immunization for certain high-risk groups groups that may receive vaccine, subject to
individual clinical decision making
This schedule includes recommendations in effect as of january 1, 2016. Any dose not administered at the recommended age should be administered at a subsequent visit, when indicated and
feasible.The use of a combination vaccine generally is preferred over separate injections of its equivalent component vaccines. Vaccination providers should consult the relevant advisory committee
on immunization practices (ACIP) statement for detailed recommendations, available online at http://www.cdc.gov/vaccines/hcp/acip-recs/index.html. Clinically significant adverse events that follow
vaccination should be reported to the vaccine adverse event reporting system (VAERS) online (http://www.vaers.hhs.gov) or by telephone (800-822-7967). Suspected cases of vaccine-preventable
diseases should be reported to the state or local health department. Additional information, including precautions and contraindications for vaccination, is available from CDC online
(http://www.cdc.gov/vaccines/recs/vac-admin/contraindocations.htm) or by telephone (800-CDC-INFO [800-232-4636]).

This schedule is approved by the advisory committee on immunization practices (http//www.cdc.gov/vaccines/acip), the american academy of pediatrics (http://www.aap.org), the american academy of
family physicians (http://www.aafp.org), and the american college of obstetricians and gynecologists (http://www.acog.org).

NOTE: The above recommendations must be read along with the footnotes of this schedule.

FIG. 245.1  Recommended immunization schedule for people from birth to 18 years of age in the United
States in 2016. An expanded version of the table and its 13 footnotes can be found at https://www.cdc.
gov/vaccines/schedules/hcp/imz/child-adolescent.html. (From Centers for Disease Control and Prevention.
Immunization schedules. http://www.cdc.gov/vaccines/schedules/hcp/child-adolescent.html.)

rates for infants and young children in the 1980s were significantly
lower.713 In a survey of 21 primarily urban areas throughout the United
States, 11% to 58% (median, 44%) of children who entered school in
1991 and 1992 were fully vaccinated by their second birthday. Failure
to immunize young children was a major factor in the outbreaks
of measles in major urban areas in the United States in 1989
through 1991.634
The measles epidemic and the recognition of low immunization
rates prompted a national campaign to achieve the US Public Health
Service’s goal of a 90% vaccine coverage rate for children by the time
they were 2 years of age. Initiatives have included improved access to
vaccines, education of health care providers in the community, and the
development of standards for pediatric immunization practice.498 The
standards have been endorsed by the AAP, AAFP, and other major
professional organizations and serve as guidelines to be followed for
improving the delivery of vaccines. They include evaluation of the
patient’s immunization status at all medical visits, use of valid contra-
indications, simultaneous administration of all indicated vaccines, and
routine audits of the immunization status of patients by providers.
These and other initiatives resulted in increasing immunization rates
among young children.
According to the National Immunization Survey, coverage rates for
children 19 to 35 months of age in 2015 were 72.2% for completion
of the combined vaccine series, which includes four or more doses of
diphtheria, tetanus toxoids, and acellular pertussis vaccine (DTaP); three
or more doses of poliovirus vaccine; one or more doses of measles-
containing vaccine; full series of Hib vaccine (i.e., three or four doses,
depending on product type); three or more doses of hepatitis B vaccine
(HepB); one or more doses of varicella vaccine; and four or more doses
of pneumococcal conjugate vaccine (PCV).344 Vaccination coverage rates
in the United States for preschool-aged children consistently have been
greater than 70% since 2013.
Vaccine Contraindications, Precautions, and Use
in Special Circumstances
Recommendations for the use of specific vaccines include contraindica-
tions and use in special circumstances, such as immunocompromised
patients (from underlying disease or therapy such as high-dose
corticosteroids) and pregnancy.29,408 Established, generic contraindications
are moderate or severe illness, a previous anaphylactic reaction to the
specific vaccine, and a severe hypersensitivity reaction (e.g., anaphylaxis)
to a vaccine constituent.
The decision to defer immunization in a febrile child should be
based on the physician’s assessment of the severity of the illness rather
than the degree of fever. Children with minor illness and low-grade
fever usually should be vaccinated, especially if a child is unlikely to
return promptly for the deferred immunization.
Administration of live virus vaccines such as varicella and measles-
mumps-rubella (MMR) vaccines usually is contraindicated in patients
with altered immunity. However, the morbidity and mortality rates of
measles and the lack of complications from vaccination of children
infected with human immunodeficiency virus (HIV) prompted recom-
mendations that these children, unless significantly immunocompromised,
receive the MMR vaccine.17,126,471
Because of a theoretical risk to the developing fetus, administration
of live virus vaccines in most cases is not recommended for pregnant
women.36,408 However, inadvertent administration of vaccine is not
necessarily a reason for termination of the pregnancy, and some live
TABLE 245.5  Catch-Up Immunization Schedule for People Age 4 Months Through 18 Years Who Start Late or Are >1 Month Behind—United
States, 2017a

Minimum Age MINIMUM INTERVAL BETWEEN DOSES

Vaccine for Dose 1 Dose 1 to 2 Dose 2 to 3 Dose 3 to 4 Dose 4 to 5
Children 4 Months–6 Years of Age
Hepatitis B1 Birth 4 wk 8 wk and at least 16 wk after first dose — —
Minimum age for the final dose is 24 wk
Rotavirus2 6 wk 4 wk 4 wk2 — —
Diphtheria, tetanus, and acellular pertussis3 6 wk 4 wk 4 wk 6 mo 6 mo3
Haemophilus influenzae type b4 6 wk 4 wk if first dose was administered before 4 wk4 if current age is younger than 12 mo and 8 wk (as final dose); dose —
first birthday first dose was administered before age 7 mo and necessary only for
at least 1 previous dose was PRP-T (ActHib, children 12–59 mo who
Pentacel, Hiberix) or unknown received 3 doses before
8 wk (as final dose) if first dose was 8 wk and age 12–59 mo (as final dose)4 first birthday
administered at age 12–14 mo
No further doses needed if first dose was If current age is younger than 12 mo and first dose
administered at age ≥15 mo was administered at age 7–11 mo or
— If current age is 12–59 mo and first dose was
administered before first birthday and second
dose administered <15 mo or
If both doses were PRP-OMP (PedvaxHIB; Comvax)
and were administered before first birthday
No further doses needed if previous dose was
administered at age ≥15 mo
Pneumococcal5 6 wk 4 wk if first dose administered before first 4 wk if current age is <12 mo and previous dose 8 wk (as final dose); dose —
birthday given at <7 mo of age necessary only for
8 wk (as final dose for healthy children) if 8 wk (as final dose for healthy children) if previous children 12–59 mo of
first dose was administered at or after first dose given between 7–11 mo (wait until at least age who received 3
birthday 12 mo old); or if current age is ≥12 mo and at doses before age 12 mo
least 1 dose was given before age 12 mo or for children at high
No further doses needed for healthy children No further doses needed for healthy children if risk who received 3 —
if first dose administered at age ≥24 mo previous dose administered at age ≥24 mo doses at any age
Continued
CHAPTER 245  Active Immunizing Agents
2547
 2548

TABLE 245.5  Catch-Up Immunization Schedule for People Age 4 Months Through 18 Years Who Start Late or Are >1 Month Behind—United
States, 2017a—cont’d

Minimum Age MINIMUM INTERVAL BETWEEN DOSES

Vaccine for Dose 1 Dose 1 to 2 Dose 2 to 3 Dose 3 to 4 Dose 4 to 5
Inactivated poliovirus6 6 wk 4 wk6 4 wk6 6 mo6 (minimum age of —
4 y for final dose).
Measles, mumps, rubella8 12 mo 4 wk — — —
Varicella9 12 mo 3 mo — — —
Hepatitis A10 12 mo 6 mo — — —
PART V  Prevention of Infectious Diseases

Meningococcal11 6 wk 8 wk11 See footnote 11 See footnote 11 —

(Hib-MenCY ≥6 wk; (MenACWY-D ≥9 mo;
MenACWY-CRM ≥2 mo)

Minimum Age MINIMUM INTERVAL BETWEEN DOSES

Vaccine for Dose 1 Dose 1 to Dose 2 Dose 2 to Dose 3 Dose 3 to Dose 4
Children and Adolescents 7–18 Years of Age
Meningococcal11 N/A 8 wk11 — —
(MenACWY-D ≥9 mo; MenACWY-CRM ≥2 mo)
Tetanus, diphtheria; tetanus, diphtheria, and acellular pertussis12 7 y12 4 wk 4 wk if first dose of DTaP/DT was administered before 6 mo if first dose of DTaP/DT
first birthday was administered before
6 mo (as final dose) if first dose of DTaP/DT or Tdap/Td first birthday
was administered at or after first birthday
Human papillomavirus13 9y Routine dosing intervals are recommended13
Hepatitis A10 N/A 6 mo — —
Hepatitis B1 N/A 4 wk 8 wk and at least 16 wk after first dose —
Inactivated poliovirus6 N/A 4 wk 4 wk6 6 mo6
Measles, mumps, rubella8 N/A 4 wk — —
Varicella9 N/A 3 mo if age <13 y — —
4 wk if age ≥13 y
a
The recommendations must be read with the numeric footnotes of this schedule (https://www.cdc.gov/vaccines/schedules/hcp/imz/catchup.html/).
N/A, Not applicable.
From Centers for Disease Control and Prevention. Immunization schedules. http://www.cdc.gov/vaccines/schedules/hcp/child-adolescent.html.

virus vaccines, such as those for yellow fever and poliomyelitis, can be
given safely to pregnant women. Inactivated bacterial and viral vaccines
such as tetanus toxoids, hepatitis B, and influenza vaccine, which are
composed of antigenic components or killed organisms, can and should
be given during pregnancy if indicated.
In some recipients, vaccines can cause severe reactions, which may
be a contraindication or precaution to subsequent administration of
the specific vaccine. An example is a child in whom a fever of 40.5°C
(105°F) or higher develops after receiving DTaP vaccine and for
whom administration of further doses of pertussis-containing vaccine
is not indicated in most cases. This recommendation is based on the
unproven but reasonable presumption that children who experience
adverse reactions after receiving pertussis immunization are at risk for
similar reactions of equal or greater magnitude on subsequent
immunization.188
Anaphylactic reactions caused by allergenic components of a vaccine
(e.g., gelatin or egg protein in vaccine prepared in embryonated chicken
eggs) have occurred rarely. Vaccines posing a potential risk for egg-
sensitive people include those against measles, mumps, inactivated
influenza, and yellow fever. Before administering vaccines to people
with possible hypersensitivity to vaccine constituents, physicians should
review current recommendations for these vaccines. In other circum-
stances, specific immunizations may be contraindicated because of
previous reactions and the child’s medical history, such as with DTaP
(e.g., evolving neurologic disorders) and MMR (e.g., immune throm-
bocytopenia associated temporally with vaccination).408
Misconceptions
Appropriate and safe use of vaccines requires knowledge of the patient’s
relevant medical history, adverse reactions associated with previous
receipt of vaccines, and specific indications and contraindications.
Without this information, vaccines may be administered inadvertently
or not given in circumstances in which immunization is indicated,
thereby resulting in missed opportunities for receiving the recommended
immunization and susceptibility of the child to a preventable disease.
Examples of common misconceptions concerning contraindication to
vaccines are given in Box 245.1.
International Travel
Foreign travel often is an indication for giving vaccines not routinely
administered to children. The risk of exposure to certain vaccine-
preventable diseases may be greater than in the United States, and
travelers may be exposed to infections that are uncommon or do not
occur in the United States. Examples include vaccines against
hepatitis A, typhoid fever, yellow fever, and Japanese encephalitis (JE)
(Table 245.6), depending on the location and circumstances of the
person’s visit. Some countries may require yellow fever vaccination for
entry. The second dose of measles vaccine should be given to children
and adolescents who have received only one dose (provided 4 weeks
or more have elapsed since administration of the first dose), irrespective
of age because the risk of exposure to measles cases may be substantial
in some foreign countries. Children and adolescents should have received
all vaccines routinely recommended for their age.
Information on vaccine requirements for international travel is
provided in a semiannually revised publication by the CDC, Health
Information for International Travel678 (https://wwwnc.cdc.gov/travel/
page/yellowbook-home). Information also is available from the CDC
International Travelers Hotline (800-232-4636) or the CDC Traveler’s
Health website (http://wwwnc.cdc.gov/travel/).
Vaccine Safety
Immunizations are among the most cost-effective and widely used public
health interventions. Public health recommendations for vaccine
programs and practices represent a dynamic balancing of risks and
benefits. Vaccine safety or risk monitoring is necessary to weigh these
factors accurately and adjust vaccination policies accordingly.
No vaccine is perfectly safe or effective. As the incidence of vaccine-
preventable diseases is reduced, public concern refocuses from the risk
of contracting disease to the health risks associated with vaccines. A
higher standard of safety typically is expected for vaccines compared
CHAPTER 245  Active Immunizing Agents 2549
BOX 245.1  Misconceptions About Vaccine
Contraindications
• Mild acute illness with low-grade fever or mild diarrheal illness in an
otherwise well child.
• Current antimicrobial therapy or the convalescent phase of illness.
• Reaction to previous vaccine dose that involved only soreness, redness,
or swelling in the immediate vicinity of the vaccination site or
temperature of less than 40.5°C (105°F).
• Prematurity. The appropriate age for initiating most immunization in the
prematurely born infant is the usual recommended chronologic age.
Vaccine doses should not be reduced for preterm infants.
• Pregnancy of mother or other household contact. Vaccine viruses in
MMR vaccine are not transmitted by vaccine recipients. Although
varicella vaccine and influenza vaccine viruses have been transmitted
by a healthy vaccine recipient to contacts, the frequency is rare, only
mild or asymptomatic infection has been reported, and use of vaccine is
not contraindicated by pregnancy of the child’s mother or other
household contacts.
• Recent exposure to an infectious disease.
• Breastfeeding. The only vaccine virus that has been isolated from breast
milk is rubella vaccine virus. No evidence indicates that breast milk from
women immunized against rubella is harmful to infants.
• A history of nonspecific allergies or relatives with allergies.
• Allergies to penicillin or any other antibiotic, except anaphylactic
reactions to neomycin or streptomycin. These reactions occur rarely, and
none of the vaccines licensed in the United States contains penicillin.
• Allergies to duck meat or duck feathers. No vaccine available in the
United States is produced in substrates containing duck antigens.
• Family history of convulsions in persons considered for pertussis or
measles vaccination.
• Family history of sudden infant death syndrome in children considered
for DTaP vaccination.
• Family history of an adverse event, unrelated to immunosuppression
after vaccination.
• Malnutrition.
DTaP, Diphtheria-tetanus–acellular pertussis; MMR, measles-mumps-rubella.
Modified from American Academy of Pediatrics. Active immunization. In: Kimberlin DW,
Brady MT, Jackson MA, Long SS, eds. Red Book: 2015 Report of the Committee on
Infectious Diseases. 30th ed. Elk Grove Village, IL: American Academy of Pediatrics;
2015:1–56.
with other medical interventions because in contrast to most pharma-
ceutical products that are administered to ill people for curative purposes,
vaccines usually are given to healthy people to prevent disease acquisition.
Public tolerance of adverse reactions due to products given to healthy
people, especially healthy infants, is substantially lower than that to
products administered to people who are already ill.
The lower tolerance of risk for vaccines necessitates investigating
possible causes of rare adverse events after administration of vaccinations
more aggressively than would be acceptable for other pharmaceutical
products. Because vaccination is such a common event, any health
problem that occurs after immunization can be attributed to the vaccine.
Health effects reported as being associated with vaccines may be true
adverse reactions or may be associated with vaccination only by
coincidence. Because a temporal relationship alone does not prove
causation, cause-and-effect relationships often are impossible to establish.
Epidemiologic and related studies must be performed to ascertain
the incidence and nature of adverse reactions to vaccines. The studies
are important in ensuring a scientific rationale for recommendations
for vaccine use and optimal public and professional acceptance of
vaccines.
The topic of vaccine safety became prominent during the mid-1970s
with increases in the number of lawsuits filed on behalf of patients
2550 PART V  Prevention of Infectious Diseases

TABLE 245.6  Recommended Immunizations for Travelers to Developing Countries

LENGTH OF TRAVEL
Brief Intermediate Long-Term Residential
Immunizations (<2 wk) (2 wk–3 mo) (>3 mo)
Review and complete age-appropriate childhood schedule + + +
DTaP, poliovirus, pneumococcal, and Haemophilus influenzae type b vaccines may be given
at 4-week intervals if necessary to complete the recommended schedule before
departure. Rotavirus vaccine has maximum ages for the first and last doses;
consideration should be given to the timing of an infant’s travel so that the infant will
be able to receive the vaccine series.
Measles: Infants 6–11 mo of age should receive 1 dose of MMR vaccine before departure.
Two additional doses are given if younger than 12 mo of age at first dose.
Varicella
Hepatitis Aa
Hepatitis Bb
Vaccines against the following diseases should be considered depending on the
geographic area and circumstances of the visit:
Japanese encephalitisc ± ± +
Meningococcal diseased ± ± ±
Rabiese ± + +
Typhoid feverf ± + +
Yellow feverg + + +
a
Indicated for travelers to areas with intermediate or high endemic rates of hepatitis A virus infection.
b
If insufficient time to complete 6-month primary series, an accelerated series can be given.
c
For regions with endemic infection. For high-risk activities in areas experiencing outbreaks, vaccine is recommended, even for brief travel.
d
Recommended for regions of Africa with endemic infection and during local epidemics and required for travel to Saudi Arabia for the Hajj.
e
Indicated for persons at high risk for animal exposure (especially dogs) and for travelers to countries with endemic infection.
f
Indicated for travelers who will consume food and liquids in areas of poor sanitation.
g
For regions with endemic infection.
DTaP, Diphtheria-tetanus–acellular pertussis.
Modified from American Academy of Pediatrics. Immunizations in special clinical circumstances. In: Kimberlin DW, Brady MT, Jackson MA, Long SS, eds.. Red Book: 2015 Report of the
Committee on Infectious Diseases. 30th ed. Elk Grove Village, IL: American Academy of Pediatrics; 2015:101–107; Centers for Disease Control and Prevention. Health information for
international travel, 2016: international travel with infants and young children. http://wwwnc.cdc.gov/travel/yellowbook/2016/international-travel-with-infants-children/
vaccine-recommendations-for-infants-children

presumably injured by the diphtheria-tetanus-pertussis (DTP) vaccine.280

Legal decisions were made and damages awarded despite the lack of
scientific evidence to support claims of vaccine injury.280 As a result
of the liability, prices soared, and several manufacturers halted production.
A shortage of vaccines resulted, and public health officials became
concerned about the return of epidemic diseases. To reduce liability
and respond to public health concerns, Congress passed the NCVIA
in 1986.
The NCVIA mandates that all health care providers report certain
adverse events that occur after the administration of vaccination with
routinely recommended childhood vaccines. As a result, the VAERS
was established by the US Food and Drug Administration (FDA) and
the CDC in 1990. VAERS provides a mechanism for the collection and
analysis of adverse events associated with vaccines currently licensed
in the United States. Adverse events are defined as health effects occurring
after immunization that may or may not be related to the vaccine.
VAERS data are monitored continually to detect previously unknown
adverse events or increases in known adverse events.187
The gaps that exist in the scientific knowledge of rare vaccine adverse
events prompted the CDC to develop the Vaccine Safety Datalink (VSD)
project.185 It involved forming partnerships with four large health
maintenance organizations to monitor vaccine safety continually. VSD
is an example of a large, linked database and includes information on
more than 6 million people. The VSD project enables planned vaccine
safety studies and timely investigations of hypotheses. The CDC has
established an Immunization Safety Office (http://www.cdc.gov/
vaccinesafety/iso.html) that identifies possible vaccine side effects and
conducts studies to determine whether health problems are caused by
vaccines.
Reference Sources
Several comprehensive sources of information about pediatric vaccines
are available. The AAP publishes The Red Book: Report of the Committee
on Infectious Diseases every 3 years. The next edition will be published
in 2018. In the interval between editions, the AAP publishes recom-
mendations in its newsletter AAP News and subsequently in Pediatrics.
The ACIP issues vaccine recommendations and relevant information
in Morbidity and Mortality Weekly Report. Manufacturers provide product
information for each vaccine in the FDA-approved package inserts.
VACCINES RECOMMENDED FOR ROUTINE
ADMINISTRATION
Diphtheria Toxoid
The introduction of diphtheria toxoid–containing vaccine in the 1940s
led to a dramatic reduction in the incidence of diphtheria in the United
States. From 1980 through 2004, 57 cases of diphtheria were reported
in the United States, an average of 2 to 3 per year,405 and only five cases
have been reported since 2000. A confirmed case has not been reported
in the United States since 2003.31 However, diphtheria remains a
potentially significant public health problem. Serologic surveys in the
United States and England have suggested that many adults are not
immune.219,405,449
Although a study published in 1996 demonstrated that most adults
in the United States do have protective concentrations of serum anti-
toxin,321 data obtained from a national population-based serosurvey
published in 2002 revealed that the prevalence of immunity to diphtheria,
as determined by the level of diphtheria antitoxin, progressively decreased

from 91% among children 6 to 11 years of age to approximately 30%
among those 60 to 69 years of age.472 Of the reported cases with known
patient age since 1980, 58% were among people 20 years of age or older
and 44% were among people 40 years of age or older. Most cases have
occurred in unimmunized or inadequately immunized people.
The current age distribution of cases corroborates the finding of
inadequate levels of circulating antitoxin in many adults. Adequate
immunization has not eliminated the potential for transmission of
Corynebacterium diphtheriae completely because immunization does
not prevent carriage of C. diphtheriae in the nasopharynx or on the
skin.90,405
C. diphtheriae requires infection with a virus to acquire the genetic
information for toxin production, which is the primary mediator of
disease. When isolated, strains of C. diphtheriae should be tested for
toxin production to establish causality in clinical disease. Non–toxin-
producing strains can cause an undifferentiated pharyngitis that is
usually self-limited. Because the organism requires tellurite for growth,
the microbiology laboratory must be alerted to the fact that diphtheria
is suspected when specimens are submitted. Polymerase chain reaction
(PCR) methods can help in making the diagnosis if antibiotics have
been given before obtaining cultures.
C. diphtheriae is further subdivided in to four biotypes: gravis,
intermedius, mitis, and belfanti. All four biotypes have the potential to
produce toxin. Humans are the reservoir for C. diphtheriae and may
be asymptomatic. Transmission occurs by respiratory droplets or
contaminated fomites. Asymptomatic carriers and those with disease
can shed the organism for weeks after infection. Shedding is terminated
within 48 hours of initiating appropriate antimicrobial therapy.
As a result of inadequate immunity in adults, infants, and children,
an epidemic of diphtheria occurred in the 1990s throughout the former
Soviet Union, including Russia, Ukraine, and the central Asian republics.
Case-fatality rates ranged from 3% to 23%.285,334 Diphtheria continues
to be a significant cause of morbidity and mortality in developing
countries,285 and it therefore remains a source of possible exposure
during travel to endemic countries. Because humans are the only known
reservoir for C. diphtheriae, universal immunization with a diphtheria
toxoid–containing vaccine is the only effective control measure.
Preparations
Diphtheria toxoid is produced by growing toxigenic C. diphtheriae in
liquid medium. The filtrate is incubated with formaldehyde to convert
toxin to toxoid and then is adsorbed onto an aluminum salt adjuvant.
Diphtheria toxoid is available in combination with DTaP for routine
immunization of infants and children younger than 7 years and for
adolescents and adults 11 to 64 years of age as a single booster (Tdap).
Two brands of Tdap are available: Boostrix (approved for people ≥10
years of age) and Adacel (approved for people 11 to 64 years of age).
DTaP and Tdap vaccines do not contain thimerosal as a preservative.
Diphtheria toxoid also is available as a DTaP–inactivated poliovirus
(IPV)–hepatitis B combination, a DTaP–inactivated poliovirus (IPV)–Hib
conjugate combination, and in combination with tetanus toxoid (i.e.,
DT and Td) for use when pertussis vaccination is contraindicated. No
diphtheria-only vaccine is available. Hib, pneumococcal, and meningococ-
cal conjugate vaccines containing diphtheria toxoid or CRM197 protein,
a nontoxic variant of diphtheria toxin used as an adjuvant, are not
substitutes for diphtheria toxoid immunization.31
Pediatric formulations (i.e., DT and DTaP) contain an amount of
tetanus toxoid similar to adult Td, but they contain three to four times
as much diphtheria toxoid. The concentration of diphtheria toxoid (D)
for children younger than 7 years per 0.5-mL intramuscular dose of
DTaP or DT vaccine is 6.7 to 25 limit of flocculation (Lf) units, depending
on the vaccine manufacturer. Vaccines approved for children 7 years
or older and adults (i.e., Tdap and Td) contain only a fraction of the
diphtheria toxoid (d = 2–2.5 Lf) because of adverse reactions related
to dose and age.31,90,405
Immunogenicity
After a primary series of three properly spaced diphtheria toxoid doses
in adults or four doses in infants, a protective level of antitoxin (≥0.1 IU
CHAPTER 245  Active Immunizing Agents 2551
of antitoxin/mL) is reached in more than 95% of vaccinees. Diphtheria
toxoid has been estimated to have a clinical efficacy rate of 97%. Immune
response to diphtheria toxoid was measured after administration of
each adult Tdap vaccine and compared with that elaborated after Td
vaccine. Seroprotective antidiphtheria levels, defined as a titer of 0.1 IU/
mL or more, and booster response rates to diphtheria were determined
to be noninferior after administration of Tdap compared with Td
vaccination.405
Adverse Events
Other than local reactions of pain and swelling at the site of vaccine
injection, immunization does not cause significant adverse events. These
local reactions have been attributed to hypersensitivity reactions in
response to the pertussis component and are not a contraindication
for administration of further vaccination if otherwise indicated.
Regarding adverse reactions reported after administration of Tdap,
vaccination with Boostrix was associated with a statistically higher rate
of moderate to severe headache compared with Td, and vaccination
with Adacel was associated with higher rates of mild injection site pain
and low-grade fever compared with the Td vaccine. No serious adverse
events have been reported for Boostrix. There have been two reports
of serious adverse events, both characterized as neuropathic reactions,
in adults, possibly related to having received Adacel (none reported in
adolescents), and in both cases, symptoms resolved completely within
several days.90
When administered in the third trimester of pregnancy as recom-
mended by the ACIP, there has been no association with increases in
poor birth outcomes or maternal adverse events.90,243,488,625
Indications
Primary immunization consists of five doses of diphtheria toxoid, provided
as DTaP or as DT if pertussis is contraindicated.31,90,405 The first three
doses are administered routinely to children who are 2, 4, and 6 months
of age. A fourth dose is administered 6 to 12 months after the third
dose, between 12 to 18 months of age, to maintain adequate antibody
concentrations for the ensuing preschool years. For those not immunized
in infancy, the initial dose is followed by two doses given 2 and 8 to 14
months later. A single booster dose given when the child is 4 to 6 years
of age (before school entry) is indicated unless the preceding dose was
given after the fourth birthday. Interruption of the recommended schedule
or delay in administering subsequent doses during primary immunization
does not reduce immunity or necessitate restarting the series.
In 2005, the FDA licensed two vaccines containing tetanus toxoid,
reduced diphtheria toxoid, and acellular pertussis antigens (i.e., Tdap)
for routine use in adolescents and adults. Tdap is recommended only
for a single dose across all age groups, including as a one-time-only
substitute for the next scheduled or recommended Td booster in
individuals who previously completed their primary vaccination series
with DTP or DTaP. The preferred age for Tdap vaccination is 11 to 12
years. Adolescents 11 to 18 years of age who completed their primary
series with DTP or DTaP are encouraged to receive Tdap. Tdap may
be given without regard to prior immunization history (e.g., those who
received Td less than 10 years earlier) to a patient for whom pertussis
immunization is indicated.
Although longer intervals between Td and Tdap could decrease the
occurrence of local reactions, the benefits of protection against pertussis
outweigh the potential risk for adverse events.170 Every 10 years thereafter,
a tetanus booster should be provided by Td vaccine. Adolescents between
the ages of 11 and 18 years who have never been vaccinated against
tetanus, diphtheria, or pertussis initially should receive Tdap followed
by Td for the subsequent two doses at 4 weeks or more and 6 to 12
months after that.
No pertussis-containing vaccine has been FDA approved for children
between the ages of 7 and 10 years. If pertussis vaccine is not contra-
indicated, children 7 through 10 years of age who are not fully vaccinated
(i.e., have not received five doses of DTaP or four doses of DTaP if the
fourth dose was administered on or after the fourth birthday) should
receive a single dose of Tdap to provide protection against pertussis.
If additional doses of tetanus and diphtheria toxoid–containing vaccines
2552 PART V  Prevention of Infectious Diseases
are needed for children 7 through 10 years of age after Tdap vaccine
is substituted as the first dose, Td vaccine should be provided for the
subsequent two doses at 4 weeks or more and 6 to 12 months after that
if indicated for the catch-up series.31,171 Tdap is recommended in this
age group because of its reduced antigen content compared with DTaP,
resulting in reduced reactogenicity.171 Pregnant woman should receive
Tdap early in the third trimester of each pregnancy.171
After exposure to a case of strongly suspected or proven diphtheria,
asymptomatic, previously immunized people should receive a booster
of an age-appropriate diphtheria toxoid–containing vaccine if they have
not received a booster dose of a diphtheria toxoid–containing vaccine
within 5 years. For people 10 years or older, Tdap is preferred over Td
if a pertussis booster vaccine was not previously received.31 If not previ-
ously immunized, carriers should receive age-appropriate diphtheria
toxoid–containing vaccine (i.e., DTaP [or DT], Tdap, or Td) as soon
as identified and should complete the entire series. Patients recovering
from diphtheria infection should be immunized because infection does
not confer immunity.
Precautions and Contraindications
The only contraindication to diphtheria toxoid is a history of severe
hypersensitivity developing after receipt of a previous vaccine dose.
Vaccination with diphtheria or tetanus toxoid is not associated with an
increased risk of convulsions. Local reactions alone do not preclude
continued use.
Haemophilus influenzae Type b Vaccine
Before the introduction of routine infant and childhood vaccination
against Hib in 1985, this pathogen was the major cause of invasive
bacterial infections in young children in the United States. It was the
most common cause of bacterial meningitis and epiglottitis and a
significant cause of septic arthritis, osteomyelitis, septicemia, occult
febrile bacteremia, pneumonia, pericarditis, and cellulitis in children
younger than 5 years, in whom it caused an estimated 12,000 cases of
meningitis and 8000 additional cases of invasive Hib disease annually.198
The cumulative risk for Hib disease was approximately one among
every 200 US children in the first 5 years of life, with the peak incidence
of Hib meningitis occurring among infants between 6 and 12 months
of age. In high-risk populations, such as American Indians and Alaska
Natives, rates of disease in the absence of immunizations were higher,
and a greater proportion of cases of meningitis occurred early in the
first year of life than in low-risk populations.198,343,680 Although rates of
Hib disease among these vulnerable populations have decreased in the
postvaccine era, they remain 8 to 10 times higher compared with white
and black children younger than 5 years.89
In 2000, before the widespread introduction of Hib vaccines in
resource-poor countries, the WHO estimated that at least 8 million
cases of serious disease in children and approximately 371,000 deaths
were attributable to Hib annually.699 As of 2014, 192 of the 193 WHO
member states (99.5%) had adopted conjugated Hib vaccines in their
routine immunization programs. As a consequence, invasive Hib disease
has been virtually eliminated in many industrialized countries, and its
incidence has declined by more than 90% in resource-poor countries
with effective national immunization programs. However, the WHO
estimates that only 56% of the eligible population globally receives
three doses of Hib vaccine, and coverage rates are as low as 21% in the
western Pacific.
Hib remains the most common cause of nonepidemic bacterial
meningitis among unvaccinated children younger than 1 year. The
mortality rate for Hib meningitis treated with appropriate antibiotics
is approximately 4%, and 15% to 30% of survivors have hearing impair-
ment or severe permanent neurologic sequelae.89
Because most cases of Hib disease occur in infancy, vaccines that
induce protection before the age of 6 months are necessary for effective
control of Hib disease. The Hib polysaccharide capsule is the major
virulence factor, and bactericidal antibodies directed against the polysac-
charide antigens are protective. Capsular type b is responsible for more
than 90% of systemic H. influenzae infections. However, purified
polysaccharide vaccines are poor immunogens and children’s T-lym-
phocyte–independent immunoglobulin M (IgM) response is largely
ineffective, particularly in children younger than 18 months who lack
immunologic memory. Covalent linkage of the purified capsular
polysaccharide, polyribosylribitol phosphate (PRP), to a protein carrier
creates a conjugate glycoprotein that is T-lymphocyte dependent and
elicits protective antibody in infants and young children and significantly
greater concentrations of circulating anti-PRP at all ages than does the
unconjugated polysaccharide. T-cell–dependent antigens involve helper
T-lymphocyte activation of a B-cell humoral antibody response.
T-cell–dependent antigens also are able to prime a booster response
and induce immunologic memory (i.e., anamnestic response).
The introduction of Hib conjugate vaccines in the United States,
first in children at least 18 months of age in 1987 and for routine infant
immunization in 1990, dramatically decreased the incidence of meningitis
and bacteremia caused by Hib. As of 2000, the incidence of invasive
Hib disease in the United States had decreased by 99% since the prevac-
cine era, with an incidence rate of less than one case per 100,000.143
During 2000 through 2012, the average annual incidence of invasive
disease in young children was lower than the Healthy People 2020 goal
of 0.27 case per 100,000 children.89 The remarkably rapid reduction in
incidence of disease was partly the result of the ability of the vaccine
to reduce asymptomatic oropharyngeal colonization in vaccinated
children that also had the indirect effect of reducing exposure and
infection in those not immunized (i.e., community or herd immu-
nity).63,338 Colonization rates have declined from up to 7% in the prevac-
cine era to less than 1% in the vaccine era.
Preparations
Three single-antigen Hib conjugate vaccine products and two combina-
tion vaccine products that contain Hib conjugate are available
in the United States. All Hib vaccines contain polyribosylribitol
phosphate (PRP), the organism’s polysaccharide capsular antigen.
Three licensed single-antigen Hib conjugate vaccines—PRP-OMP
(PedvaxHIB, Merck), PRP-T (ActHIB, Sanofi Pasteur), and PRP-T
(Hiberix, GlaxoSmithKline)—are approved for use in early infancy
(Table 245.7).
Each conjugate vaccine is chemically and immunologically unique.
PRP preparations are composed of the type b PRP antigen conjugated
to a protein, but they have different protein carriers, sizes of the saccharide
component, and chemical linkages. The carrier proteins for PRP-OMP
and PRP-T are an outer membrane protein from Neisseria meningitidis
and tetanus toxoid, respectively. Since July 2000, the entire Hib vaccine
supply for the United States has been thimerosal free. The dose of each
Hib conjugate vaccine is 0.5 mL and given intramuscularly.
Two licensed combination vaccines containing Hib are available in
the United States: DTaP/IPV/PRP-T (Pentacel, Sanofi Pasteur), which
is approved for immunization at 2, 4, 6, and 15 to 18 months of age,
and MenCY/PRP-T (MenHibRix, GlaxoSmithKline), a combination
conjugate vaccine approved in 2012 for children 6 weeks to 18 months
of age to prevent meningococcal serogroups C and Y and Hib. Use of
DTaP/PRP-T (TriHIBit, Sanofi Pasteur) was discontinued in 2011, and
PRP-OMP/Hep B (Comvax, Merck) was discontinued in 2014.
TABLE 245.7  Haemophilus influenzae Type b
Vaccine Schedules
VACCINE AGE AT VACCINATION
Type Trade Name 2 mo 4 mo 6 mo 12–15 mo
PRP-T ActHIB X (1st) X (2nd) X (3rd) X
Pentacela X (1st) X (2nd) X (3rd) X
Hiberix X (1st) X (2nd) X (3rd) X
MenHibrixb X (1st) X (2nd) X (3rd) X
PRP-OMP PedvaxHIB X (1st) X (2nd) — X
a
Combination vaccine with DTaP/IPV + PRP-T.
b
Combination vaccine with MenCY + PRP-T.
PRP-OMP, Polyribosylribotol phosphate conjugated to the outer membrane protein
complex from Neisseria meningitides; PRP-T, polyribosylribotol phosphate conjugated to
tetanus toxoid.

Immunogenicity and Efficacy
Placebo-controlled field trials of Hib conjugate vaccines in infants in
the United States demonstrated almost 100% protection and provided
the basis for the initial approval of these vaccines for use in this country.
In a Navajo population of infants at high risk for Hib disease who
were vaccinated at 2 and 4 months of age with PRP-OMP or placebo,
vaccine efficacy was 100% at 1 year of age and 93% in total.577 Licensure
of PRP-T was based on immunogenicity in a three-dose schedule that
was comparable to that of the other two products. A clinical trial in
Great Britain found the efficacy of PRP-T comparable to that of
PRP-OMP.84,649
Although the data are limited, some evidence suggests that administra-
tion of the first dose of the Hib vaccine before the child reaches the
age of 6 weeks may result in immunologic tolerance to the Hib antigen
and reduce the immune response to subsequent doses.473 Therefore,
Hib vaccines, including combination vaccines that contain Hib conjugate,
should not be given to an infant younger than 6 weeks.
Long-term protection induced by invasive Hib disease in unvaccinated
children is associated with an anti-PRP antibody concentration of greater
than 0.15 µg/mL, whereas concentrations greater than 1.0 µg/mL are
considered to be markers of long-term protective immunity in vaccinated
children.89 Children who have invasive Hib infection before 24 months
of age may remain at risk for another Hib infection, and they should
be immunized according to the age-appropriate schedule for unim-
munized children.32 Children who develop invasive disease despite two
to three Hib vaccines and those with recurrent invasive Hib warrant
an immunologic evaluation. Nontypeable H. influenzae lacks a polysac-
charide capsule that renders the Hib vaccine ineffective against this
cause of acute otitis media (AOM), acute sinusitis, bronchitis, and
community-acquired pneumonia.
Adverse Events
Hib vaccines are well tolerated. Local reactions occur in approximately
25% of recipients but typically are mild and last less than 24 hours.232,680
Systemic reactions such as fever and irritability are infrequent occurrences.
When conjugate vaccines are administered concurrently with DTaP
vaccine, the incidence of systemic reactions is similar to that observed
when only DTaP is given.232
Indications
Routine vaccination against Hib disease is recommended for all children
beginning at approximately 2 months of age.32,89 Two or three doses,
depending on the product, given at 2-month intervals (optimal) are
indicated by the time that the child is 6 months of age. PedvaxHIB is
given as a two-dose primary series at 2 and 4 months, whereas ActHIB,
Hiberix, Pentacel, and MenHibRix are approved for immunization at
2, 4, 6, and 15 to 18 months of age (see Table 245.7). The recommended
age to initiate the primary series is 2 months, with a minimum age of
6 weeks. The minimum interval between doses is 4 weeks, with at least
8 weeks separating the last dose in the primary series and the booster.
Excellent immune responses have been achieved when vaccines from
different manufacturers have been interchanged in the primary
series.53,77,312 PRP-T and PRP-OMP are considered interchangeable for
primary and booster vaccinations. If more than a single brand of vaccine
is used, the child should receive a three-dose primary series. A final
dose of any product, irrespective of the previous vaccines received, is
acceptable when the child is 12 to 15 months of age for completion of
the Hib vaccine immunization schedule. When feasible, the conjugate
vaccine product used for the first dose should be used for subsequent
doses in children younger than 12 months.
For American Indian and Alaska Natives, PRP-OMP is the preferred
vaccine for the primary series doses. Hib meningitis incidence peaks
at a younger age among American Indian and Alaska Native infants.218,608
PRP-OMP vaccine produces a protective antibody response after the
first dose and provides early protection that American Indian and Alaska
Native infants particularly need.20,232,230
For children in whom immunization for Hib infection has not been
initiated by the time that they reach 7 months of age, the recommended
schedules depend on the child’s age and the choice of conjugate
vaccine.32,89 Previously unimmunized children between 15 and 59 months
CHAPTER 245  Active Immunizing Agents 2553
should be immunized with at least a single dose of any licensed conjugate
Hib vaccine. For previously unimmunized children 5 years or older,
immunization is indicated only if they have an underlying condition
predisposing to Hib disease, such as anatomic or functional asplenia,
sickle cell disease, immunoglobulin deficiency and immunoglobulin
G2 subclass deficiency, early component complement deficiencies, and
HIV infection or if they are recipients of hematopoietic stem cell
transplants or are immunosuppressed because of chemotherapy or
radiation therapy. More than one dose may be recommended for this
population.32,89
Precautions and Contraindications
Adverse reactions to Hib-containing monovalent vaccines are uncommon,
usually mild, and usually resolve within 12 to 24 hours.232,230,282,352 Rates
of adverse reactions to Hib combination vaccines are similar to those
observed with separately administered vaccines.79,319,493 More complete
information about adverse reactions to a specific vaccine is available
in the package insert for each vaccine.
Vaccination with a Hib-containing vaccine is contraindicated in
infants younger than 6 weeks. Vaccination with a Hib-containing vaccine
is contraindicated for people known to have a severe allergic reaction
to any component of the vaccine. The tip caps of the Hiberix prefilled
syringes can contain natural rubber latex, and the vial stoppers for
Comvax, ActHib, and PedvaxHIB contain natural rubber latex, which
can cause allergic reactions in people who are latex sensitive. Vaccination
with these vaccines is therefore contraindicated for those known to
have a severe allergic reaction to dry natural rubber latex. The vial
stoppers for Pentacel and MenHibRix do not contain latex.
As with all pertussis-containing vaccines, benefits and risk should
be considered before administering Pentacel to those with a history of
fever higher than 40.5°C, hypotonic-hyporesponsive episode, persistent
inconsolable crying lasting 3 or more hours within 48 hours after receipt
of a pertussis-containing vaccine, or seizures within 3 days of receiving
a pertussis-containing vaccine.
Hib monovalent and combination conjugate vaccines are inactivated
vaccines and can be administered to people with immunocompromising
conditions. However, immunologic response to the vaccine may be
suboptimal.408
Hepatitis A Vaccine
The occurrence of hepatitis A is highest in developing countries and
reflects the primary route of transmission: fecal-oral, person-to-person
spread. In the United States, before vaccine became available, hepatitis
A was a common infection that caused substantial morbidity with
significant associated costs.151,400 In 1995, the hepatitis A vaccine was
licensed by the FDA, and during the decades that followed, acute hepatitis
A infection in the United States dramatically declined, from 31,032
reported infections in 1995 to an all-time low of 1398 in 2011.270,494 In
2012 and 2013, however, the first increases in cases occurred since 1995,
with 1562 and 1781 reported cases, respectively.494
In the prevaccine era, the incidence of hepatitis A varied considerably
among different populations.270,619 A shift occurred in the epidemiology
of hepatitis A in the United States after the introduction of hepatitis A
vaccine. Disease in the United States most commonly occurred in children
5 to 14 years of age.270 After vaccines were licensed, rates of infection
among children declined more rapidly than did rates among adults,
resulting in similar rates among all age groups. Historically, rates of
infection were highest among Alaska Natives and American Indians,
and most cases occurred in a small number of states and counties in
the western and southwestern regions of the country. During the decades
after vaccine licensure, we have seen near-elimination of age-specific,
racial, and geographic disparities.270,494
Individuals at risk for hepatitis A infections include close contacts
of people infected with hepatitis A virus (HAV), travelers to developing
countries, those who engage in homosexual and bisexual activity, and
injecting drug users. However, in approximately 50% of reported cases,
no risk factor is identified.33 These infections likely are attributable to
fecal-oral spread from asymptomatic contacts. Because children frequently
have asymptomatic infections and can shed virus for prolonged periods,
they play an important role in transmission of HAV. Children and
2554 PART V  Prevention of Infectious Diseases
infants shed virus for longer periods than adults do, up to several months
after the onset of clinical illness. In one study involving adults without
an identified source of infection, 52% of their households included a
child younger than 6 years.270
It has long been recognized that the control and ultimate elimination
of hepatitis A by active immunization could best be achieved through
universal childhood immunization.651 However, it was not until 2005
that hepatitis A vaccine was licensed for use in children from 12 to 23
months of age. Before then, it had been restricted to children older
than 2 years and consequently could not be incorporated readily into
routine infant vaccinations. In May 2006, the ACIP recommended
including hepatitis A vaccine in the routine infant immunization
schedule.270
Before vaccine was available, community-wide outbreaks, recurring
every 3 to 10 years in high-risk communities, accounted for much of
the occurrence of hepatitis A infection and disease. Outbreaks among
children attending childcare and the staff are common occurrences and
have been associated with community outbreaks.326 However, the
prevalence of hepatitis A infection among childcare center staff and
the children and adolescents who previously attended is not increased,
a finding suggesting that infections within childcare settings most
commonly reflect transmission within the community that extends to
these settings.326 Transmission of HAV also can occur in institutions
for the developmentally disabled and in neonatal intensive care units.
Transmissions from hospitalized patients to health care professionals
have been reported.33
In addition to direct person-to-person transmission, infection can
be acquired by the ingestion of contaminated water or food, especially
that imported from endemic countries. An outbreak in 2013 from
contaminated pomegranate seeds, which were imported to the United
States from Turkey, infected 165 people across 10 states; 42% were
hospitalized, three developed fulminate hepatitis, and one required liver
transplantation.494
Preparations
Inactivated and attenuated HAV vaccines have been developed.239
However, only inactivated vaccines are licensed in the United States.
Inactivated HAV vaccine is prepared by methods similar to those used
for inactivated poliomyelitis vaccine. Virus is propagated in human
diploid fibroblast cell cultures, formalin inactivated, and adsorbed to
aluminum hydroxide adjuvant. Two inactivated HAV vaccines are licensed
in the United States: Havrix (SmithKline Beecham Biologicals) and
Vaqta (Merck & Co.). Vaqta and Havrix have two formulations, an adult
and a pediatric product with different antigen content (Table 245.8).
The pediatric formulation is indicated for people 12 months to 18 years
of age. The vaccines can be used interchangeably.95
Limited data indicate that hepatitis A vaccine may be administered
simultaneously with other vaccinations.33 A combination HAV and
TABLE 245.8  Recommended Doses and Schedules for Inactivated Hepatitis A Vaccines
Vaccine Hepatitis A
Age (y) Trade Name Antigen Dose Volume per Dose (mL)
1–18 Havrix 720 ELU
1–18 Vaqta 25 Ua
≥19 Havrix 1440 ELU
≥19 Vaqta 50 Ub
≥18 Twinrixc 720 ELU
a
Antigen units; each unit is equivalent to 1 µg of viral protein.
b
A combination of hepatitis B (Engerix-B, 20 µg) and hepatitis A (Havrix, 720 ELU) vaccine.
c
Twinrix is licensed for use in people ≥18 years in 3-dose and 4-dose schedules.
ELU, Enzyme-linked immunosorbent assay units.
Modified from American Academy of Pediatrics. Hepatitis A. In: Kimberlin DW, Brady MT, Jackson MA, Long SS, eds. Red Book: 2015 Report of the Committee on Infectious Diseases. 30th
ed. Elk Grove Village, IL: American Academy of Pediatrics; 2015:391–9.
hepatitis B vaccine (Twinrix) is licensed in the United States for people
18 years and older. All HAV-containing vaccines are administered
intramuscularly.
Immunogenicity and Efficacy
Inactivated hepatitis A vaccine is highly immunogenic. After receiving
a single dose, 95% of children and most adults seroconvert within 1
month.33,270 After receipt of a second dose in children, seroconversion
approximates 100%. Hepatitis A vaccine is immunogenic in children
younger than 2 years old who do not have passively acquired maternal
antibody.536,643 In two large clinical trials of inactivated hepatitis A vaccine
in children older than 2 years, the protective efficacy rate was greater
than 90%.358,682 In a double-blind, placebo-controlled, randomized study
in Thailand involving approximately 34,000 vaccinees, the protective
efficacy rate against clinical hepatitis A was 94% after administration
of two doses given 1 month apart; it was 100% after subsequent
administration of a 12-month booster dose.358
Vaccination has been effective in controlling outbreaks in communities
with high rates of disease.270 For example, in a New York State community
in which HAV was highly endemic among children, a single dose of
vaccine was 100% effective beginning 3 weeks after immunization in
preventing symptomatic disease.682 Moreover, observations from countries
where routine hepatitis A vaccination of infants or children has been
implemented suggest a strong herd immunity effect.221,240 The duration
of protection after vaccination is likely to be prolonged. Protective
antibody levels of anti-HAV were observed in 99% of children evaluated
5 to 6 years after receiving Vaqta.681 Kinetic models of antibody decline
indicate that protective levels of antibody could exist for more than 25
years in adults and up to 20 years in children.650,652 No data are available
to determine whether and when children will need a hepatitis A booster
vaccine. In an ongoing study designed to address the need for a booster
dose, no cases of hepatitis A among children 9 years after initial vaccina-
tion have been reported.683
Reduced vaccine immunogenicity has been observed in infants with
passively acquired anti–hepatitis A antibody who are administered
hepatitis A vaccines.221,428,433 Studies demonstrated that despite lower
antibody levels in infants born to anti–hepatitis A–positive mothers,
most infants with passively acquired antibody had an anamnestic response
to a booster dose 1 to 6 years later.221,269,380 In most infants, maternally
acquired anti–hepatitis A antibody declines to undetectable levels by
the time the child reaches 12 months of age.432 Hepatitis A vaccine is
highly immunogenic for all infants when administered when they are
older than 1 year, irrespective of maternal antibody status.72,221
Concurrent administration of immune globulin and vaccine inhibits
the peak serum antibody concentration achieved but not the rate of
seroconversion.666 Because antibody concentrations reach much higher
than protective levels, this inhibition is not considered clinically significant
and supports passive-active immunoprophylaxis when indicated.
No. of Doses Schedule
0.5 2 Initial and 6≥12 mo later
0.5 2 Initial and 6≥18 mo later
1.0 2 Initial and 6≥12 mo later
1.0 2 Initial and 6≥18 mo later
1.0 3 or 4 Initial, 1 and 6 mo later
or
Initial, 7 days and 21–30 d, followed
by a dose at 12 mo

Adverse Events
Except for rare reports of anaphylaxis and anaphylactoid reaction in
adults in Europe and Asia, serious reactions to inactivated HAV vaccine
have not been reported.269,380 Pain, tenderness, and infection at the
injection site can occur.358
Indications
HAV immunization is recommended routinely for children 12 through
23 months of age, for people who are at increased risk for infection, for
those who are at increased risk for severe manifestations of hepatitis A
if infected, and for anyone who wants to obtain immunity.22,33,151,156,270
All children in the United States should receive hepatitis A vaccine
routinely according to the licensed two-dose schedule, with the initial
dose administered at 1 year of age (i.e., 12 to 23 months) and the second
dose 6 to 12 months later. Children who are not immunized by 2 years
of age can be immunized at subsequent visits.
Hepatitis A vaccination is recommended routinely for the following
people who are at increased risk for infection22,33,270:
• All susceptible people traveling to or working in countries that have
a high or intermediate hepatitis A endemicity should be vaccinated
or receive immune globulin before departure.151 HAV vaccine at the
age-appropriate dose is preferred to immune globulin. The first dose
of HAV vaccine should be administered as soon as travel is considered.
One dose of single-antigen vaccine administered at any time before
departure can provide adequate protection for most healthy people.
Travelers who are younger than 12 months should receive a single
dose of immune globulin (0.02 mL/kg), which provides effective
protection for up to 3 months; 0.06 mL/kg for travel provides protec-
tion up to 6 months.
• Susceptible household members and other close personal contacts
of international adoptees newly arriving from countries with high
or intermediate hepatitis A endemicity should be vaccinated.27,156
Data from a study conducted at three adoption clinics in the United
States indicate that 1% to 6% of newly arrived international adoptees
have acute HAV infection. The risk of HAV infection among close
personal contacts of international adoptees is estimated at 106 (range,
90–819) per 100,000 household contacts of international adoptees
within the first 60 days after their arrival in the United States. HAV
vaccine should be administered to all previously unvaccinated people
who anticipate close personal contact (e.g., household contact, regular
babysitters) with an international adoptee from a country with high
or intermediate endemicity during the first 60 days after arrival of
the adoptee in the United States. The first dose of the two-dose HAV
vaccine series should be administered as soon as adoption is planned,
ideally two or more weeks before the arrival of the adoptee.
• Male adolescents and adults who have sex with men should be
immunized. Outbreaks of hepatitis A among men who have sex
with men have been reported often, including in urban areas in the
United States, Canada, and Australia.
TABLE 245.9  Recommendations for Postexposure Immunoprophylaxis of Hepatitis A Virus
Time Since Exposure Age of Patient
≤2 wk <12 mo
12 mo–40 y
≥41 y
People of any age who are immunocompromised, have chronic
liver disease, or a contraindication to vaccination
≥2 wk <12 mo
≥12 mo
a
Dosage and schedule of HAV vaccine as recommended according to age in Table 245.8.
HAV, Hepatitis A virus; IGIM, immune globulin intramuscular.
Modified from American Academy of Pediatrics. Hepatitis A. In: Kimberlin DW, Brady MT, Jackson MA, Long SS, eds. Red Book: 2015 Report of the Committee on Infectious Diseases. 30th
ed. Elk Grove Village, IL: American Academy of Pediatrics; 2015: 391–399.
CHAPTER 245  Active Immunizing Agents 2555
• Adolescent and adult users of injection and noninjection drugs
should be vaccinated. Periodic outbreaks among injection and
noninjection drug users have been reported in many parts of the
United States and in Europe.
• Susceptible patients with chronic clotting disorders who receive
clotting factor concentrates should be immunized. Reported outbreaks
of hepatitis A in patients with hemophilia receiving solvent-detergent–
treated factor VIII and factor IX concentrates were identified during
the 1990s, primarily in Europe, although one case was reported in
the United States.
• People at risk for occupational exposure (e.g., handlers of HAV-
infected primates, people working with HAV in a research laboratory
setting) should be immunized. Outbreaks of hepatitis A have been
reported among people working with nonhuman primates that were
born in the wild rather than those born and raised in captivity.
• People with chronic liver disease are at increased risk for fulminant
hepatitis A. Susceptible patients who are awaiting or have received
liver transplants should be immunized.
Although the ACIP guidelines do not recommend routine vaccination
of food handlers, vaccination of these workers should be considered
in areas where state and local health authorities or private employers
determine that vaccination is cost-effective.
Postexposure Prophylaxis
People who have been exposed to HAV but have not received HAV
vaccine should have one dose of single-antigen HAV vaccine or immune
globulin as soon as possible.151 Table 245.9 provides prophylaxis guidance
and dosages. The efficacy of immune globulin or vaccine for postexposure
prophylaxis when administered more than 2 weeks after exposure has
not been established. Information about the relative efficacy of vaccine
compared with immune globulin after exposure is limited, and no data
are available for people older than 40 years or those with underlying
medical conditions.
All previously unimmunized people with close personal contact
with a person with serologically confirmed HAV infection, such as
household and sexual contacts, should receive vaccine or immune
globulin within 2 weeks after the most recent exposure. Serologic testing
of contacts is not recommended because testing adds unnecessary cost
and may delay administration of postexposure prophylaxis.
Outbreaks of HAV infection at childcare centers have been recognized
since the 1970s, but their frequency has decreased as HAV immunization
rates for children have increased and as hepatitis A incidence among
children has declined. HAV vaccine or immune globulin should be
administered to all previously unimmunized staff members and attendees
of childcare centers or homes if one or more cases of hepatitis A are
recognized in children or staff members or cases are recognized in two
or more households of center attendees. In centers that provide care
only to children who do not wear diapers, vaccine or immune globulin
need be given only to classroom contacts of an index-case patient.
Recommended Prophylaxisa
IGIM, 0.02 mL/kg
HAV vaccine
IGIM, 0.02 mL/kg but HAV vaccine can be used if IGIM
is unavailable
IGIM, 0.02 mL/kg
No prophylaxis
No prophylaxis, but HAV vaccine may be indicated for
ongoing exposure
2556 PART V  Prevention of Infectious Diseases
When an outbreak occurs (i.e., hepatitis A cases identified in two
or more families), vaccine or immune globulin also should be considered
for members of households that have children (i.e., center attendees)
in diapers. Children and adults with hepatitis A should be excluded
from the center until 1 week after onset of illness, until the postexposure
prophylaxis program has been completed in the center, or until directed
by the health department. Although precise data concerning the
onset of protection after postexposure prophylaxis are not available,
allowing prophylaxis recipients to return to the childcare center setting
immediately after receipt of the vaccine or immune globulin dose seems
reasonable.
Schoolroom exposure usually does not pose an appreciable risk for
infection, and postexposure prophylaxis is not indicated when a single
case occurs and the source of infection is outside the school. However,
HAV vaccine or immune globulin can be used for unimmunized people
who have close contact with the index patient if transmission within
the school setting is documented.
Usually, health care–associated HAV in hospital personnel has
occurred through spread from patients with acute HAV infection for
whom the diagnosis was not recognized. Careful hygienic practices
should be emphasized when a patient with jaundice or known or
suspected hepatitis A is admitted to the hospital. When outbreaks occur,
HAV vaccine or immune globulin is recommended for people in close
contact with infected patients. There is no recommendation for routine
preexposure use of HAV vaccine for hospital personnel.
If a food handler is diagnosed with hepatitis A, HAV vaccine or
immune globulin should be provided to other food handlers at the
same establishment. Food handlers with acute HAV infection should
be excluded for 1 week after the onset of illness. Because common-source
transmission to patrons is unlikely, postexposure prophylaxis with HAV
vaccine or immune globulin typically is not indicated but may be
considered if the food handler directly handled food during the time
when he or she likely was infectious and had diarrhea or poor hygiene
practices and if prophylaxis can be provided within 2 weeks of exposure.
Routine HAV immunization of food handlers is not recommended.
Precautions and Contraindications
Hepatitis A vaccine should not be administered to people with a
hypersensitivity reaction to any of the vaccine components, such as
alum or, in the case of Havrix, phenoxyethanol.15 Safety data for pregnant
women are not available, but the risk is considered to be low or nonexistent
because the vaccine contains inactivated, purified viral proteins.
Hepatitis B Vaccine
Hepatitis B virus (HBV) infection is a leading cause of acute hepatitis
and a major public health problem of global importance. Its incidence
is especially high in many Asian and African countries. Individuals with
chronic infection are at risk for chronic hepatitis, cirrhosis, and primary
hepatocellular carcinoma. Rates of new infection are highest among
adults, but chronic infection is more likely to occur in individuals infected
as infants or children. They are at increased risk for chronic and malignant
liver disease, and as chronic carriers, they serve as the reservoir for
transmission of HBV.
The initial strategies for prevention of hepatitis B through vaccination
reflect the various epidemiologic patterns of HBV infection in different
areas of the world.116 In the United States, for example, infection is of
comparatively low endemicity and occurs primarily in adolescents and
adults. The risk of infection, however, is much greater in certain popula-
tions. Examples include those born and living in areas or among groups
in which HBV is highly endemic and those with lifestyles predisposing
to the acquisition of HBV, such as male homosexual activity, intravenous
drug abuse, and promiscuous heterosexual activity.11 In geographic areas
in which HBV infection is highly endemic, infection usually is acquired
at birth or during childhood, a pattern prompting the recommendation
for universal vaccination of infants. Many countries have adopted hepatitis
B vaccine into their national campaigns, and children recently immigrated
to the United States from endemic areas confirm this trend, with higher
levels of neutralizing antibodies found in newer immigrants.709
In 1991, the CDC initiated a comprehensive hepatitis B vaccination
strategy to eliminate transmission of HBV in the United States.116 Critical
elements of this strategy included preventing perinatal transmission of
HBV by identifying and providing immunoprophylaxis to infants of
hepatitis B virus surface antigen (HbsAg)–positive mothers and universal
hepatitis B vaccination of infants to interrupt transmission and prevent
future infection. This approach provided effective programs for routine
childhood immunization, protection without any need to identify specific
risk factors, and protection before significant exposure occurred. The
positive effects of universal infant immunization had been observed in
Taiwan, where the strategy of universal infant immunization already
was being used. In Taiwan, the overall prevalence rate of HBV for children
1 to 10 years of age decreased from 9.8% in 1984 to 1.3% in 1994.182
In 1994, the ACIP expanded the recommendations to include previ-
ously unvaccinated children 11 to 12 years old.124 In October 1997,
these recommendations were expanded to include all unvaccinated
children from birth to 18 years old and made hepatitis B vaccine available
through the Vaccines for Children (VFC) program for those from birth
to 18 years of age who were eligible for the program.135 The goal of the
1997 recommendations was to increase access to hepatitis B vaccine by
encouraging the vaccination of previously unvaccinated children and
adolescents when they were seen for routine medical visits.15 Expansion
of the recommended age group for receiving vaccination and for VFC
eligibility simplified previous recommendations and eligibility criteria
for receiving HBV vaccine. The other ACIP priorities for giving hepatitis
B vaccination to children remained unchanged and included the following
groups: all infants; children in populations at high risk for HBV infection,
such as Alaska Natives, Pacific Islanders, and children who reside in
households of first-generation immigrants from countries where HBV
infection is moderately or highly endemic; previously unvaccinated
children 11 to 12 years of age; and older adolescents and adults in
defined at-risk groups.124,116
Between 1990 and 2004, the incidence of HBV infection in the United
States declined by 75%. The decline was greatest among children and
adolescents. Coincident with the decline in HBV incidence, vaccine
coverage for children 19 to 35 months of age increased from 16% to
92% from 1991 to 2004.147 Among adolescents 13 to 15 years old, vaccine
coverage increased from 0% to 74% between 1993 and 2004 according
to CDC data. Since its inception in 1991, many aspects of the national
immunization strategy to eliminate HBV transmission have been
implemented with great success, especially the routine vaccination of
all infants. Nonetheless, many challenges remain.
Despite the overall decline in hepatitis B incidence and the recom-
mendations for routine vaccination of infants and children, increasing
proportions of new HBV infections in the United States occur among
adolescents and adults who have defined risk factors, including those
with multiple sex partners (i.e., more than one partner during the
preceding 6 months), men who have sex with men, and injecting
drug users.441 The primary means of preventing these infections is to
identify settings such as correctional facilities, sexually transmitted
disease clinics, and drug treatment centers where adolescents and adults
with high-risk drug and sexual practices can be routinely accessed and
vaccinated. In correctional facilities where previously unvaccinated
inmates are offered HBV vaccination, 60% to 80% of inmates accepted
offered vaccination.677
Although universal screening of all pregnant women has been widely
adopted across the United States, fewer than half of all HBsAg-positive
pregnant women are identified through prenatal screening.261 These
women with unknown HBsAg status are not screened consistently, even
when they are hospitalized during labor and delivery; consequently,
their infants do not receive appropriate postexposure prophylaxis.635
The birth dose of HBV vaccine, which can serve as a safety net for
infants born to mothers for whom testing was not performed or not
performed correctly, was administered to only 45% of infants born in
the United States in 2004, less than the rate of 54% seen before July of
1999, when recommendations were made to suspend the birth dose of
hepatitis B vaccine temporarily until a thimerosal-free vaccine became
available.440
To enhance existing strategies aimed at prevention of perinatal HBV
transmission, the ACIP recommended in December of 2005 that all
delivery hospitals institute specific policies and procedures to improve
identification of infants born to HBsAg-positive mothers and mothers

with unknown HBsAg status.464 These recommendations were made
to ensure administration of appropriate postexposure prophylaxis and
a birth dose of HBV vaccine to all medically stable infants. A study of
prospectively collected data from 5 of 64 US-funded Perinatal Hepatitis
B Prevention Programs from 2007 through 2013 found that perinatal
hepatitis B virus infection occurred among 1.1% of infants, despite
94.9% of infants receiving hepatitis B vaccine and hepatitis B immune
globulin within 12 hours of birth.583 Infants born to mothers who were
younger, hepatitis B e antigen (HbeAg) positive, or who had a high
viral load or received fewer than three hepatitis B vaccine doses were
at greatest risk for infection.
The 2005 ACIP statement also updated recommendations to improve
vaccination coverage of adolescents and children by implementing
immunization record reviews for all children 11 to 12 years old and
children younger than 19 years who were born in countries with high
or intermediate HBV endemicity and by vaccinating all unvaccinated
adolescents in settings that provide health care services to this age
group.464
Preparations
Hepatitis B vaccines consisting of inactivated, purified HBsAg derived
from chronic hepatitis B plasma were introduced in the early 1980s. In
the late 1980s, two recombinant vaccines (Recombivax HB, Merck &
Co.; Engerix-B, SmithKline Beecham Biologicals) were licensed in the
United States and are available in single-antigen and combined formula-
tions. Only the recombinant vaccines are available in the United States,
but plasma-derived vaccines are widely used in other areas of the world.
The recombinant vaccines contain 5 to 40 µg/mL of HBsAg protein.
Pediatric formulations contain no thimerosal or only trace amounts.
Vaccine is administered intramuscularly in the anterolateral thigh
or deltoid area, depending on the age and size of the recipient. Admin-
istration in the buttocks or intradermally has been associated with
decreased immunogenicity and is not recommended at any age.
Immunogenicity and Efficacy
The recommended series of three doses of vaccine induces a protective
antibody response in more than 95% of infants, children, adolescents,
and adults younger than 40 years.34,464 In field trials, the efficacy
rates have been 80% to 95% and usually correlate with immunogenicity.
Protection against disease is virtually 100% for people who develop
adequate serum antibody concentrations (anti-HBs ≥10 mIU/mL)
after receiving vaccination. Adults older than 40 years and immunosup-
pressed people are less likely to develop protective anti-HBs
concentrations.
Hepatitis B vaccine is highly immunogenic. Postvaccination serologic
testing is not indicated except for infants born to HBsAg-positive women,
people with ongoing occupational exposure to blood, and people with
immunosuppressive conditions. Active immunization in combination
with passive immunoprophylaxis with hepatitis B immune globulin
(HBIG) administered within 12 to 24 hours after birth to infants born
to chronically infected mothers is more than 90% effective in preventing
transmission of HBV to the infant. Active postexposure vaccination
without HBIG administered soon after birth has been effective in prevent-
ing perinatal transmission and is used in areas where the use of HBIG
is impractical.310
Vaccine-induced protection against symptomatic infection in a normal
host is prolonged and correlates with immunologic memory, which
has been demonstrated in immunized children and adults for at least
12 years after vaccination. Children immunized at birth are protected
for at least 10 years. The need for routine booster doses has not been
demonstrated.
Vaccine failures related to HBV variants with mutations in the S
gene leading to conformational changes in the HBsAg protein, the major
target for neutralizing anti-HBs antibody, have occurred in fully vac-
cinated children and perinatally exposed infants who received appropriate
active and passive postexposure prophylaxis and in many cases had
protective anti-HBs antibody levels.356 Although no evidence establishes
that these escape mutations pose a threat to the effectiveness of current
hepatitis B vaccine programs, surveillance to detect emergence of HBV
variants in immunized populations is warranted.464,717
CHAPTER 245  Active Immunizing Agents 2557
Adverse Events
Other than soreness at the injection site, reactions to hepatitis B vaccine
rarely occur. Postvaccination surveillance performed after licensure of
the plasma-derived vaccine indicated a possible association between
Guillain-Barré syndrome and receipt of the first vaccine dose, but no
evidence indicates an association of Guillain-Barré syndrome with
recombinant vaccine.464,465 Anaphylaxis has been estimated to occur in
one of 600,000 doses distributed.464,465 Several nonfatal pediatric cases
have been reported.
Indications
Routine immunization with hepatitis B vaccine is recommended for
all infants in the United States and should be completed by 6 to 18
months of age for all infants born to HBsAg-negative mothers.34,464
Delivery hospitals should develop policies that ensure administration
of a birth dose for all infants weighing 2000 g or more at birth
unless a physician’s order to defer immunization is in place and the
serologic status of the mother is in the infant’s medical record. Admin-
istering the first dose of hepatitis B vaccine soon after birth
should minimize the risk of infection because of errors in maternal
HBsAg testing or reporting or from exposure to people with chronic
HBV infection in the household and can increase the likelihood of
completing the vaccine series. For infants weighing less than 2 kg who
are born to HBsAg-negative mothers, initiation of vaccine should begin
at 1 month of chronologic age. Administration of the second dose of
vaccine is recommended 1 to 2 months after administration of the
first dose, followed by a third dose when the infant is 6 to 18 months
of age.
Only single-antigen hepatitis B vaccine can be used for doses
given to infants between birth and 6 weeks of age. Single-antigen or
combination vaccine may be used to complete the series; four doses
of vaccine can be administered if a birth dose is given and a combination
vaccine containing a hepatitis B component is used to complete
the series.
Routine screening of all pregnant women for HBsAg is recommended
because of the necessity for administering a birth dose of vaccine and
HBIG.34,464 Infants born to HBsAg-positive mothers, including preterm
and low-birth-weight infants, should be given HBIG (0.5 mL) within
12 hours after birth at a separate injection site, as well as the birth dose
of HBV vaccine.34,464 If a preterm infant weighing less than 2000 g is
born to an HBsAg-positive mother, the birth dose of hepatitis B vaccine
should not be counted toward completion of the vaccine series, and
three additional doses of hepatitis B vaccine should be administered
beginning when the child is 1 month of age. In addition to receiving
HBIG and the hepatitis B vaccine series within 12 hours of birth, infants
of HBsAg-positive mothers should be tested for HBsAg and antibody
to HBsAg (i.e., anti-HBs) at 9 to 12 months of age (or 1–2 months
after the final dose of the vaccine series, if the series is delayed) to
identify those with chronic HBV infection and those who may require
revaccination.464,582
A woman whose HBsAg status is unknown at delivery should undergo
blood testing as soon as possible to determine it. The infant should
receive the first dose of hepatitis B vaccine within 12 hours. If the
woman is found to be HBsAg positive, her infant should receive HBIG
as soon as possible within 7 days. In populations for which HBsAg
testing of pregnant women is not feasible, all infants should receive
hepatitis B vaccine at birth and 2 months and complete the series by
the time they reach 6 months of age.
Hepatitis B vaccination is recommended for all children and ado-
lescents younger than 19 years in the United States. Children who
have not been immunized previously may begin the vaccine series
during any visit. All children 11 to 12 years of age should have a
review of their immunization records and receive the complete
hepatitis B vaccine series if they have not been vaccinated previously.
All children and adolescents younger than 19 years who were born
in Asia, the Pacific Islands, Africa, or other intermediate- or high-
endemic countries or have at least one parent who was born in one of
these areas should have a review of their immunization records and
complete the hepatitis B vaccine series if they were not vaccinated
previously.464
2558 PART V  Prevention of Infectious Diseases
TABLE 245.10  Recommended Doses and Schedules of Hepatitis B Virus Vaccines in the United States
Group
Infants of HBsAg-negative mothers and children and adolescents <20 y
Infants of HBsAg-positive mothers (HBIG also recommended)
Children 1–10 y
Adolescents 11–15 y
Adolescents 11–19 y
Adults (≥20 y)
Patients undergoing dialysis and other immunocompromised persons
  <20 yd
  ≥20 y
Unvaccinated adults with diabetes mellitus 19–59 yg
a
Pediatric formulation licensed for use in a 3-dose schedule at 0, 12, and 24 months for children 5 to 16 y and at 0, 1, and 6 mo for adolescents 11 to 16 y.
b
Also licensed as a 4-dose schedule at 0, 1, 2, and 12 mo for all age groups.
c
Adult formulation administered on a 2-dose schedule at 0 mo and then 4 to 6 mo later, licensed for adolescents 11 to 15 y.136
d
Higher doses may be more immunogenic, but no specific recommendations have been made.
e
Special formulation for patients undergoing dialysis given at 0, 1, and 6 mo.
f
Two 1.0-mL doses administered as one or two injections in a 4-dose schedule at 0, 1, 2, and 6 mo.
g
Three doses administered at 0, 1, and 6 months.172
HBIG, Hepatitis B immune globulin; HBsAg, hepatitis B surface antigen.
Modified from American Academy of Pediatrics. Hepatitis B. In: Kimberlin DW, Brady MT, Jackson MA, Long SS, eds. Red Book: 2015 Report of the Committee on Infectious Diseases. 30th
ed. Elk Grove Village, IL: American Academy of Pediatrics; 2015:400–23; Centers for Disease Control and Prevention. A comprehensive immunization strategy to eliminate transmission of
hepatitis B virus infection in the United States: recommendations of the Advisory Committee on Immunization Practices (ACIP). Part 1: immunization of Infants, children, and adolescents.
MMWR Recomm Rep. 2005;54RR-16):1–32.
Vaccination also is recommended for those with one or more of the
following risk factors for acquiring HBV infection34:
• Sexually active adolescents and adults who have a recently acquired
sexually transmitted disease, are seeking evaluation or treatment for
a sexually transmitted infection, are identified as sex workers, or
have had one or more sex partners in the previous 6 months
• Sexually active men who have sex with men
• Household contacts or sexual partners of HBsAg-positive people
• Injecting drug users
• People at occupational risk for infection through exposure to blood
or blood-contaminated body fluids, such as health care workers and
public safety workers
• Residents and staff of institutions for the developmentally disabled
• Patients undergoing hemodialysis (vaccination of those with early
renal failure is encouraged before they require hemodialysis)
• Patients with human immunodeficiency virus (HIV) infection, chronic
liver disease, or diabetes mellitus
• Members of households with international adoptees who are HBsAg
positive
• Travelers, especially children, to areas with high and intermediate
rates of infection with HBV who have close contact with the local
population or are likely to have contact with blood, such as in a
medical setting or by sexual contact with residents
• Inmates in long-term correctional facilities
In addition to active and passive immunoprophylaxis of infants
born to HBsAg-positive mothers, postexposure prophylaxis is recom-
mended in the following circumstances:
• Sexual partner of an HBsAg-positive person. A single dose of HBIG
within 14 days of the last sexual contact and initiation of the three-
dose hepatitis B vaccination is recommended for susceptible people.
• Household exposure or close contact of an unvaccinated infant younger
than 12 months old to a primary caregiver who has acute or chronic
hepatitis B infection. Infants in this circumstance should receive HBIG
and be vaccinated against hepatitis B. If at the time of exposure only
one dose of vaccine has been administered, the second dose should
be administered if the interval is appropriate, or HBIG should be
administered if immunization is not yet due. If the infant has been
immunized fully or has received at least two doses of vaccine, the
infant should be presumed protected, and HBIG is not required.
• Accidental percutaneous or per mucosal exposure of a susceptible
person to HBsAg-positive blood, such as a needlestick or other
VACCINE
Recombivax HB Dose µg (mL) Engerix-B Dose µg (mL)
5 (0.5) 10 (0.5)
5 (0.5) 10 (0.5)
5 (0.5)a 10 (0.5)a,b
10 (0.5)c N/A
5 (0.5)a 10 (0.5)a,b
10 (1.0) 20 (1.0)b
5 (0.5) 10 (0.5)
40 (1.0)e 40 (2.0)f
10 (1.0) 20 (1.0)
accident involving blood in a hospital or an injury to a susceptible
person caused by the bite of an HBsAg-positive child. For this
indication, HBIG and vaccine are given. Recommendations in these
circumstances are complex and based on the availability of the blood
source for HBsAg testing and the hepatitis B vaccination status of
the exposed person.
Booster doses are not recommended except for patients undergoing
hemodialysis and possibly other immunocompromised patients, who
should undergo annual antibody testing to assess the need. An additional
dose is indicated for those whose serum anti-HBsAg concentration is
less than 10 mIU/mL.
The current recommended doses and schedule for the use of hepatitis
B vaccines licensed in the United States in infants and other age groups
are shown in Table 245.10, and more information can be found else-
where.34,464,465 For completing the hepatitis B vaccine series and achieving
complete vaccination for hepatitis B, the two licensed hepatitis B vaccines
are interchangeable when administered in doses recommended by the
manufacturers.34,464 In September 1999, the FDA approved an optional
two-dose schedule of Recombivax HB for vaccination of adolescents
11 to 15 years of age. The ACIP recommended that this schedule be
included in the VFC program in February 2000.136 With the two-dose
schedule, the adult dose of Recombivax HB is administered to adolescents
11 to 15 years old, with the second dose given 4 to 6 months after the
first dose. In immunogenicity studies enrolling adolescents 11 to 15
years of age, antibody concentrations and seroprotection rates were
similar with the two-dose schedule and the currently licensed three-dose
schedule. Follow-up data collected during the course of 2 years indicated
that the rate of decline in concentration of antibody for the two-dose
schedule was similar to that for the three-dose schedule.
No data are available to assess long-term protection or immune memory
after vaccination with the two-dose schedule, and whether booster doses
of vaccine will be required is not known. Children and adolescents who
have begun vaccination with a dose of the pediatric formulation should
complete the three-dose series with this dose. Similarly, if the formulation
administered to an adolescent at the start of a series is not known, the
series should be completed with the three-dose schedule.
A combination of hepatitis B (Engerix-B, 20 µg) and hepatitis A
(Havrix, 720 enzyme-linked immunosorbent assay units [ELU]) vaccine
(i.e., Twinrix) is licensed for use in people 18 years or older in a three-dose
schedule administered at birth, 1 month, and 6 or more months later.
An alternative four-dose schedule was approved in 2007; vaccinations

are given at birth, day 7, and between days 21 and 30 and followed by
a booster dose at 12 months.34
In December of 2006, the ACIP approved recommendations for
hepatitis vaccine use in adults.465 In settings in which high proportions
of adults are at risk for HBV infection, the ACIP recommends universal
hepatitis B vaccination for all unvaccinated adults. Settings include
sexually transmitted infection treatment facilities, HIV testing and
treatment facilities, facilities providing drug abuse treatment and preven-
tion services, health care settings targeting services to injection drug
users, correctional facilities, health care settings serving men who have
sex with men, chronic hemodialysis facilities and end-stage renal disease
programs, and institutions and nonresidential care facilities for people
with developmental disabilities.
For other primary care and specialty medical settings in which adults
at risk for HBV infection receive care, the ACIP recommends that health
care providers inform all patients about the health benefits of vaccination,
including the risk of acquiring HBV infection, and other people for
whom vaccination is recommended. They should vaccinate adults who
report a risk of developing HBV infection and any adults requesting
protection from HBV infection. To promote vaccination in all settings,
health care providers should implement standing orders to identify
adults recommended for hepatitis B vaccination and administer vac-
cination as part of routine clinical services, not require acknowledgment
of an HBV infection risk factor for adults to receive vaccine, and use
available reimbursement mechanisms to remove financial barriers to
receiving hepatitis B vaccination.
In 2011, the ACIP recommended that all previously unvaccinated
adults 19 through 59 years of age with type 1 or type 2 diabetes mellitus
be vaccinated against hepatitis B as soon as possible after a diagnosis
of diabetes is made. Unimmunized adults with diabetes mellitus who
are 60 years or older may be vaccinated at the discretion of the treating
clinician after assessing their risk.172
Contraindications
The only contraindication to receiving HBV vaccination is a history of
anaphylaxis to a previous dose of vaccine. Data on the safety of HBV
vaccines are not available for pregnant women, but because the vaccines
contain only HBsAg and not live virus, they should not harm the
developing fetus. Because HBV infection during pregnancy can result
in transmission to the neonate, susceptible women at increased risk for
infection should be vaccinated during pregnancy. Inadvertent vaccination
of HBsAg-positive people has no deleterious effects.
Human Papillomavirus Vaccine
Genital HPV infection is thought to be the most common sexually
transmitted viral infection, accounting for more than 14 million new
cases annually in the United States.579 The estimated prevalence of HPV
infection among 15- to 19-year-olds is 32.9%, and among 20-to 24-year-
old, sexually active women, it is 53.8%.579 Prevalence is thought to be
similar among males.249 HPV typically infects girls and women soon
after sexual exposure.208,690 Median time from first intercourse to first
detection of HPV is only 3 months.208 The estimated lifetime risk of
acquiring HPV infection by those with at least one sexual partner is
more than 84% for women and more than 91% for men.189 More than
80% of women and men acquire HPV infection by 45 years of age.189
More than 40 HPV types can infect the genital tract and are classified
on the basis of their association with cervical cancer.492 The low-risk,
nononcogenic HPV types (i.e., types 6 and 11) are associated with
anogenital warts, mild cervical dysplasia, and recurrent respiratory
papillomatosis. The high-risk, oncogenic HPV types are causally linked
to several human cancers in women and men, including cancers of the
cervix, vulva, vagina, anus, and penis and a subset of head and neck
cancers.439 Infection with HPV causes almost all cases of cervical cancer,
and before vaccine development, it was the second most common cause
of death from cancer among women globally, surpassed only by breast
cancer.439 Cervical cancer remains a significant cause of cancer death
worldwide.265 The development of cervical cancer often occurs decades
after initial infection. HPV types 16 and 18 account for 70% of cervical
cancers.196 A variety of other types account for the remaining 30% of
cervical cancers, and these types vary in their distribution globally.
CHAPTER 245  Active Immunizing Agents 2559
Although the incidence of HPV is high, most infections clear without
intervention. Seventy percent of new infections clear within 1 year, and
91% clear within 2 years.196 Persistent infection with high-risk HPV
types, defined as detection of the same viral type at two or more visits
6 months apart, is the most important risk factor for developing cervical
cancer precursor lesions. Studies have demonstrated that persistent
infection with a high-risk HPV type is associated with a greater than
10-fold risk of high-grade cervical cancer precursors.350,483
Three prophylactic HPV subunit vaccines are licensed and recom-
mended for use in the United States.457,533 Use of these vaccines has
significantly decreased the prevalence of vaccine-type HPV infection.
In one study, vaccine-type HPV prevalence in the study population
decreased by 75% among women and more than 90% among vaccinated
women.379 Areas with high HPV vaccine coverage have seen decreases
in anogenital warts.244,245,547 The impact on the incidence of HPV-related
cervical and other anogenital cancers will take years to assess because
the cancers can occur decades after infection. Incidence of recurrent
respiratory papillomatosis and associated cancers also is likely to decrease
as a result of widespread vaccination.
Preparations
In 2006, the FDA licensed the first HPV vaccine for use in girls and
women 9 through 26 years of age in the United States, and this was
done for use in boys and men 9 through 26 years of age in 2009.35,167,456
The quadrivalent vaccine (Gardasil, Merck & Co.) contains HPV types
6, 11, 16, and 18 virus-like particles (VLPs) and protects against four
HPV types, which together cause 70% of cervical cancers (i.e., HPV
types 18 and 16) and 90% of genital warts (i.e., HPV types 6 and 11).
The quadrivalent HPV vaccine (HPV4) is prepared from the highly
purified VLPs of the major capsid (L1) protein of HPV types 6, 11, 16,
and 18. The L1 proteins are produced by Saccharomyces cerevisiae and
self-assemble into VLPs. The VLPs mimic the HPV virus, but they
contain no viral DNA. Each 0.5-mL dose contains 20 µg of HPV 6 L1
protein, 40 µg of HPV 11 L1 protein, 40 µg of HPV 16 L1 protein, and
20 µg of HPV 18 L1 protein.
A bivalent vaccine (HPV2) (Cervarix, GlaxoSmithKline), which is
directed against two oncogenic HPV types (i.e., 16 and 18), was licensed
for use in girls and women 10 through 25 years of age in 2009 and not
licensed for males.35,159
A 9-valent vaccine (9vHPV) (Gardasil 9, Merck), which protects
against the same four HPV types as the quadrivalent HPV vaccine plus
HPV 31, 33, 45, 52, and 58 VPs, was approved by the FDA in 2014 and
recommended by the ACIP in 2015.277,533 It was licensed for use in men
and women 9 to 26 years of age.277
The HPV vaccines use alum as an adjuvant and do not contain
thimerosal or antibiotics. The vaccines should be stored at 2°C to 8°C
(36°F–46°F) and not frozen.159
Primary vaccination dosing schedules with HPV vaccines are the
same and consist of three 0.5-mL doses administered intramuscularly.
The second and third doses should be administered 2 and 6 months
after administration of the first dose. In 2016, the ACIP recommended
that 9- to 14-year-old children receive two HPV vaccine doses instead
of the previously recommended three doses because studies showed
good immune responses compared with earlier groups receiving three
doses.474 The recommendation for three doses remained the same for
ages 15 to 26 years. The FDA also announced approval of the two-dose
schedule for the 9vHPV vaccine.278 Due to licensing and manufacturing
issues, 9vHPV will be the primary HPV vaccine going forward.
Immunogenicity and Efficacy
Data from randomized, controlled trials (RCTs) have shown consistently
that prophylactic HPV VLP vaccines are immunogenic and efficacious
in preventing infection and lesions caused by the targeted HPV
types.336,402,439,476,616 Vaccine efficacy seems to be mediated by a type-specific
humoral immune response.
Evaluations of the quadrivalent HPV4 vaccine have demonstrated
that vaccinated individuals develop high antibody titers to the respective
HPV types that exceed the antibody titers seen with natural HPV
infection.616 However, the level of antibody that confers a protective
response is unknown.616 For the HPV4 VLP vaccine, an antibody response
2560 PART V  Prevention of Infectious Diseases
significantly greater than placebo was sustained for at least 3 years
without booster doses.336,663 Although vaccine efficacy studies have been
done only enrolling adolescents 13 years or older, immunogenicity
bridging studies have been performed with children as young as 9 years
of age. Antibody titers to HPV types 6, 11, 16, and 18 were found to
be higher in younger adolescents than in young adults. From these data,
investigators inferred that protection exists against cervical cancer, cancer
precursor lesions, and genital warts, even for young adolescent girls
who receive the HPV4 vaccine.
The results from four RCTs demonstrate that a regimen of three
intramuscular injections of HPV VLP vaccine provides high-level
protection from infection and lesions caused by targeted HPV types.402,439
A combined analysis of HPV4 vaccine efficacy in phase II and phase
III clinical trials showed 100% protection against precancerous lesions
(i.e., carcinoma in situ II/III or adenoma in situ) caused by HPV type
16 or 18 and 99% protection against genital wart development.476
A randomized, multicenter, double-blind study found the 9vHPV
vaccine antibody response to HPV types 6, 11, 16, and 18 to be non-
inferior to the response with the HPV4 vaccine.378 From this result, the
9vHPV vaccine can be inferred to have the same protective efficacy as
the HPV4 vaccine. The 9vHPV vaccine prevented infection and disease
related to HPV types 31, 33, 45, 52, and 58; for high-grade cervical,
vulvar, or vaginal disease related to these HPV types, the vaccine had
a 96.7% efficacy rate.378
It is not known whether HPV vaccines provide long-term protection
or booster doses will be necessary. The quadrivalent HPV4 vaccine does
not have efficacy against existing disease or infection caused by HPV.
HPV2 vaccine efficacy was evaluated in two randomized, double-blind,
controlled clinical trials in females 15 through 25 years of age. In the
analysis, 99% or more of participants developed an HPV 16 and 18
antibody response 1 month after completing the three-dose series. After
concomitant administration of HPV2 with tetanus toxoid, diphtheria
toxoid, and acellular pertussis vaccine and/or with meningococcal
conjugate vaccine in females 11 through 18 years of age compared with
those after administration at separate visits, the antibody responses for
bivalent vaccine antigens were noninferior.159
In summary, HPV vaccines are highly effective in preventing HPV-16
and HPV-18–related cervical precancerous lesions in females. The HPV4
vaccine is highly effective in preventing HPV-6 and HPV-11–related
genital warts in females and males, and HPV4 vaccine also is effective
in preventing anal precancerous lesions in males. Vaccines offer no
protection against progression of infection to disease from HPV acquired
before immunization.35
Adverse Events
HPV vaccines appear to be generally safe and well tolerated.620 The
HPV4 and 9vHPV vaccines have similar safety profiles.533 The most
common adverse events are local injection site reactions such as mild
to moderate pain, redness, pruritus, or swelling.533 For females 9 to 26
years of age, 9vHPV compared with HPV4 vaccine recipients had more
injection site adverse events, including swelling (40.3% vs. 29.1%) and
redness (34.0% vs. 25.8%).533
In analyses of local and general adverse events after bivalent HPV2
vaccine administration versus control vaccines, 92% reported injection
site pain, 48%, had redness, and 44% had swelling in the HPV2 group.
These findings compared with 64% to 87%, 24% to 28%, and 17% to
21% in the control groups for the same findings. Fatigue, headache,
and myalgia were the most common general symptoms reported.159
Additional data on vaccine safety, including data on pregnancy and
fetal and infant outcomes, are being collected. Data will continue to be
collected in postlicensure studies.
Indications
The ACIP issued recommendations for the use of the HPV4 vaccine
in March 2007, the bivalent HPV2 vaccine in May 2010, and the
9vHPV in March 2015.159,160,167,457,456,533 Routine vaccination with three
doses of vaccine is recommended for girls 11 to 12 years of age. The
vaccination series can be started in girls as young as 9 years of age at
the discretion of physicians and parents. Catch-up vaccination is recom-
mended for girls and women 13 to 26 years of age who have not been
vaccinated previously or who have not completed the full vaccination
series.
Only HPV4 and 9vHPV vaccines are recommended for routine
immunization of boys at 11 or 12 years of age (the series can be started
at 9 years of age), and it is recommended for boys and men 13 through
21 years of age not previously immunized.209 Men 22 through 26 years
of age may be immunized on request. Vaccine is recommended for men
who have sex with men and males who are immunocompromised
(including those with HIV infection) through 26 years of age.
Ideally, vaccination should be administered before potential exposure
to HPV through sexual contact occurs. HPV vaccines are not licensed
for use in people older than 26 years.35
Vaccine is administered in a three-dose schedule, and the second
and third doses should be administered 2 and 6 months after the first
dose. Immunogenicity data allow for some degree of flexibility in the
dosing schedule, which is often an important consideration in providing
multidose vaccines to adolescents for whom contact with health providers
can be sporadic. For both vaccines, the minimum interval from dose
1 to dose 2 is 4 weeks. The minimum interval from dose 2 to dose 3
should not be less than 12 weeks. For ages 9 to 14 years, vaccine can
be administered in a two-dose schedule, with the second dose admin-
istered at least 6 months after the first dose. The three-dose schedule
should be used for ages 15 to 26 years.474
HPV vaccine can be administered at the same visit when other
age-appropriate vaccines, such as Tdap, Td, and MCV4 (meningococcal),
are provided.508 Women who have received an HPV vaccine must continue
to have regular Papanicolaou test screening. HPV vaccines do not provide
protection against all HPV types associated with development of cancer,
and vaccines do not alter the progression of HPV infection acquired
before immunization.
People through 26 years of age with evidence of current HPV infec-
tion, such as cervical dysplasia, a positive HPV DNA test result, or
anogenital warts or a history of anogenital warts, should receive HPV
immunization because infection with all vaccine HPV types is unlikely
and the vaccine can provide protection against HPV infection with
types not already acquired.35 Vaccine recipients should be advised
that data from clinical trials do not indicate the vaccine will have any
therapeutic effect on existing abnormalities found by Papanicolaou
testing, on HPV infection, or on genital warts. However, HPV vaccination
can provide protection against infection with HPV types not already
acquired.
Lactating women can receive HPV4 or 9vHPV vaccine, but the
bivalent vaccine has not been studied in lactating women. Patients of
the appropriate age who are immunocompromised due to disease or
medication can receive HPV vaccine. However, the immune response
to vaccination and vaccine effectiveness may be less than in those who
are immunocompetent.
Contraindications and Precautions
HPV4 and 9vHPV vaccines are contraindicated for people with a history
of immediate hypersensitivity to yeast or to any vaccine component. 533
Bivalent HPV2 vaccine is contraindicated for people with a history of
immediate hypersensitivity to any vaccine component. HPV2 vaccine
in the prefilled syringe formulation should not be administered to
latex-sensitive individuals because the rubber stopper contains latex.35
HPV vaccine is listed under pregnancy category B and is not recom-
mended for use in pregnancy.159,457 If an adolescent becomes pregnant
during the vaccination period, subsequent doses should be deferred
until after parturition. The vaccine has not been associated causally
with adverse outcomes of pregnancy or adverse effects on the developing
fetus. However, data on vaccination during pregnancy are limited.
Influenza Vaccine
Influenza virus infection continues to cause significant morbidity and
mortality despite the availability of effective vaccines and antiviral therapy
for prevention and treatment of influenza. In the United States, epidemics
of influenza typically occur during the winter months and have been
associated with an average of approximately 36,000 deaths per year,
and between 1976 and 2007, estimated cases ranged from 3000 to 49,000
each year.158,638

Influenza viruses cause disease among all age groups.300,301,486 Rates
of infection are highest among children, but rates of serious illness and
death are highest among those 65 years or older, children 2 years or
younger, and people of any age who have medical conditions that increase
the risk of complications from influenza.65,64,299,486 The impact of influenza
on normal children and those with underlying high-risk conditions is
appreciable, and the burden of disease in young children attributed to
influenza is underrecognized.542 Attack rates among normal children
have been estimated at 10% to 40% each year, and approximately 1%
of influenza infections result in hospitalization.302,542 Influenza also causes
a significant burden in outpatient settings, especially for those 2 to 17
years of age.279
A major difficulty in the development and provision of satisfactory
immunizing agents for the prevention of influenza is the antigenic
variation of the viruses. Periodic minor antigenic changes in influenza
A or B virus are the major factors in the continuing occurrence of
yearly influenza. Although outbreaks usually are limited in magnitude,
the resulting morbidity and mortality remain discouragingly high. Major
antigenic changes in influenza A virus, as occurred in 1957 to 1958
(Asian strain), in 1968 to 1969 (Hong Kong strain), and again in 2009
(pH1N1) account for the pandemic spread of disease associated with
greater overall morbidity and mortality. The CDC estimates that in the
2009 pandemic the H1N1 influenza virus caused more than 60 million
Americans to become ill and led to more than 270,000 hospitalizations
and 12,500 deaths.371 People younger than 65 years accounted for 90%
of hospitalizations and deaths. With typical seasonal influenza, approxi-
mately 90% of the people who die are older than 65 years.
Preparations
An assortment of influenza vaccines are licensed for use in the United
States: inactivated trivalent influenza vaccine (IIV3), adjuvanted
inactivated trivalent influenza vaccine (aIIV3), recombinant trivalent
influenza vaccine (RIV3), inactivated quadrivalent influenza vaccine
(IIV4), inactivated quadrivalent cell culture-based influenza vaccine
(ccIIV4), and live attenuated quadrivalent influenza vaccine (LAIV).101,315
The trivalent vaccines contain three virus strains (usually two type
A and one type B), and the composition is changed periodically in
anticipation of the prevalent influenza strains expected to circulate in
the United States in the following winter. The quadrivalent vaccines
include an additional type B strain.315 Most vaccines are prepared from
virus grown in the allantoic sac of the chick embryo. Exceptions include
one IIV4 preparation with virus propagated through canine kidney
cells and the RIV3 preparation, which is manufactured without the use
of influenza viruses.315
IIV3, aIIV3, IIV4, and ccIIV4 are inactivated influenza vaccines (IIVs)
that contain no live virus. IIVs distributed in the United States consist
of subvirion vaccine, prepared by disrupting the lipid-containing
membrane of the virus, or purified surface-antigen vaccine. All IIV
formulations are available for intramuscular use, except ccIIV4, which
is intradermal.
IIV4 is licensed and recommended for children 6 months or older
and for adults, including those with or without chronic medical condi-
tions. Vaccine is available in pediatric (0.25-mL dose) and adult (0.5-mL
dose) formulations. IIV3 and ccIIV4 (using the 0.5-mL dose) are licensed
and recommended for children 4 years or older and for adults. RIV3,
also in the 0.5-mL dose, is licensed and recommended for those18 years
or older.
IIV is administered intramuscularly into the anterolateral thigh of
infants and young children and into the deltoid muscle of older children
and adults. RIV3 is administered intramuscularly into the deltoid muscle.
The volume of vaccine depends on age. Infants and toddlers 6 months
through 35 months of age should receive a dose of 0.25 mL, and all
individuals 36 months or older should receive 0.5 mL per dose. Children
younger than 9 years who are being immunized against influenza for
the first time should receive two doses of TIV given 4 weeks apart before
the start of the influenza season. IIV is shipped and stored at 2°C to
8°C (35°F–46°F).
The intradermal formulation of IIV4 is licensed for the 2016–2017
influenza season for use in individuals 18 through 64 years of age.315
It is administered preferably over the deltoid muscle and only by using
CHAPTER 245  Active Immunizing Agents 2561
the device included in the vaccine package. Vaccine is supplied in a
single-dose, prefilled microinjection system (0.1 mL). The intradermal
formulation of IIV4 is shipped and stored at 2°C to 8°C (35°F–46°F).
Many manufacturers produce inactivated influenza vaccine each
year for the US market. Vaccines are available in single-dose syringes
and vials or multidose vials and in preservative-free formulations.
Approved age indications vary by manufacturer and product. Clinicians
should obtain inactivated influenza vaccine appropriate for the age
groups they plan to vaccinate. The ACIP does not recommend use of
influenza vaccine outside the vaccine’s FDA-approved age indication.
Tables listing each year’s influenza vaccines are available in the annual
ACIP and AAP influenza statements and on the CDC influenza website
(https://www.cdc.gov/flu/professionals/vaccination/vaccine_safety.htm).
Package inserts should be consulted for recommended age groups and
possible contraindications for each vaccine in addition to information
regarding additional components of various vaccine formulations.
LAIV is cold adapted, developed by passaging the viruses at succes-
sively lower temperatures in tissue culture so that replication occurs
only in the upper respiratory tract.74 LAIV is licensed by the FDA for
healthy individuals 2 through 49 years of age. It has not been recom-
mended for those with a history of asthma or other high-risk medical
conditions associated with an increased risk of complications from
influenza.
LAIV is administered intranasally in a prefilled, single-use sprayer
containing 0.2 mL of vaccine. A removable dose-divider clip is attached
to the sprayer to administer 0.1 mL separately into each nostril. Children
younger than 9 years being immunized against influenza for the first
time should receive two doses of LAIV given 4 weeks apart before the
start of the influenza season. The LAIV formulation licensed in the
United States must be shipped and stored at 2°C to 8°C (35°F–46°F).
After the vaccine is warmed to room temperature for intended use, it
must be used within 30 minutes.
Trivalent influenza vaccines contain A (H1N1), A (H3N2), and B
viral antigens. The quadrivalent influenza vaccines include an additional
B viral antigen because of the difficulty of predicting which B virus
lineage will predominate during a given season.
Immunogenicity and Efficacy
Children 6 months or older typically have protective levels of anti-
influenza antibody against specific influenza virus strains after receiving
the recommended number of doses of seasonal inactivated influenza
vaccine.226,305,417,499,702,704 Immunogenicity studies using the influenza A
(H1N1) 2009 monovalent vaccine indicated that more than 90% of
children 9 years or older responded to a single dose with anti-influenza
antibody levels considered to be protective. Young children had incon-
sistent responses to a single dose of the influenza A (H1N1) 2009
monovalent vaccine across studies, with 20% of children 6 to 35 months
of age responding to a single dose with protective anti-influenza antibody
levels. However, in all studies, 80% to 95% of vaccinated infants, children,
and adolescents developed protective anti-influenza antibody levels to
the 2009 H1N1 influenza virus after two doses.56,506,538
In most seasons, one or more seasonal vaccine antigens are changed
compared with the previous season. In consecutive years when vaccine
antigens change, children younger than 9 years who received only one
dose of vaccine in their first year of vaccination are less likely to have
protective antibody responses when administered only a single dose
during their second year of vaccination compared with children who
received two doses in their first year of vaccination.258,502,668
When the vaccine antigens do not change from one season to the
next, priming children 6 to 23 months of age with a single dose of
vaccine in the spring followed by a dose in the fall results in similar
antibody responses compared with a regimen of two doses in the fall.257
However, one study conducted during a season when the vaccine antigens
did not change compared with the previous season estimated 62%
effectiveness against influenza-like illness for healthy children who had
received only one dose in the previous influenza season and only one
dose in the study season compared with 82% for those who received
two doses separated by 4 weeks or more during the study season.10
The antibody response for children at higher risk for influenza-related
complications (e.g., children with chronic medical conditions) may be
2562 PART V  Prevention of Infectious Diseases
lower than those reported typically for healthy children.71,316 However,
antibody responses among children with asthma are similar to those
of healthy children and are not substantially altered during asthma
exacerbations requiring short-term prednisone treatment.522
Vaccine effectiveness studies also have indicated that two doses are
needed to provide adequate protection during the first season that
young children are vaccinated. Among children younger than 5 years
who have never received influenza vaccine previously or who received
only one dose of influenza vaccine in their first year of vaccination,
vaccine effectiveness is lower compared with children who received two
doses in their first year of being vaccinated. Two large, retrospective
studies of young children who had received only one dose of IIV in
their first year of being vaccinated found no decrease in influenza-like
illness–related office visits compared with unvaccinated children.10,558
Similar results were reported in a case-control study of children 6 to
59 months of age in which laboratory-confirmed influenza was the
outcome measured.602 These results, along with the immunogenicity
data indicating that antibody responses are substantially higher when
young children are given two doses, are the basis for the recommendation
that all children 6 months to 8 years of age who are being vaccinated
for the first time should receive two vaccine doses separated by 4 weeks
or more.
Estimates of vaccine efficacy or effectiveness among children 6 months
or older have varied by season and study design. In a randomized trial
conducted during five influenza seasons (1985–90) in the United States
for children 1 to 15 years of age, annual vaccination reduced laboratory-
confirmed influenza A substantially (77–91%).501 A 1-year, placebo-
controlled study reported vaccine efficacy rates against laboratory-confirmed
influenza illness of 56% for healthy children 3 to 9 years of age and
100% for healthy children and adolescents 10 to 18 years old.197
A randomized, double-blind, placebo-controlled trial conducted
during two influenza seasons among children 6 to 24 months of age
indicated that the efficacy rate was 66% against culture-confirmed
influenza illness during the 1999–2000 influenza season but did not
reduce culture-confirmed influenza illness substantially during the
2000–01 influenza season.351 A case-control study conducted during
the 2003–04 season indicated vaccine effectiveness of 49% against
laboratory-confirmed influenza.602 An observational study of children
6 to 59 months of age with laboratory-confirmed influenza compared
with children who tested negative for influenza reported vaccine
effectiveness of 44% in the 2003–04 influenza season and 57% during
the 2004–05 season.255 Partial vaccination (i.e., only one dose for children
being vaccinated for the first time) was not effective in either study.
During an influenza season (2003–04) with a suboptimal vaccine
match, a retrospective cohort study conducted among approximately
30,000 children 6 months to 8 years of age indicated vaccine effectiveness
of 51% against medically attended, clinically diagnosed pneumonia or
influenza (i.e., no laboratory confirmation of influenza) among fully
vaccinated children and 49% among approximately 5000 children 6 to
23 months old.558
Another retrospective cohort study of similar size conducted during
the same influenza season in Denver but limited to healthy children 6
to 21 months of age estimated clinical effectiveness of 2 IIV doses to
be 87% against pneumonia or influenza-related office visits.10
Among children, TIV effectiveness may increase with age.501,711 A
systematic review of published studies estimated vaccine effectiveness
at 59% for children 2 years or older but concluded that additional
evidence was needed to demonstrate effectiveness among children 6
months to 2 years old.370
Because of the recognized influenza-related disease burden among
children with other chronic diseases or immunosuppression and the
long-standing recommendation for vaccination of these children,
randomized, placebo-controlled studies to determine efficacy in high-risk
children are needed but are currently unavailable. Although data about
influenza vaccine in specific immunocompromised states are limited,
the Infectious Diseases Society of America (IDSA) publishes guidelines
for specific immune-compromising diagnoses.568 In a nonrandomized,
controlled trial enrolling children 2 to 6 years old and 7 to 14 years old
who had asthma, vaccine efficacy was 54% and 78% against laboratory-
confirmed influenza type A infection and 22% and 60% against
laboratory-confirmed influenza type B infection, respectively. Vaccinated
children 2 to 6 years of age with asthma did not have substantially fewer
type B influenza virus infections compared with the control group in
this study.623
The association between vaccination and prevention of asthma
exacerbations is unclear. Vaccination provided protection against asthma
exacerbations in some studies.403,511
IIV has reduced AOM in some studies. Two studies reported that
IIV decreased the risk of influenza-related otitis media by approximately
30% among children with mean ages of 20 and 27 months, respec-
tively.194,339 However, a large study conducted among children with a
mean age of 14 months indicated that IIV was not effective against
AOM.351 Influenza vaccine effectiveness against a nonspecific clinical
outcome such as AOM, which is caused by a variety of pathogens and
is not typically diagnosed using influenza virus culture, is expected to
be relatively low.
The relative effectiveness of LAIV and IIV for medically attended,
laboratory-confirmed influenza was evaluated using US Influenza Vaccine
Effectiveness Network data.192 For the 2013–14 season, children 2 to 8
years of age who received LAIV had significantly higher odds of influenza
(odds ratio, 5.36) than those who received IIV192 The greater odds of
illness with influenza A/H1N1pdm09 included the 2010–11 and 2013–14
seasons. Another study of the 2013–14 season found the effectiveness
of LAIV against influenza A/(H1N1)pdm09 to be 17%, compared with
60% for IIV, for children 2 to 17 years of age.284
After the ACIP recommendation for preferential use of LAIV during
the 2014–15 season for children 2 to 8 years of age, another study examined
vaccine effectiveness by type.716 In this study with 9311 participants at
5 US sites, the preference for use of LAIV in young children was not
supported. Based on these and several other studies, LAIV was not recom-
mended for use for any age for the 2016–17 season.101,315
Adverse Events
All inactivated influenza vaccines contain killed viruses and therefore
cannot produce signs or symptoms of influenza caused by active virus
infection. The most common symptoms associated with IIV administra-
tion are soreness at the injection site and fever. Fever, usually occurring
6 to 24 hours after immunization, affects 10% to 35% of children younger
than 2 years. Mild systemic symptoms, such as nausea, lethargy, headache,
muscle aches, and chills also can occur after receipt of IIV.
Before the 2010–11 influenza season, an increased risk of febrile
seizures after IIV3 administration had not been observed in the United
States.313,329 The CDC and the FDA conducted enhanced monitoring
for febrile seizures after influenza vaccination because of reports of an
increased risk of fever and febrile seizures in young children in Australia
that were associated with a 2010 Southern Hemisphere vaccine produced
by CSL Biotherapies. The risk was up to nine febrile seizures per 1000
doses during the 2010–11 influenza season. Due to the increased risk,
the ACIP does not recommend the US licensed Afluria (CSL Biotherapies’
IIV3) for children younger than 9 years.164
For the 2010–11 season, surveillance for US licensed influenza vaccines
detected safety signals for febrile seizures in younger children after IIV
administration.426,645 On further review, the increased risk was found for
children 6 months through 4 years of age, ranging from the day of vac-
cination to the day after vaccination (i.e., 0–1-day risk window). The
risk was found to be higher when children received concomitant PCV13,
and the risk peaked at about 16 months of age.645 No increased risk was
observed for children 5 years or older after IIV or for children of any
age after LAIV. The magnitude of the increased risk of febrile seizures
in young children in the United States (<1 case/1000 children vaccinated)
was substantially lower than the risk observed in Australia in 2010.
After evaluating the data on febrile seizures from the 2010–11
influenza season and taking into consideration benefits and risks of
vaccination, no policy change was recommended for use of IIV or
PCV13. According to the CDC, surveillance data on febrile seizures in
young children after administration of influenza vaccine for the 2011–12
influenza season (i.e., same vaccine formulation as for the 2010–11
season) were consistent with those from the 2010–11 influenza season.
No changes in the use of IIV or PCV13 are recommended, although
surveillance is ongoing.315

LAIV usually is well tolerated and may produce mild signs or
symptoms related to influenza virus infection that include headache
and runny nose or nasal congestion in vaccinees. Transmission of LAIV
strains to unimmunized contacts has been documented only once in
prelicensure studies. The proposed explanation for the uncommon
occurrence of transmission is that the vaccine virus is shed for a shorter
duration and in a much smaller quantity than are wild-type strains.
Indications
Routine annual influenza vaccination is recommended for all people
6 months or older.37,101,315 To permit time for production of protective
antibody levels,91,317 vaccination optimally should occur before the onset
of influenza activity in the community. Vaccination providers should
offer vaccination as soon as the vaccine is available. Vaccination should
be offered throughout the influenza season (i.e., as long as influenza
viruses are circulating in the community).101,315 Due to the previously
described issues with vaccine effectiveness, LAIV was not recommended
by the ACIP for any age group for the 2016–17 influenza season.315
Particular focus should be on the administration of IIV for all children
and adolescents who have underlying medical conditions associated
with an increased risk of complications from influenza, including the
following:
• Asthma or other chronic pulmonary diseases, including cystic
fibrosis
• Hemodynamically significant cardiac disease
• Immunosuppressive disorders or therapy
• HIV infection
• Sickle cell anemia and other hemoglobinopathies
• Diseases that require long-term aspirin therapy, including juvenile
idiopathic arthritis or Kawasaki disease
• Chronic renal dysfunction
• Chronic metabolic disease, including diabetes mellitus
• Any condition that can compromise respiratory function or handling
of secretions or can increase the risk of aspiration, such as neuro-
developmental disorders, spinal cord injuries, seizure disorders, or
neuromuscular abnormalities
Although universal immunization for all individuals 6 months or
older is recommended, particular immunization efforts should be made
for the following groups to prevent transmission of influenza to those
at risk, unless contraindicated:
• Household contacts and out-of-home care providers of children
younger than 5 years and at-risk children of all ages should be
immunized.
• Any female who is pregnant, is considering pregnancy, has just
delivered, or is breastfeeding during the influenza season should be
immunized.. Studies have shown that infants born to immunized
women have better influenza-related health outcomes. However, the
estimated median seasonal vaccination coverage among women with
a live birth was only 47% during the 2009–10 influenza season, even
though pregnant women and their infants are at higher risk for
complications. Data from some studies suggest that influenza vac-
cination during pregnancy may decrease the risk of preterm birth.
• Health care personnel or health care volunteers should be immunized..
Despite the recent AAP recommendation for mandatory influenza
immunization for all health care personnel,76,101 many remain unvac-
cinated. The CDC estimated that only 77% of health care personnel
received the seasonal influenza vaccine for the 2014–15 season.81
The AAP recommends mandatory vaccination of health care personnel
because they frequently come into contact in their clinical settings
with patients at high risk for influenza illness.
• Close contacts of immunosuppressed individuals should be
immunized.
Previously unimmunized children between 6 months to 9 years of
age should receive two doses of influenza vaccine before the onset of
influenza season. Available data suggest that children younger than 9
years who did not receive the second dose of influenza vaccine in the
initial year that influenza vaccine was given may not be adequately
protected the next influenza season with only one dose. In this group,
levels of protection can be suboptimal, especially if the antigenic
specificity of the predominant strains has changed from the previous
CHAPTER 245  Active Immunizing Agents 2563
Has the child received 2 total doses of
trivalent or quadrivalent influenza
vaccine before July 1, 2016? (doses need not
have been received during the same
season or consecutive seasons)
Yes No or don’t know
1 dose of 2016–17 2 doses of 2016–17
influenza vaccine influenza vaccine
(administered
4 weeks apart)
FIG. 245.2  Influenza vaccine dosing algorithm for children age 6 months
through 8 years for the US 2016–17 influenza season. (From Centers
for Disease Control and Prevention. Prevention and control of seasonal
influenza with vaccines recommendations of the Advisory Committee
on Immunization Practices—United States, 2016–17 influenza season.
https://www.cdc.gov/mmwr/volumes/65/rr/rr6505a1.htm.)
year. The AAP recommends that two doses be given to these children
the following influenza season.101 This recommendation applies only
to the influenza season that follows the first year that a child younger
than 9 years old receives influenza vaccine (Fig. 245.2).
Precautions and Contraindications
IIVs are contraindicated for infants younger than 6 months and children
who have a moderate to severe febrile illness on the basis of clinical
judgment of the pediatrician.179 People with acute febrile illness usually
should not be vaccinated until their symptoms have abated. However,
minor illnesses with or without fever do not contraindicate the use of
influenza vaccine, particularly in children with mild upper respiratory
tract infection or allergic rhinitis.101,315
Pregnancy is not a contraindication to influenza vaccine administra-
tion. Vaccination with IIVs are advised for pregnant girls and women
who have an underlying high-risk condition.
IIVs can be used to prevent influenza in those who are in close
contact with most immunosuppressed individuals, such as those receiving
care in a protective environment after undergoing hematopoietic stem
cell transplantation.
Severe allergic and anaphylactic reactions can occur in response to
several influenza vaccine components, but such reactions are rare.
Currently available influenza vaccines are prepared by means of inocula-
tion of virus into chicken eggs, with the exception of the RIV3 and
ccIIV4 preparations.315 The use of influenza vaccines for people with
a history of egg allergy was reviewed by the ACIP.315 For the 2016–17
influenza season, the ACIP recommended that people with egg allergy
who report only hives after egg exposure should receive IIVs, with
several additional safety measures. For the 2016–17 influenza season,
the ACIP recommended the following:
• People with a history of egg allergy who have experienced only hives
after exposure to egg should receive influenza vaccine.315
• People who report having had reactions to egg involving symptoms
such as angioedema, respiratory distress, lightheadedness, or recurrent
emesis or who required epinephrine or another emergency medical
intervention, particularly those that occurred immediately or within
minutes to hours after egg exposure, should receive influenza
vaccine.315
Measles Vaccine
Since the introduction of an inactivated and a live virus, attenuated
measles vaccine (i.e., Edmonston B strain) in the United States in 1963,
2564 PART V  Prevention of Infectious Diseases
the reported incidence of measles has decreased by more than 99%.
Although the incidence of measles has declined in all age groups, the
decline has been greatest among children 5 to 14 years of age.
Measles was targeted for elimination in the United States by 1982.
Efforts to eliminate measles were not successful as a result of two factors.
The first was vaccine failure. In the late 1980s, outbreaks occurred among
older children in schools in which immunization rates usually were
greater than 95%.459,505 Attack rates were 1% to 5% because of the
accumulation of measles-susceptible individuals from vaccine failure.
The recurrent measles outbreaks among vaccinated school-aged children
in the mid-1980s prompted the ACIP and the AAP in 1989 to recommend
that all children be given two doses of measles-containing vaccine,
preferably as MMR.13,109 Although administration of the second dose
originally was recommended at entry to primary school (ACIP) or
middle/secondary school (AAP), the ACIP, the AAP, and the AAFP now
recommend that a child be given the second dose at age 4 to 6 years
rather than delaying it until the child is 11 to 12 years old.38,471 The
major benefit of administering the second dose is a reduction in the
proportion of people who remain susceptible because of primary vaccine
failure. Waning immunity is not a major cause of vaccine failure and
has little influence on transmission of measles, and revaccination of
children who have low concentrations of measles antibody produces
only a transient rise in antibody concentration.454,458,505,518,669
The second factor leading to outbreaks of measles was the failure
to implement current immunization strategies, especially in the inner
cities, where a high proportion of preschool-aged children had not
been vaccinated. From 1989 through 1991, the proportion of unvaccinated
people with measles increased, as reflected by outbreaks among unvac-
cinated inner-city preschool-aged children. Many barriers to providing
timely immunization to these children were identified during investiga-
tion of the measles resurgence that occurred between 1989 and 1991.
Reported cases of measles declined rapidly after the 1989–91 resurgence
because of intensive efforts to vaccinate preschool-aged children. Measles
vaccination levels among 2-year-old children increased from 70% in
1990 to 91% in 1997. From 2001 to 2008, a median of 56 measles cases
were reported to the CDC annually.523
In 2000, the United States achieved measles elimination, defined as
interruption of year-round endemic measles transmission.382 However,
importations of measles into the United States continue to occur, posing
risks for measles outbreaks and sustained measles transmission. Since
2000, the annual number of cases has ranged from a low of 37 in 2004
to a high of 667 in 2014.267,287 Most cases have been among people who
are not vaccinated against measles. Most cases are imported from other
countries or linked to imported cases. Most imported cases originate
in Asia, Africa, and Europe and occur among US citizens traveling
abroad and people visiting the United States from other countries.614
Since 1993, the largest outbreaks of measles in the United States have
occurred in populations that refuse vaccination for religious or personal
belief reasons.534,610 Most outbreaks have involved limited spread from
measles imported from outside the United States. The increased numbers
of outbreaks and measles importations into the United States underscore
the ongoing risk of measles among unvaccinated people and the
importance of vaccination against measles.
The recommended age for receiving routine vaccination with measles
vaccine has been lowered in the past decade from 15 months to 12 to 15
months of age.141 The decision to lower the age for receiving routine
primary vaccination was based on the observation that most children
are susceptible to measles by the time that they reach 12 months of age
because of waning transplacental immunity.447,455 Most mothers have
vaccine-induced immunity rather than immunity conferred by infection
with wild virus. Because antibody concentrations induced by measles
vaccination typically are lower than those induced by natural measles,
measles-specific antibodies acquired transplacentally are lower in infants
of vaccinated mothers, and these infants are susceptible at an earlier age.
Preparations
The live measles virus vaccine (Moraten strain) available in the United
States is prepared in chick fibroblast cell culture. Each dose of vaccine
contains neomycin, sorbitol, and hydrolyzed gelatin as a stabilizer.
Preparations include MMR and measles-mumps-rubella-varicella
(MMRV) vaccines. MMRV vaccine was licensed in the United States
in September 2005 and may be used instead of MMR and varicella
vaccine to implement the recommended two-dose vaccine schedule for
prevention of measles, mumps, rubella, and varicella among children
12 months to 12 years of age. Single-component measles vaccine is not
available in the United States.
Inadequate protection against measles can result from the administra-
tion of improperly stored vaccine. Before reconstitution, measles vaccine
must be stored at a temperature between 2°C and 8°C (35.6°F–46.4°F)
or colder and must be protected from light, which may inactivate the
virus. Reconstituted vaccine should be stored in a refrigerator and
discarded if not used within 8 hours.
Immunogenicity and Efficacy
Immunization produces a mild or unapparent, noncommunicable
infection. Measles antibodies develop in approximately 95% of children
vaccinated at 12 months of age and in 98% of children vaccinated at
15 months of age.455 Studies indicate that serologic evidence of measles
immunity develops in more than 99% of people who receive two doses
of measles vaccine, separated by at least 1 month, on or after their first
birthday.191,206 Although vaccine-induced antibody titers are lower than
those after natural disease, persistence of protective titers for as long
as 16 years after administration of vaccine has been demonstrated.410,458
Most vaccinated people who appear to lose antibody have an anamnestic
response after revaccination, indicating that they most likely are still
immune.514 A small percentage of vaccinated individuals may lose
protection after several years as a result of secondary vaccine failure.466
Adverse Events
Vaccine-associated symptoms, consisting of fever higher than 39.4°C
(102.9°F) or rash occurring 5 to 10 days after immunization, develop
in 5% to 18% of recipients.421,530 Serious complications related to vaccine
use occur far less frequently than after natural measles.525
Thrombocytopenia occurs at a rate of one case for every 30,000 to
40,000 doses distributed. Based on data from Sweden and Finland, the
IOM concluded that a causal association exists between MMR and
thrombocytopenia.362 The decrease in platelet count presumably is caused
by the measles component and usually is not clinically apparent. However,
thrombocytopenic purpura occurring after vaccination has been reported.
Central nervous system disease, specifically encephalitis or encepha-
lopathy, is reported at a rate of less than one case per 1 million doses
of vaccine administered. Because the incidence of encephalitis or
encephalopathy after the administration of measles vaccination to healthy
children is lower than the observed incidence of encephalitis of unknown
origin, some or most of the reported severe neurologic disorders may
be only temporally, rather than causally, related to measles immunization.
The risk of subacute sclerosing panencephalitis (SSPE) developing in
vaccinated children is extremely low and is estimated to be approximately
one twelfth of the risk for SSPE developing after a case of natural
measles (0.7 SSPE cases/1 million vaccine doses vs. 8.5 cases/1 million
natural measles infections).82,106,362 Vaccine-strain measles virus never
has been confirmed in a case of SSPE.38
Reactions to measles vaccine are not age related and occur only in
susceptible vaccinees. After revaccination, reactions should be expected
only in those who failed to respond to the first immunization.
No convincing evidence establishes that any vaccine causes autism
or autistic spectrum disorder. Concern has been raised about a possible
relation between MMR vaccine and autism by some parents of children
with autism. Symptoms of autism often are noticed by parents during
the second year of life and may manifest after administration of MMR
by weeks or months. Two independent nongovernmental groups, the
IOM and the AAP, reviewed the evidence regarding a potential link
between autism and MMR vaccine.328,360,361 Both groups independently
concluded that available evidence does not support an association and
that the United States should continue its current MMR vaccination
policy.
Indications
Unless otherwise contraindicated, measles vaccine is indicated for people
susceptible to measles.38,471 The recommended age for receiving the first

dose of measles vaccine is 12 to 15 months. In high-risk areas, such as
those with recurrent measles transmission, the initial dose should be
administered when the child reaches 12 months of age. The second
dose is given routinely at 4 to 6 years and no later than 11 to 12 years
of age. The minimal interval between the two doses is 4 weeks.
Adults born before 1957 usually can be considered immune to measles
because of previous natural infection. Those born after 1956 and for
whom immunoprophylaxis is indicated should receive two doses of
vaccine.
During outbreaks, when the likelihood of exposure to measles is
high, measles vaccine should be given to infants as young as 6 months.
Seroconversion rates are significantly less for children vaccinated before
reaching 1 year of age than those for older children. Children immunized
before their first birthday then should be revaccinated with MMR at
12 to 15 months of age, with a third dose given according to local policy.
Measles remains endemic in many areas of the world. Although
vaccination against measles is not a requirement for entry into any
country, susceptible children, adolescents, and adults born after 1956
should be offered measles vaccination (usually as MMR) before embark-
ing on international travel. Infants 6 months or older who are traveling
to areas where measles is endemic or epidemic should be vaccinated
before departure and revaccinated at 12 to 15 months. Vaccination of
infants younger than 6 months is not necessary because most young
infants are protected by maternally derived antibodies.
Exposure of susceptible individuals to measles is not a contraindica-
tion to administering vaccination; MMR vaccine given within 72 hours
of exposure may provide protection. For vaccine-eligible people 12
months or older who are exposed to measles, administration of MMR
vaccine is preferable to using immune globulin if administered within
72 hours of initial exposure. If exposure does not result in infection,
immunization will protect against future infection.
MMRV vaccine may be used instead of MMR and varicella vaccine
to implement the recommended two-dose vaccine schedule for children
12 months to 12 years of age. At the time of its licensure, use of MMRV
vaccine was preferred for the first and second doses over separate
injections of equivalent component vaccines (i.e., MMR vaccine and
varicella vaccine), which was consistent with the ACIP’s 2006 general
recommendations on the use of combination vaccines.407
In February 2008, on the basis of preliminary data from two studies
conducted after licensure that suggested an increased risk of febrile
seizures 5 to 12 days after vaccination among children 12 to 23 months
of age who had received the first dose of MMRV vaccine compared
with children the same age who had received the first dose of MMR
vaccine and varicella vaccine administered as separate injections at the
same visit, the ACIP issued updated recommendations regarding MMRV
vaccine use.155 The updated recommendations expressed no preference
for use of MMRV vaccine over separate injections of equivalent com-
ponent vaccines for the first and second doses.
The final results of the two postlicensure studies indicated that among
children 12 to 23 months of age, one additional febrile seizure occurred
5 to 12 days after vaccination per 2300 to 2600 children who had received
the first dose of MMRV vaccine compared with children who had
received the first dose of MMR vaccine and varicella vaccine administered
as separate injections at the same visit.394 Data from postlicensure studies
do not suggest that children 4 to 6 years of age who received the second
dose of MMRV vaccine had an increased risk of febrile seizures after
vaccination compared with children the same age who received MMR
vaccine and varicella vaccine administered as separate injections at the
same visit.395
In June 2009, after consideration of the postlicensure data and other
evidence, the ACIP adopted new recommendations regarding use of
MMRV vaccine for the first and second doses and identified a personal
or family (i.e., sibling or parent) history of seizure as a precaution for
the use of MMRV vaccine.450 For the first dose of measles, mumps,
rubella, and varicella vaccines at 12 to 47 months of age, the MMR
vaccine and varicella vaccine or MMRV vaccine may be used. Providers
who are considering administering MMRV vaccine should discuss the
benefits and risks of vaccination options with the parents or caregivers.
Unless the parent or caregiver expresses a preference for MMRV vaccine,
the CDC recommends that MMR vaccine and varicella vaccine should
CHAPTER 245  Active Immunizing Agents 2565
be administered for the first dose in this age group. For the second dose
of measles, mumps, rubella, and varicella vaccines at any age (i.e., 15
months to 12 years) and for the first dose at an age older than 48
months, use of MMRV vaccine usually is preferred over separate injections
of its equivalent component vaccines (i.e., MMR vaccine and varicella
vaccine). This recommendation is consistent with the ACIP’s 2011 general
recommendations regarding use of combination vaccines, which state
that use of a combination vaccine usually is preferred over its equivalent
component vaccines.408
Precautions and Contraindications
Immunocompromised patients with conditions such as lymphoreticular
or other generalized malignant disease and primary or secondary
immunodeficiency states should not be given live virus, attenuated
measles vaccine.38,471 After cessation of their chemotherapy, these individu-
als usually should not receive measles vaccine for at least 3 months.
However, because the intensity and type of immunosuppressive therapy,
radiation therapy, underlying disease, and other factors determine when
immunologic responsiveness will be restored, arriving at a definitive
recommendation for an interval after cessation of immunosuppressive
therapy when measles vaccine can be safely and effectively administered
often is not possible.
An exception to the contraindication of administering measles vaccine
to immunocompromised patients is asymptomatic HIV-infected patients,
for whom measles vaccination given as MMR at 12 to 15 months of
age is recommended. The need to protect HIV-infected people who are
at increased risk for severe complications if infected with measles has
been balanced against the risk of adverse reactions. Measles vaccine is
not recommended for HIV-infected people with evidence of severe
immunosuppression. A case of progressive measles pneumonitis occurred
in a person with acquired immunodeficiency syndrome (AIDS) and
severe immunosuppression to whom MMR vaccine was administered,126
and morbidity related to measles vaccination has been reported for
people with severe immunosuppression unrelated to HIV infection.
The antibody response to measles vaccine in severely immuno-
compromised HIV-infected people is diminished.58
In the United States, the incidence of measles currently is very low.
Among HIV-infected people who do not have evidence of severe
immunosuppression, no serious or unusual adverse events have been
reported after receiving measles vaccination.470,512,519,615 MMR vaccination
is recommended for all asymptomatic HIV-infected people who do not
have evidence of severe immunosuppression and for whom measles
vaccination would otherwise be indicated. MMR vaccination also should
be considered for all symptomatic HIV-infected people who do not
have evidence of severe immunosuppression.568 Testing asymptomatic
people for HIV is not necessary before administering MMR.17
Systemically absorbed corticosteroids can suppress the immune
system of an otherwise healthy person. However, neither the minimal
dose nor the duration of therapy sufficient to cause immune suppression
is well defined. Although the immunosuppressive effects of corticosteroid
treatment vary, many clinicians consider that a corticosteroid dose
equivalent to or greater than a prednisone dose of 2 mg/kg per day or
a total of 20 mg/day is sufficiently immunosuppressive to raise concern
about the safety of administering live virus vaccines. People who have
received systemic corticosteroids in doses of 2 mg/kg per day or 20 mg
daily or on alternate days for an interval of 14 days or longer should
avoid receiving vaccination with MMR for at least 1 month after cessation
of corticosteroid therapy.471,568 People who have received prolonged or
extensive topical, aerosolized, or other local corticosteroid therapy that
causes clinical or laboratory evidence of systemic immunosuppression
also should avoid receiving vaccination with MMR for at least 1 month
after cessation of therapy.471
The live attenuated measles virus vaccine used for immunization is
not communicable. Contacts of immunocompromised patients
should be vaccinated to prevent the spread of natural measles to these
patients.
Although no direct evidence has demonstrated that measles vaccine
is harmful to a pregnant woman or her fetus, the vaccine should not
be administered to women known to be pregnant or who are considering
becoming pregnant because of the theoretical risk of fetal infection
2566 PART V  Prevention of Infectious Diseases

TABLE 245.11  Suggested Intervals Between Immune Globulin Administration and Measles or
Varicella Vaccination
DOSE
Product and Indication Route U or mL mg/kg Interval (mo)a
RSV monoclonal antibody (Synagis) IM — 15 (monoclonal) None
Tetanus (as TIG) IM 250 U 10 3
Hepatitis A prophylaxis (as IG)
  Contact prophylaxis IM 0.02 mL/kg 3.3 3
  International travel IM 0.06 mL/kg 10 3
Hepatitis B prophylaxis (as HBIG) IM 0.06 mL/kg 10 3
Rabies prophylaxis (as RIG) IM 20 IU/kg 22 4
Varicella prophylaxis (as VariZIG) IM 125 U/10 kg (maximum, 625 U) 20–40 5
Measles prophylaxis (as IG)
 Standard IM 0.25 mL/kg 40 5
  Immunocompromised contact IM 0.50 mL/kg 80 6
Botulinum immune globulin Intravenous (human, as BabyBIG) IV 1.5 mL/kg 75 6
Blood transfusion
  Washed RBCs IV 10 mL/kg Negligible None
  RBCs, adenine-saline added IV 10 mL/kg 10 3
  Packed RBCs IV 10 mL/kg 20–60 5
  Whole blood IV 10 mL/kg 80–100 6
  Plasma/platelet products IV 10 mL/kg 160 7
CMV immune globulin IV 3 mL/kg 150 6
IGIV
  Replacement therapy for immune deficiencies IV — 330–400 8
  Therapy for ITP IV — 400 8
  Varicella prophylaxis — 400 8
  Therapy for ITP IV — 1000 10
  Therapy for ITP or Kawasaki disease IV — 1600–2000 11
a
These intervals should provide sufficient time for decreases in passive antibodies in all children to allow an adequate response to measles or varicella vaccine. Physicians should not
assume that children are fully protected against measles during these intervals. Additional doses of immune globulin or measles vaccine may be indicated after exposure to measles.
BabyBIG, Botulinum immune globulin; CMV, cytomegalovirus; HBIG, hepatitis B immune globulin; IG, immune globulin; IM, intramuscular; ITP, immune thrombocytopenic purpura; IV,
intravenous; IGIV intravenous immune globulin; RIG, rabies immune globulin; RBCs, red blood cells; RSV, respiratory syncytial virus; TIG, tetanus immune globulin; VariZIG, varicella-zoster
immune globulin.
Modified from American Academy of Pediatrics. Active Immunization in People Who Recently Received Immune Globulin and Other Blood Products. In: Kimberlin DW, Brady MT, Jackson
MA, Long SS, editors. Red Book: 2015 Report of the Committee on Infectious Diseases. 30th ed. pp. 38-40, Elk Grove Village, IL: American Academy of Pediatrics; 2015 and Kroger A,
Sumaya C, Pickering L, et al. General recommendations on immunization—recommendations of the Advisory Committee on Immunization Practices (ACIP). MMWR Recomm Rep.
2011;60:1-64.

associated with a live virus vaccine. Women vaccinated with MMR
should avoid conception for 28 days after being vaccinated.139
Because measles vaccination may diminish cutaneous manifestations
of cell-mediated immunity temporarily, a tuberculin test performed
several days to 6 weeks after receiving immunization can yield a false-
negative result. Although natural measles infection can exacerbate
tuberculosis, no evidence indicates that measles vaccination is associated
with such an effect. Tuberculin skin testing is not a prerequisite for
administering measles immunization. If a tuberculin test is indicated,
it should be performed on the day of immunization or postponed for
4 to 6 weeks because measles vaccination may suppress tuberculin
reactivity temporarily.
For people who are allergic to eggs, the risk of having serious allergic
reactions such as anaphylaxis after receiving MMR vaccine is extremely
low, and skin testing with vaccine cannot predict an allergic reaction
to vaccination.38,369,386 Obtaining a skin test is not required before
administering MMR to people who are allergic to eggs. Similarly, the
administration of gradually increasing doses of vaccine is not required.471
Data indicate that most anaphylactic reactions to measles- and mumps-
containing vaccines are not associated with hypersensitivity to egg
antigens but rather to other components of the vaccines, such as the
gelatin stabilizer.311,340,385,419
Children with a history of thrombocytopenic purpura or throm-
bocytopenia may be at risk for clinically significant thrombocytopenia
after receiving immunization with MMR.70,362 The decision to
vaccinate should be based on the benefits of immunity to measles,
mumps, and rubella and the risk of recurrence or exacerbation of the
thrombocytopenia after receiving vaccination or from natural infection
with measles or rubella. For children in whom thrombocytopenia
develops in the month after receiving a dose of measles-containing
vaccine, withholding the second dose of measles vaccine is prudent if
the incidence of measles remains low.
Receipt of antibody-containing blood products (i.e., whole blood,
plasma, or parenteral immune globulin) may interfere with seroconver-
sion in response to the measles vaccine. High doses of immune globulin
preparations can inhibit the immune response to measles vaccine for
3 or more months, depending on the dosage.603 The length of time that
passively acquired antibody persists depends on the concentration and
quantity of the blood product received (Table 245.11).38,471
As with any condition that induces fever during the second year of
life, children predisposed to having febrile seizures may experience
seizures after receiving measles vaccination. Most convulsions that
develop after receiving measles immunization are simple febrile seizures
and occur in children without known risk factors. Febrile seizures that
occur after the administration of vaccinations do not increase the risk
of epilepsy or other neurologic disorders.66 The risk of seizures after
receiving measles vaccination may be increased for children with a
history of convulsions or those with a history of convulsions in first-
degree family members.662 Although the exact risk cannot be determined,
it appears to be low. The recommendation to immunize children with
a personal history of seizures or those with a history of seizures in
first-degree family members is based on factors indicating that the
benefits greatly outweigh the risks. Prophylactic use of anticonvulsants
usually is not feasible because therapeutic concentrations of many

currently prescribed anticonvulsants are not achieved for some time
after the initiation of therapy.
Meningococcal Vaccine
N. meningitidis causes a spectrum of infections, including meningitis,
bacteremia, and rarely bacteremic pneumonia. Meningococcal disease
develops rapidly and is fatal in 10% to 15% of cases. Of patients who
recover, 11% to 19% have permanent hearing loss, neurologic disability,
loss of limbs, or other serious sequelae.
In the United States since the introduction of Hib and pneumococcal
polysaccharide-protein conjugate vaccines for infants, N meningitidis
has become the leading cause of bacterial meningitis in children and
remains an important cause of bacteremia and sepsis.586,686 Disease
most often occurs in previously healthy children 2 years or younger;
the peak incidence occurs among children younger than 1 year.442 Another
peak occurs among adolescents and young adults 16 through 21 years
of age. Historically, college freshman who lived in dormitories and
military recruits in boot camp had a higher rate of disease compared
with people who are the same age and who are not living in such
accommodations.
Close contacts of patients with meningococcal disease are at increased
risk for infection. The attack rate for household contacts is 500 to 800
times the rate in the general population. Patients with persistent comple-
ment component deficiencies (i.e., C5 to C9, properdin, or factor H or
factor D deficiencies) or anatomic or functional asplenia are at increased
risk for invasive and recurrent meningococcal disease. Although surveil-
lance data for cases of meningococcal disease among HIV-infected
persons are limited in the United States, a growing body of evidence
demonstrates an increased risk of meningococcal disease among HIV-
infected people.445
There are 12 known serogroups of N. meningitidis. Six serogroups
(i.e., A, B, C, W, X, and Y) are responsible for invasive human disease.
Serogroups A and X are rare in the United States. Distribution of the
other serogroups in the United States has shifted in the past 2 decades.205
Serogroups B, C, and Y each account for approximately 30% of reported
cases. Approximately three fourths of cases among adolescents and
young adults are caused by serogroups C, Y, or W135. Among infants,
50% to 60% of cases are caused by serogroup B.
For unknown reasons, the incidence of meningococcal disease has
declined since the peak of disease in the late 1990s.205 Approximately
800 to 1200 cases are reported annually in the United States. The decline
began before the implementation of routine adolescent conjugate
polysaccharide meningococcal immunization and has occurred in all
serogroups, including those not included in the available vaccines.
In the United States, the incidences of serogroups C and Y, which
represent most cases of meningococcal disease, are at historic lows.
However, a peak in disease incidence among adolescents and young
adults 16 to 21 years of age has persisted, even after routine vaccination
of adolescents was recommended in 2005. From 2006 through 2010,
the first 5 years after routine use of meningococcal vaccine was recom-
mended, the CDC received reports of approximately 30 cases of serogroup
C and Y meningococcal disease among people who had received the
vaccine. The case-fatality ratio was similar among people who had
received vaccine compared with those who were unvaccinated. Of the
13 reports of breakthrough disease for which data on underlying condi-
tions were available, four people had underlying conditions or behaviors
associated with an increased risk of bacterial infections, including type
1 diabetes mellitus, current smoking, history of bacterial meningitis
and recurrent infections, and aplastic anemia, paroxysmal nocturnal
hemoglobinuria, and receipt of eculizumab, an immune modulator
that blocks complement protein C5.443
Serogroup B disease incidence has declined despite the fact that
serogroup B is not contained in any of the existing conjugate polysac-
charide meningococcal vaccines. Approximately 50 to 60 cases of
serogroup B meningococcal disease occur annually among adolescents
and young adults 11 through 24 years of age in the United States.205
Outbreaks occur in communities and institutions, including childcare
centers, schools, colleges, and military recruit camps. In the United
States, approximately 98% of cases of meningococcal disease are sporadic;
however, outbreaks of meningococcal disease continue to occur.93 From
CHAPTER 245  Active Immunizing Agents 2567
2009 through 2015, there were seven outbreaks of serogroup B meningitis
at US universities that resulted in 43 cases and 3 deaths.
In other parts of the world, the number of cases is much higher.368
In the sub-Saharan African meningitis belt, which extends from Ethiopia
to Senegal, peaks of serogroup A meningococcal disease occur regularly
during the dry season. Major epidemics occur every 8 to 12 years. In
each epidemic, tens of thousands of cases and thousands of deaths can
occur. Approximately 350 million people are at risk. The phased introduc-
tion of MenAfriVac, a novel serogroup A meningococcal conjugate
vaccine that is being implemented through preventive national campaigns
in meningitis belt countries for all individuals 1 to 29 years of age,
holds great promise to end epidemic meningitis.406
Meningococcal disease continues to cause epidemics outside the
meningitis belt.368 Serogroup W135 has emerged as an epidemic strain
causing disease in Saudi Arabia in association with the Hajj pilgrimage.
Since 2002, serogroup W meningococcal disease has also been reported
in sub-Saharan African countries during epidemic seasons. More recently,
serogroup W outbreaks have occurred in South America. Serogroup X,
previously a rare cause of sporadic meningitis, has been responsible
for outbreaks between 2006 and 2010 in Kenya, Niger, Togo, Uganda,
and Burkina Faso.705 Prolonged outbreaks of serogroup B meningococcal
disease have occurred in New Zealand, France, and Oregon. Serogroup
Y emerged in Colombia and Venezuela, where it became the common
disease-causing serogroup in 2006.571
Preparations
MenACWY vaccines.  Four meningococcal vaccines that contain purified
capsular polysaccharide alone or that are conjugated to a carrier protein
are licensed and available in the United States for the prevention of
invasive disease caused by N. meningitidis serogroups A, C, W135, and
Y (Table 245.12).
Quadrivalent meningococcal polysaccharide vaccine (MPSV4;
Menomune, Sanofi Pasteur) was licensed in 1981 for use in children 2
years or older. Each vaccine dose contains 50 mg of each of the four
purified bacterial capsular polysaccharides from serogroups A, C, Y,
and W135. MPSV4 is available as a single dose or multidose (10-dose)
vial of lyophilized vaccine, with a corresponding single-dose or multidose
vial of diluent. After reconstitution of the lyophilized vaccine with the
diluent, each dose consists of a 0.5-mL solution for injection. Vaccine
supplied in single-dose vials should be used immediately after reconstitu-
tion. Vaccine supplied in multidose vials may be used for up to 35 days
after reconstitution if stored at 2°C to 28°C (35°F–46°F). MPSV4 is
administered subcutaneously and can be given concurrently with other
vaccines but at different anatomic sites.
Two meningococcal conjugate vaccines (i.e., MenACWY-D [Menactra,
Sanofi Pasteur] and MenACWY-CRM [Menveo, Novartis Vaccines]) are
licensed for use in people 2 through 55 years of age. MenACWY-D is a
liquid solution supplied in 0.5-mL single-dose vials. Each dose contains
4 µg each of the four capsular polysaccharides from serogroups A, C, Y,
and W135 conjugated to 48 µg of diphtheria toxoid. MenACWY-CRM
consists of two components: 10 µg of lyophilized meningococcal serogroup
A capsular polysaccharide conjugated to CRM197 (MenA) and 5 µg each
of capsular polysaccharide of serogroup C, Y, and W135 conjugated to
CRM197 in 0.5 mL of phosphate buffered saline, which is used to recon-
stitute the lyophilized MenA component before injection. The reconstituted
vaccine should be used immediately but may be held at or below 25°C
(77°F) for up to 8 hours. Meningococcal conjugate vaccines are administered
intramuscularly as a single 0.5-mL dose and can be given concurrently
with other recommended vaccines. Limited data suggest that different
conjugate vaccine products can be used interchangeably.204
MenACWY-D and MenACWY-CRM are also licensed for infants
but with different administration schedules. MenACWY-D is licensed
as a two-dose primary series, 3 months apart, for children 9 through
23 months of age. MenACWY-CRM is licensed for use in children 2
through 23 months of age. For children initiating vaccination at 2 months
of age, MenACWY-CRM is administered as a four-dose series at 2, 4,
6, and 12 months of age. For children initiating vaccination at 7 months
through 23 months of age, MenACWY-CRM is administered as a two-
dose series with the second dose administered in the second year of
life and at least 3 months after the first dose.
2568 PART V  Prevention of Infectious Diseases

TABLE 245.12  Licensed Meningococcal Vaccines—United States, 1981–2015

Formulation Type Trade Name Manufacturer Licensed (y) Age Group Doses Serogroups
MPSV4a
Polysaccharide Menomune Sanofi Pasteur 1981 ≥2 y Single dose A, C, W, and Y
MenACWY-Db Conjugate Menactra Sanofi Pasteur 2005 11–55 y Single dose A, C, W, and Y
MenACWY-Db Conjugate Menactra Sanofi Pasteur 2007 2–10 y Single dose A, C, W, and Y
MenACWY-Db Conjugate Menactra Sanofi Pasteur 2011 9–23 mo 2-dose series A, C, W, and Y
MenACWY-CRMc Conjugate Menveo Novartis 2010 11–55 y Single dose A, C, W, and Y
MenACWY-CRMc Conjugate Menveo Novartis 2011 2–10 y Single dose A, C, W, and Y
MenACWY-CRMc Conjugate Menveo Novartis 2011 2–23 mo 4-dose series A, C, W, and Y
Hib-MenCY-TTd Conjugate MenHibrix GlaxoSmithKline 2012 6 wk–18 mo 4-dose series C and Y
MenB-FHbpe Recombinant Trumenba Wyeth 2014 10–25 y 3-dose series B
MenB-FHbpe Recombinant Trumenba Wyeth 2014 10–25 y 2-dose series B
MenB-4Cf Recombinant Bexsero Novartis 2015 10–25 y 2-dose series B
a
Package insert available at http://www.fda.gov/downloads/BiologicsBloodVaccines/Vaccines/ApprovedProducts/UCM308370.pdf.
b
Package insert available at http://www.fda.gov/downloads/BiologicBloodVaccines/Vaccines/ApprovedProducts/UCM131170.pdf.
c
Package insert available at http://www.fda.gov/downloads/BiologicsBloodVaccines/Vaccines/ApprovedProducts/UCM201349.pdf.
d
Package insert available at http://www.fda.gov/downloads/BiologicsBloodVaccines/Vaccines/ApprovedProducts/UCM308577.pdf.
e
Package insert available at http://www.fda.gov/downloads/BiologicsBloodVaccines/Vaccines/ApprovedProducts/UCM421139.pdf.
f
Package insert available at http://www.fda.gov/downloads/BiologicsBloodVaccines/Vaccines/ApprovedProducts/UCM431447.pdf.

In June 2012, a combination conjugate vaccine against Hib (i.e.,
PRP-T) and N. meningitidis serogroups C and Y (i.e., Hib-MenCY-TT
[MenHibrix, GlaxoSmithKline]) was licensed. Hib-MenCY-TT contains
5 µg of N. meningitidis serogroup C capsular polysaccharide, 5 µg of
N. meningitidis serogroup Y capsular polysaccharide, and 2.5 µg of
Haemophilus influenzae serogroup B capsular polysaccharide, with each
conjugated to tetanus toxoid. The vaccine is lyophilized and should be
reconstituted with a 0.9% saline diluent . After reconstitution of the
lyophilized vaccine with the diluent, each dose consists of a 0.5-mL
solution for injection. Hib-MenCY-TT is administered intramuscularly
and is approved as a four-dose series for children at 2, 4, 6, and 12
through 18 months.
MenB vaccines.  In October 2014, the first serogroup B meningococcal
vaccine, MenB-FHbp (Trumenba, Wyeth Pharmaceuticals) was licensed.
A second serogroup B vaccine, MenB-4C (Bexero, Novartis Vaccines),
was licensed in January 2015 (see Table 245.12). Both vaccines are
licensed for use in people 10 through 25 years of age.
MenB-FHbp is a bivalent vaccine consisting of two recombinant
lipidated factor H binding protein (FHbp) antigens, one from
FHbp subfamily A and one from subfamily B. FHbp is one of many
proteins found on the surface of meningococci and contributes to the
ability of the bacterium to avoid host defenses. The FHbp proteins are
individually produced in Escherichia coli. Each 0.5-mL dose contains
60 µg of each FHbp variant, 0.018 mg of polysorbate 80, and 0.25 mg
of Al3+ as AlPO4 in 10 mM histidine buffered saline at pH 6.0. The vaccine
is administered as a 0.5-mL dose intramuscularly. MenB-FHbp is licensed
as for a three-dose series and a two-dose series. In April 2016, the FDA
approved a label change giving MenB-FHbp a flexible three-dose schedule
of 0, 1 to 2 months, and 6 months and a two-dose schedule of 0 and 6
months.
MenB-4C is a multicomponent vaccine consisting of three recom-
binant proteins (i.e., neisserial adhesion A [NadA], factor H binding
protein [FHbp] fusion protein, and neisserial heparin binding
antigen [NHBA] fusion protein) and outer membrane vesicles (OMVs)
containing outer membrane protein PorA serosubtype P1.4 (i.e.,
New Zealand epidemic strain N298/254). The three recombinant
proteins are individually produced in E. coli. The OMV antigenic
component is produced by fermentation of N. meningitidis strain
NZ98/254 (expressing outer membrane protein PorA serosubtype P1.4),
followed by inactivation of the bacteria by deoxycholate, which also
mediates vesicle formation. The antigens are adsorbed onto aluminum
hydroxide. Each 0.5-mL dose of MenB-4C contains 50 µg each of
recombinant proteins NadA, NHBA, and FHbp; 25 µg of OMV; 1.5 mg
of aluminum hydroxide (0.519 mg of Al3+);, 3.125 mg of sodium
chloride; 0.776 mg of histidine; and 10 mg of sucrose at pH 6.4 to
6.7. The vaccine is administered as a 0.5-mL dose intramuscularly.
MenB-4C is licensed as a two-dose series, with doses administered at
least 1 month apart.
Immunogenicity and Efficacy
MenACWY vaccines.  The polysaccharide capsule of N meningitidis
is an important determinant of virulence. Serum antibody to capsular
polysaccharide protects against disease by activating complement-
mediated bacteriolysis or opsonization, or both. Complement-dependent
bactericidal activity induced by immunization with meningococcal
vaccine is measured by use of a serum bactericidal antibody assay
with a human (hSBA) complement source. A defined bactericidal
antibody titer that indicates protection against invasive meningococcal
disease is assay dependent. When sera are tested using a human
complement source, SBA titers of 1 : 4 or higher are considered
protective. Studies have demonstrated that almost all people who
developed invasive serogroup C meningococcal disease had sera that
lacked bactericidal activity to the pathogenic meningococcal strain.304,307
In contrast, people with detectable SBA against a specific strain rarely
developed disease.
The characteristics of MPSV4 are similar to other polysaccharide
vaccines (e.g., pneumococcal polysaccharide). The vaccine is usually
not effective in children younger than 18 months. The response to the
vaccine is typical of a T-cell independent antigen, with an age-dependent
response and poor immunogenicity in children younger than 2 years.
Little boost in antibody titer occurs with repeated doses; the antibody
that is produced is relatively low-affinity IgM, and switching from IgM
to IgG production is poor.
Protective antibody concentrations are achieved within 10 to 14
days of administration of MPSV4. The vaccine elicits protective levels
of bactericidal antibody to all four serogroups in more than 97% of
recipients as measured at 28 days after vaccination. The antibody
responses to each of the four polysaccharides in the polysaccharide
vaccine are serogroup specific and independent. Group A polysaccharide
induces antibody in some children as young as 3 months, although a
response comparable to that in adults is not achieved until the child is
4 to 5 years of age.531 The serum antibody response to serogroup C is
age dependent, with a poor response in children younger than 2 years.303
Serum concentrations of antibodies against group A and C polysac-
charides decrease markedly during the first 3 years after receipt of a
single dose of vaccine. The decrease in antibody occurs more rapidly
in infants and young children than in adults.384,712
Field trials of A and C meningococcal vaccines in Europe and Africa
have demonstrated efficacy rates against serogroup A of 85% to 95%
1 year after vaccination.531,667 After 3 years, efficacy rates were 67% for
older children but only 10% for children younger than 4 years at the
time of immunization with serogroup A vaccine.553 In an epidemic,

serogroup C vaccine demonstrated clinical efficacy rates similar to those
for the serogroup A vaccine.633
Serogroup Y and W135 antigens are immunogenic and safe in children
older than 2 years. However, clinical efficacy has not been demonstrated
for these preparations.12,57,664
People with deficiencies of the terminal components of serum
complement and those with anatomic or functional asplenia have
antibody responses to quadrivalent meningococcal vaccines consistent
with protection.565,567 However, the clinical efficacy of vaccination has
not been evaluated in these people.
Meningococcal conjugate vaccines prime the immune system, and
immunologic memory persists even in the absence of detectible bac-
tericidal antibodies. Although vaccine-induced immunologic memory
often protects against infection with other encapsulated bacteria such
as Hib, detectable circulating antibody appears to be important for
protection against N. meningitidis.304 Effectiveness of the three menin-
gococcal conjugate vaccines, which were licensed after MPSV4, was
inferred by comparing SBA responses induced by the new vaccines
compared with SBA responses induced by MPSV4 in people 2 through
55 years of age or by achieving a seroresponse at or above a predefined
bactericidal antibody titer among children 2 through 23 months of age.
Protective antibody concentrations are achieved within 8 days after
administration of MenACWY-D.78 In studies conducted among people
11 to 55 years of age comparing the immunogenicity of conjugate vaccine
with that of the polysaccharide vaccine at 28 days after vaccination, the
percentage of those achieving at least a fourfold increase in bactericidal
titer for each serogroup was higher in the MPSV4 group than in the
MenACWY-D group for people older than 18 years. Nonetheless, the
criteria for demonstrating immunologic noninferiority to MPSV4 were
still achieved. The percentage of those with at least a fourfold rise was
highest for serogroup W135 and lowest for serogroup Y. The percentage
of people achieving a protective level of bactericidal antibody was greater
than 97% for all serogroups in the MenACWY-D and MPSV4 groups.
Response to revaccination with MenACWY-D was assessed by
administering MenACWY-D to people previously vaccinated with MPSV4
or MenACWY-D and to vaccine- naïve control subjects. All people in all
three groups achieved protective bactericidal antibody titers at 8 and 28
days after receiving MenACWY-D. Those initially primed with MenACWY-
D achieved higher bactericidal antibody concentrations than those of
the naïve controls for all serogroups except A. In contrast, bactericidal
antibody titers of those primed with MPSV4 were lower than those of
vaccine-naïve controls on days 8 and 28 for all serogroups.
In study participants 11 to 18 years of age, noninferiority of
MenACWY-CRM to MenACWY-D was demonstrated for all four
serogroups.166 The proportions of people with seroresponses were statisti-
cally higher for serogroups A, W, and Y in the MenACWY-CRM group,
compared with the MenACWY-D group. The clinical relevance of higher
postvaccination immune responses is not known.
The immunogenicity of MenACWY-CRM in children 2 through 10
years of age was evaluated in a multicenter, randomized, controlled
trial.327 After a single MenACWY-CRM dose, seroresponses to group
C, Y, and W135 in children 2 through 5 years and 6 through 10 years
of age were noninferior to responses after a single MenACWY-D dose.
MPSV4 is administered subcutaneously, whereas MCV4 is admin-
istered intramuscularly. More than 100 people have inadvertently received
the MCV4 vaccine by the subcutaneous route. For a subset of these
individuals, the CDC determined that although the serologic responses
were lower after MCV4 was administered subcutaneously compared
with intramuscularly, the proportions of individuals who achieved
antibody levels thought to be protective were similar. The CDC therefore
did not recommend that those who had received MCV4 needed to be
reimmunized.149
In clinical trials Hib-MenCY-TT was coadministered with DTaP-
HepB-IPV and 7-valent pneumococcal conjugate vaccine (PCV7) at
ages 2, 4, and 6 months and with MMR, varicella, and PCV7 vaccines
at 12 to 15 months of age. No decreased immunogenicity of coadmin-
istered vaccines was observed.96,460 A randomized, controlled, multicenter
study evaluated the percentage of subjects with hSBA titers of 1 : 8 or
higher at 2 months after the second dose was administered at 4 months
of age. In the group vaccinated with Hib-MenCY-TT, 94% and 83% of
CHAPTER 245  Active Immunizing Agents 2569
children achieved hSBA antibody titers of 1 : 8 or higher for meningococ-
cal serogroups C and Y, respectively, after the second dose.507
When the MenACWY-D vaccine was licensed in 2005, some experts
predicted that the vaccine would be effective for up to 10 years, providing
protection through the period of highest risk in late adolescence and
early adulthood. Since the 2005 ACIP recommendations, additional
data have improved our understanding of meningococcal conjugate
vaccines, including the duration of vaccine-induced immunity. Antibody
persistence studies indicate that circulating antibody declines 3 to 5
years after a single dose of MenACWY-D or MenACWY-CRM.296,388,665
Results from a vaccine effectiveness study demonstrate waning effective-
ness, and many adolescents are not protected 5 years after vaccination.203
ACIP concluded that a single dose of meningococcal conjugate vaccine
administered at age 11 or 12 years is unlikely to protect most adolescents
through the period of increased risk at ages 16 through 21 years. On
the basis of this information, in 2011, ACIP recommended adding a
booster dose at 16 years of age.169
MenB vaccine.  The immunogenicity of both serogroup B meningococ-
cal vaccines (i.e., MenB-4C and MenBFHbp) has been evaluated in
numerous published clinical trials.391,461,546,556,576,575,591,640 Both vaccines
appear to provide short-term immunogenicity in healthy populations.
Studies on vaccine efficacy are not available. Licensure was based on
the ability of the vaccines to elicit detection of bactericidal antibody
that is presumed to indicate protection. Studies regarding antibody
persistence are limited. Immunogenicity studies in populations at
increased risk for invasive meningococcal disease have not been
completed.
MenB-FHbp has been administered concomitantly with the following:
quadrivalent human papillomavirus (HPV) vaccine591 but not 9-valent
HPV vaccine, with MenACWY (unpublished data), and with Tdap
vaccine (Adacel, Sanofi Pasteur [unpublished data]).
Adverse Events
MenACWY vaccines.  MPSV4 has been used extensively in mass-
immunization programs and in the military and among international
travelers. Adverse reactions to MPSV4 usually are mild; the most frequent
reactions are pain and redness at the injection site that last for 1 or 2
days.62 Estimates of the incidence of local reactions range from 4% to
56%. Transient fever occurs in as many as 5% of vaccine recipients in
some studies but is less common in older children and adults.
The most frequently adverse events reported to VAERS for MenACWY-
D include fever (16.8%), headache (16.0%) injection-site erythema
(14.6%), and dizziness (13.4%). Syncope has been identified as an adverse
event after any vaccination, with a higher proportion of syncope events
reported to VAERS occurring in adolescents than other age groups.154
Syncope was listed in 10% of reports involving MenACWY-D. Twenty-
four deaths (0.3%) were reported.
The most frequently reported adverse events for MenACWY-CRM
were injection-site erythema (19.7%) and injection site swelling (13.7%).
Syncope was listed in 8.8% of reports involving MenACWY-CRM. One
death (0.4%) was reported.
Rates of local and systemic adverse events observed after administra-
tion of Hib-MenCY-TT were comparable to rates observed after
administration of Hib-TT. Hib-MenCY-TT was found to be safe and
immunogenic for Hib and meningococcal serogroups C and Y.
MenB vaccine.  The safety of both serogroup B meningococcal vaccines
(i.e., MenB-4C and MenBFHbp) have been evaluated in numerous
published clinical trials.391,461,556,575,591,597 There were no deaths considered
to be related to either vaccine. The most frequently reported severe
local and systemic adverse events for MenB-4C include injection site
pain (20–29%), fever of 38°C or higher (1–5%), headache (4–6%),
fatigue (4–6%), myalgias (12–13%), and joint pain (2%). For MenBFHbp,
the most frequently reported severe local and systemic adverse events
include injection site pain (5–8%), fever of 38°C (2–8%), headache
(1%), fatigue (1–4%), myalgias (1–3%), and joint pain (1%).
Indications
Meningococcal polysaccharide vaccine.  Routine vaccination of civilians
with MPSV4 is not recommended.204 Use of MPSV4 should be limited
to people older than 55 years or when MenACWY is not available.
2570 PART V  Prevention of Infectious Diseases

TABLE 245.13  Recommended Meningococcal TABLE 245.14  Meningococcal Vaccine

Vaccines for Immunocompetent Children Recommendations by Risk Group
Age Vaccine Status MenACWY Vaccines MenB Vaccines
2 mo–10 y MenACWY-Da Not routinely recommended Complement deficiencya Complement deficiencya
MenACWY-CRMb Anatomic or functional aspleniab Anatomic/functional aspleniab
HibMenCY-TTc Outbreakc Outbreakc
10–25 y MenB-FHbp Not routinely recommended Microbiologistsd Microbiologistsd
or HIV infection
MenB-4C Travelerse
11–21 y MenACWY-D Primary: First-year college studentsf
or Age 11–12 y: 1 dose
Military recruits
MenACWY-CRM Age 13–18 y: 1 dose if not
previously immunized a
Inherited or chronic deficiencies of C3, C5–C9, properdin, factor D, or factor H or those
Age 19–21 y: not routinely receiving eculizumab.
b
recommended but may be given as Includes sickle cell disease.
c
catch-up immunization for those The CDC defines outbreaks and those at risk.
d
who have not received a dose Only microbiologists who routinely work with N meningitidis.
e
To areas with hyperendemic or epidemic meningococcal disease.
after their 16th birthday f
Unvaccinated or inadequately vaccinated first-year college students who live in
Booster: residence halls.
1 dose recommended for adolescents Modified from Committee on Infectious Diseases, American Academy of Pediatrics.
if first dose administered before Recommendations for serogroup B meningococcal vaccine for persons 10 years and older.
16th birthday Pediatrics. 2016;138:e20161890.
a
Licensed only for people 9 mo to 55 y.
b
Licensed only for people 2 mo to 55 y.
c
Licensed only for children 6 wk to 18 mo. children with meningococcal conjugate vaccines are shown in Table
Modified from American Academy of Pediatrics. Meningococcal infections. In: Kimberlin 245.15.28,39,204,445
DW, Brady MT, Jackson MA, Long SS, eds. Red Book: 2015 Report of the Committee on MenB vaccines.  Routine vaccination with meningococcal serogroup
Infectious Diseases. 30th ed. Elk Grove Village, IL: American Academy of Pediatrics; B vaccine is recommended for those 10 years or older who are at increased
2015:547–58. risk for serogroup B disease (see Tables 245.14 and 245.15), including
the following groups: (1) people with persistent complement component
diseases, including inherited or chronic deficiencies in C3, C5-C9,
Meningococcal conjugate vaccines.  Routine childhood immunization properdin, factor D, or factor H, and people receiving eculizumab; (2)
with meningococcal conjugate vaccine (i.e., MenACWY) is recommended people with anatomic or functional asplenia, including sickle cell disease;
for adolescents 11 through 18 years of age, but it is not recommended and (3) healthy people who are at increased risk because of a serogroup
for children 2 months through 10 years of age because the infection B meningococcal disease outbreak.211,276,444 The AAP and the CDC do
rate is low for this age group; the immune response is less robust than not express a preference for the two licensed vaccines, but the same
in older children, adolescents, and adults; and duration of immunity product must be used for the entire series.
is unknown.28,39,204 Recommendations for routine use of MenACWY in A three-dose schedule for MenB-FHbp is recommended for people
adolescents are shown in Table 245.13 and are as follows:28,39,204 at increased risk for meningococcal serogroup B disease. For healthy
• Adolescents should be immunized routinely at the 11- to 12-year people 16 to 23 years of age who are not at increased risk for meningococ-
of age health care visit, when immunization status and other preven- cal serogroup B disease, the ACIP has a permissive recommendation
tive health services can be addressed. A booster dose at 16 years of that allows use of one of the meningococcal serogroup B vaccines if
age is recommended for adolescents immunized at 11 through 12 the patient desires to be immunized.211,444 If an adolescent so chooses
years of age. and MenB-FHbp is selected, the ACIP recommends a two-dose schedule.
• Adolescents 13 through 18 years of age should be immunized routinely If a patient receives a second dose of MenB-FHbp less than 6 months
with a meningococcal conjugate vaccine if not previously immunized. after the first dose, a third dose should be given at least 6 months after
Adolescents who receive the first dose at 13 through 15 years of age the first.
should receive a one-time booster dose at 16 through 18 years of
age. Postexposure Immunoprophylaxis
• Adolescents who receive their first dose of meningococcal conjugate Because secondary cases can occur several weeks or more after onset
vaccine at or after 16 years of age do not need a booster dose unless of disease in the index case, meningococcal vaccine is an adjunct to
they have risk factors. chemoprophylaxis when an outbreak is caused by a serogroup prevented
• People 19 to 21 years of age are not routinely recommended to by a meningococcal vaccine. For control of meningococcal outbreaks
receive meningococcal conjugate vaccine, but vaccine may be caused by vaccine-preventable serogroups (i.e., A, C, Y, and W135), the
administered as a catch-up dose for those who have not received a preferred vaccine for adults and children 2 years and older is a menin-
dose after their 16th birthday. gococcal conjugate vaccine (i.e., MenACWY).204 For outbreaks caused
The ACIP and the AAP recommend routine use of meningococcal by serogroup B meningococcal disease, vaccination with a serogroup
conjugate vaccines (e.g., MenACWY) for people 2 months or older who B meningococcal vaccine is recommended for those 10 years or older
have certain medical conditions that increase the risk of meningococcal identified as being at increased risk because of the outbreak.178
disease, including those who have persistent (e.g., genetic) deficiencies
in the complement pathway (e.g., C3, properdin, factor D, factor H, Precautions and Contraindications
C5-C9), people receiving eculizumab (because the drug binds C5 Vaccination with MenACWY, MPSV4, or Hib-MenCY-TT is contrain-
and inhibits the terminal complement pathway), and people with dicated for people known to have a severe allergic reaction to any
functional or anatomic asplenia, including people with sickle cell component of the vaccine, including diphtheria or tetanus toxoid. The
disease (Table 245.14).28,39,204 In 2016, the ACIP recommended ACIP does not consider a history of Guillain-Barré syndrome to be a
that people 2 months or older with HIV infection also be given menin- contraindication or precaution for meningococcal vaccination.204 Because
gococcal conjugate vaccines based on data indicating an increased risk MenACWY, MPSV4, and Hib-MenCY-TT are inactivated vaccines, they
of disease.445 Specific recommendations for immunization of high-risk can be administered to people who are immunosuppressed as a result
 CHAPTER 245  Active Immunizing Agents 2571

TABLE 245.15  Recommended Immunization Schedule and Intervals for Children at Risk for
Invasive Meningococcal Diseasea
Age Subgroup Primary Immunization Booster Doseb
c
2–18 mo Children who have persistent complement 4 doses of HibMenCY-TT at 2, Person remains at increased risk and
deficiencies, have functional or anatomic asplenia 4, 6, and 12–15 moc first dose received at following age:
are at risk during a community outbreak For 2 mo–6 y of age: should receive
attributable to a vaccine serogroup additional dose of MenACWY 3 y after
2–23 mo with Children who have persistent complement 4 doses of MenACWY-CRM primary immunization; boosters should
high-risk conditions deficiencies, have functional or anatomic asplenia, (Menveo) at 2, 4, 6, and be repeated every 5 y thereafter
have HIV, travel to or are residents of countries 12 mo For ≥7 y of age: should receive
where meningococcal disease is hyperendemic or additional dose of MenACWY 5 y after
epidemic are at risk during a community outbreak primary immunization; boosters should
attributable to a vaccine serogroup be repeated every 5 y thereafter
9–23 mo with Children who have persistent complement 2 doses of MenACWY
high-risk conditions deficiencies, travel to or are residents of countries (Menactra), 12 wk apartd
where meningococcal disease is hyperendemic or
epidemic are at risk during a community outbreak
attributable to a vaccine serogroup
2–55 y with high-risk People who have persistent complement deficiencies, 2 doses of MenACWY, 8–12 wk
conditions and not have functional or anatomic asplenia, have HIV apart
immunized People who travel to or are residents of countries 1 dose of MenACWYe
previouslye,f where meningococcal disease is hyperendemic or
epidemic are at risk during a community outbreak
attributable to a vaccine serogroup
≥10 y with high-risk People who have persistent complement deficiencies, 2 doses of MenB-4C 4 wk apart —
conditions have functional or anatomic asplenia are at risk or
during a community outbreak attributable to a 3 doses of MenB-FHbp
vaccine serogroup administered at 0, 2 and 6 mo
a
Includes children who have persistent complement deficiencies (e.g., C5–C9, properdin, factor H or factor D) and anatomic or functional asplenia; travelers to or residents of countries in
which meningococcal disease is hyperendemic or epidemic; and children who are part of a community outbreak of a vaccine-preventable serogroup.
b
If child remains at increased risk of meningococcal disease.
c
Infants and children who received Hib-MenCY-TT and are traveling to areas with highly endemic rates of meningococcal disease, such as the African “meningitis belt,” are not protected
against serogroups A and W and should receive a quadrivalent meningococcal vaccine licensed for children age ≥2 mo before travel.
d
Because of high risk of invasive pneumococcal disease, children with functional or anatomic asplenia should not be immunized with MenACWY-D (Menactra) before age 2 y to avoid
interference with the immune response to the pneumococcal conjugate vaccine (PCV) series.
e
If MenACWY-D is used, administer at least 4 weeks after completion of all PCV doses.
f
If an infant is receiving the vaccine before travel, two doses can be administered as early as 2 months apart.
Modified from American Academy of Pediatrics. Meningococcal Infections. In: Kimberlin DW, Brady MT, Jackson MA, Long SS, eds. Red Book: 2015 Report of the Committee on Infectious
Diseases. 30th ed. Elk Grove Village, IL: American Academy of Pediatrics; 2015:547–58.

of disease or medications; however, response to the vaccine may be less
than optimal.
No RCTs have been conducted primarily to evaluate use of MPSV4
or MenACWY vaccines in pregnant or lactating women. VAERS reports
of exposure to MPSV4 during pregnancy have not identified adverse
effects among pregnant women or newborns of women vaccinated
during pregnancy. From the VAERS reports available for women found
to be pregnant at the time of MenACWY-D vaccination, no major
safety concerns associated with vaccination have been identified in the
mother or fetus. Pregnancy should not preclude vaccination with
MenACWY or MPSV4, if indicated.204 Women of childbearing age who
become aware that they were pregnant at the time of MenACWY vac-
cination should contact their health care provider or the vaccine
manufacturer so that their experience can be captured in the manu-
facturer’s registry of vaccination during pregnancy.
Before administering MenB vaccines, treating clinicians should consult
the package insert for a full list of precautions, warnings, and contra-
indications.211,444 Pregnancy and breastfeeding are precautions because
neither vaccine has been evaluated in these situations. A severe allergic
reaction to a previous dose of MenB vaccine or any of its components
is a contradiction.
Mumps Vaccine
Live virus mumps vaccine became available in the United States in 1967
and was recommended for routine use in 1977. The incidence of reported
mumps cases decreased rapidly after vaccine licensure until 1986 through
1987, when a resurgence of mumps occurred resulting in 20,638 reported
cases.111,199 The resurgence was attributed to a susceptible cohort of
adolescents and young adults entering high school and college who
were not targeted for vaccination and spared from natural infection by
declining disease rates. In 1989, the ACIP and AAP implemented a
two-dose combined MMR schedule given at 4 to 6 or at 11 to 12 years
of age.110 By the early 2000s, on average, fewer than 270 cases were
reported annually, and seasonal peaks were no longer seen.67
Before vaccine licensure in 1967 and during the early years of vaccine
use, most reported cases occurred in the 5- to 9-year age group, with
90% of cases occurring among children 15 years of age and younger.
In the late 1980s, a shift toward older children occurred. Since 1990,
people 15 years or older have accounted for 30% to 40% of cases per
year.
In 2006, an outbreak of 6584 cases occurred and was centered on
highly two-dose vaccinated college students in the American Midwest.229
The 2006 outbreak underscored limitations in the 1998 recommendations
about prevention of mumps transmission in health care and other
settings with a high risk of mumps transmission. After reviewing data
from this outbreak and previous evidence of mumps vaccine effectiveness
and transmission, the ACIP issued updated recommendations, specifying
that all children and adults in certain high-risk groups, including students
at post–high school educational institutions, health care personnel, and
international travelers, should receive two doses of mumps-containing
vaccine.110 In the next 2 years, the number of reported cases returned
to usual levels, and outbreaks involved fewer than 20 cases.
Outbreaks have continued to occur, particularly in high-density,
close-contact settings, despite high two-dose coverage. Because two
2572 PART V  Prevention of Infectious Diseases
doses of mumps-containing vaccine are not 100% effective, most mumps
cases in settings of high immunization coverage such as the United
States most often occur among people who have received two doses.
In the 2009–10 season, a large outbreak occurred in the northeastern
United States, affecting more than 3500 people, primarily members of
traditional observant communities in New York and New Jersey.163 There
was also an outbreak in the US territory of Guam, with 505 cases
reported.500 Most patients had received two doses of MMR vaccine and
were exposed in communal settings. In 2011 through 2013, there were
several smaller mumps outbreaks reported on college campuses in
California,173 Virginia, and Maryland. However, they had limited spread,
and national case counts for these years were at several hundred cases
per year.
In 2014, several outbreaks affiliated with universities were reported
from multiple states, including one community outbreak in Ohio linked
to a university that involved over 400 people and an outbreak affecting
the National Hockey League. Outbreaks have been reported from several
university campuses in 2015 through 2016, including a number of smaller
outbreaks with limited spread. The two largest outbreaks were from
Iowa and Illinois, each involving several hundred university students;
both held wide-scale vaccination campaigns that included providing a
third dose of MMR as a control measure.7
In 2016, the greatest number of mumps cases since the outbreaks
of 2006 was reported. These outbreaks involved 45 states and more
than 2800 individuals. Six states (i.e., Arkansas, Illinois, Indiana, Iowa,
Massachusetts, and Oklahoma) reported more than 100 cases in 2016.
Preparations
The live attenuated mumps virus vaccine (i.e., Jeryl Lynn strain) used
in the United States is prepared in chick embryo cell culture and is
available in combination as MMR and MMRV. The AAP and ACIP
recommend that combined MMR vaccine be used when any of the
individual components is indicated, and MMRV is recommended if
the vaccinee is 12 months through 12 years of age.
Each dose of vaccine contains neomycin, sorbitol, and hydrolyzed
gelatin as stabilizers. Before reconstitution, MMR vaccine must be stored
at 2°C to 8°C (35.6°F–46.4°F) or colder and protected from light to
avoid inactivation. After reconstitution, the vaccine should be used
within 8 hours or discarded.
Immunogenicity and Efficacy
The vaccine induces an asymptomatic, noncommunicable infection.
After vaccination with MMR vaccine, approximately 94% of infants
and children develop detectable mumps antibodies with (range,
89–97%).85,254,264,396,425,544,548,588,589,647,648 Vaccination induces relatively low
levels of antibodies compared with natural infection.347,675 After a second
dose of MMR vaccine, most people mounted a secondary immune
response, approximately 50% had a fourfold increase in antibody titers,
and the proportion with low or undetectable titers was significantly
reduced from 20% before vaccination with a second dose to 4% at 6
months after vaccination.92,306,422
Although antibody measurements are often used as a surrogate measure
of immunity, no serologic tests are available for mumps that consistently
and reliably predict immunity. The immune response to mumps vaccina-
tion probably involves the humoral and cellular immune response, but
no definitive correlates of protection have been identified.
Clinical studies conducted before vaccine licensure involving
approximately 7000 children found a single dose of mumps vaccine to
be approximately 95% effective in preventing mumps disease.348,624,675
However, vaccine effectiveness estimates have been lower in postlicensure
studies. The median vaccine effectiveness against mumps has been
estimated at 78% for one dose and 88% for two doses.471 In the United
States, estimated vaccine effectiveness for one dose of mumps-containing
vaccine is between 81% and 91% in junior high and high school set-
tings180,183,341,389,626,684 and between 64% and 76% among household or
close contacts.452,626 Population and school-based studies conducted in
Europe and Canada report comparable estimates of 49% to 92% for
vaccine effectiveness.104,181,202,233,241,335,431,555,584,612,641
Fewer studies have been conducted to assess the effectiveness of two
doses of mumps-containing vaccine. In the United States, outbreaks
among populations with high two-dose coverage found two doses of
mumps-containing vaccine to be 80% to 92% effective in preventing
clinical disease.452,581 In the 1988 through 1989 outbreak among junior
high school students, the risk of mumps was five times higher for students
who received one dose compared with students who received two doses.341
Population and school-based studies in Europe and Canada estimate
two doses of mumps-containing vaccine to be 66% to 95% effec-
tive.104,202,233,241,335,578,612 Despite relatively high two-dose vaccine effective-
ness, high two-dose vaccine coverage may not be sufficient to prevent
all outbreaks.5,216,229
Studies indicate that one dose of MMR vaccine can provide persistent
antibodies to mumps. Most people (70–99%) examined approximately
10 years after initial vaccination had detectable mumps antibodies.92,306,422
T-lymphocyte immunity to mumps was found in 70% of adults vac-
cinated in childhood compared with 80% of adults who acquired a
natural infection during childhood.213,332 In two-dose recipients, mumps
antibodies were detectable in 74% to 95% of people followed over 12
years after receipt of a second dose of MMR vaccine, but antibody levels
declined with time.227,422 Mumps antigen–specific lymphoproliferative
responses have been detected in vaccine recipients without detectable
mumps antibodies, but the role of these responses in protection against
mumps disease is not clear.377,653
Adverse Events
The use of mumps vaccine is associated with very few side effects.
Parotitis and fever have been reported rarely. Hypersensitivity reactions,
including rash, pruritus, and purpura, have been associated temporally
with vaccination, but they are transient and usually mild. Administration
of MMR is not harmful if it is given to an individual already immune
to one or more of the viruses.40,471
The frequency of reported central nervous system dysfunction after
vaccination is not greater than the observed background rate for unim-
munized people.471 The IOM concluded that evidence is inadequate to
establish a causal relationship between the Jeryl Lynn strain of mumps
vaccine used in the United States and aseptic meningitis, encephalitis,
or sensorineural deafness.362
Indications
Routine active immunization as MMR of children 12 to 15 months of
age is recommended.40,471 Most children receive a second dose of mumps
vaccine in childhood as a result of the recommendation for routine
measles revaccination with MMR. Susceptible older children, adolescents,
and adults also should be vaccinated against mumps.
Evidence of immunity through documentation of vaccination is
defined as one dose of live mumps vaccine for preschool-aged children
and adults not at high risk for exposure and infection and two doses
of live mumps vaccine for school-aged children (i.e., kindergarten to
grade 12) and adults at high risk for exposure and development of
infection (i.e., health care workers, international travelers, and students
at post–high school education institutions). Additional recommendations
for outbreak control include administering a second dose of MMR for
preschool-aged children and adults not at high risk for exposure and
acquisition of infection if these people are part of a group that is
experiencing an outbreak.150
To ensure high levels of immunity, especially among groups at high
risk for exposure and development of infection, every opportunity
should be used to provide the first or second dose of MMR vaccine to
those without adequate evidence of immunity (e.g., documentation of
vaccination). No formal recommendation for a third MMR dose exists,
but the CDC has provided guidelines for public health agencies consider-
ing its use as a control measure during mumps outbreaks.266 Factors
that can trigger a recommendation include outbreaks in populations
with two-dose MMR vaccination coverage of greater than 90%, intense
exposure settings such as universities, evidence of sustained transmission
for greater than 2 weeks, and high attack rates (>5 cases/1000 people).
Mumps remains endemic throughout most of the world. Although
vaccination against mumps is not a requirement for entry into any
country, susceptible children, adolescents, and adults born after 1956
should be offered mumps vaccination, usually as MMR, before engaging
in international travel.

Mumps vaccine has no proven value in the prevention of
disease in susceptible individuals after exposure to mumps, probably
because the time required to develop protective antibody titers after
immunization exceeds the incubation period of clinical mumps. However,
if the exposure does not result in infection, the vaccine confers subsequent
immunity.
Precautions and Contraindications
For people who are allergic to eggs, the risk of serious allergic reactions
such as anaphylaxis after receiving MMR is extremely low, and skin
testing with vaccine cannot predict an allergic reaction to vaccina-
tion.40,369,386 Performing skin testing is not required before administering
MMR to people who are allergic to eggs. Similarly, the administration
of gradually increasing doses of vaccine is not required.471 Data indicate
that most anaphylactic reactions to measles- and mumps-containing
vaccines are not associated with hypersensitivity to egg antigens but
rather with hypersensitivity to other components of the vaccines, such
as the gelatin stabilizer.311,340,385,419
Because of the theoretical risk of fetal damage, mumps vaccine should
not be administered to women known to be pregnant or who are
considering becoming pregnant. Women vaccinated with MMR should
avoid conception for 28 days after vaccination.471
Lymphoreticular or other generalized malignancy and primary or
secondary immunodeficiency states represent contraindications to the
use of mumps vaccine. Exceptions are children with HIV infection who
are immunized against measles with MMR (see Measles Vaccine). Because
infection after vaccination is noncommunicable, susceptible close contacts
of immunosuppressed patients should be vaccinated to avoid exposure
to mumps in these patients.
After cessation of immunosuppressive therapy, mumps vaccine usually
is withheld for at least 3 months. Because the intensity and type of
immunosuppressive therapy, radiation therapy, underlying disease, and
other factors determine when immunologic responsiveness will be
restored, making a definitive recommendation for an interval after
cessation of immunosuppressive therapy when mumps vaccine can be
safely and effectively administered often is not possible.
The effect of immune globulin preparations on the response to
mumps vaccine is unknown. High doses of immune globulin preparations
can inhibit the immune response to measles vaccine for 3 or more
months, depending on the dosage.29 If mumps vaccine is given as the
MMR vaccine, the recommendations for measles vaccine should be
followed (see Table 245.11).
Administration of mumps vaccine should be avoided if the individual
is receiving immunosuppressive dosages of systemic corticosteroids.
The effects of corticosteroids vary, but many clinicians consider that a
dose equivalent to 2 mg/kg per day or 20 mg/day of prednisone is
sufficiently immunosuppressive to raise concern about the safety of
vaccination with live virus vaccines.
Pertussis Vaccine
Pertussis (i.e., whooping cough), which is caused by the fastidious,
gram-negative, pleomorphic bacillus B. pertussis, continues to produce
significant morbidity and mortality worldwide among young children.491
In the absence of vaccination, the WHO estimated that approximately
1 million deaths would have occurred from the disease and its complica-
tions. In the United States, the number of cases has been reduced by
approximately 95% during the vaccine era.
Despite an effective vaccine, pertussis continues to occur in the
United States in all age groups. Since the historic low point achieved
in the 1980s, the incidence of pertussis has increased steadily. Outbreaks
have occurred recently in California, Washington, and Minnesota. In
the California outbreak, there was a degree of clustering within popula-
tions for whom vaccination rates, largely due to nonmedical exemptions,
were low.60 Nonmedical exemption laws appear to increase the rates of
pertussis in local areas of undervaccination in the unvaccinated and
vaccinated population.60,706
Surveillance data collected by the CDC’s National Immunization
Program for the periods from 1994 through 1996 and 1997 through
2000 demonstrated that the incidence of pertussis increased 60% among
adolescents and adults and 11% among infants younger than 6 months.142
CHAPTER 245  Active Immunizing Agents 2573
Data from the National Notifiable Disease Surveillance System reveal
an escalation in the increase in all age groups between 2001 and 2004.90
Incidence rates for the pediatric population peak for infants younger
than 6 months and again during adolescence between 11 and 18 years
of age.21 The increase in the number of cases among young infants
suggests that a true increase in pertussis circulation has occurred. The
number of cases among children old enough to receive vaccine has
remained stable. The likely reason that pertussis remains endemic in
the United States despite high vaccination rates is that neither infection
nor immunization provides life-long immunity.
Humans are the only known reservoir for pertussis. Vaccine effective-
ness falls off rapidly after immunization, with rates of 68% after the
first year dropping to 8.9% after 4 years.393 Pregnant woman who have
received Tdap in the third trimester of pregnancy had significant declines
in immunity 9 to 15 months after delivery.1
The experiences of countries where rates of pertussis vaccination
have markedly declined provide strong support for continuing routine
immunization of infants and young children.188 In the United Kingdom,
as a result of adverse publicity about pertussis vaccination, a decrease
in immunization rates for 2-year-old children from 77% in 1974 to
30% in 1978 was followed by an epidemic of 102,500 cases of pertussis.
A similar experience occurred in Japan, which reported 13,105 cases
and 41 deaths in 1979 after routine immunization had been suspended
temporarily in 1975.
In the United States during the 1980s, publicity about alleged serious
reactions to pertussis vaccine generated public controversy about the
risk of receiving pertussis vaccine. This resulted in costly litigation and
escalating vaccine costs and jeopardized vaccine supply and develop-
ment.490,532 The experience in countries such as England and Japan, the
severity of pertussis in young infants, and the usually benign or self-
limited sequelae of pertussis vaccination clearly justify continuing routine
childhood immunization. Several risk-benefit analyses provided
additional evidence in support of vaccination.188,349
Effective primary preventive programs necessitate immunizing young
infants, usually beginning at 2 months of age, because the morbidity
and mortality of pertussis are greatest for infants, especially those younger
than 6 months.123,188 Approximately 26% of reported cases in the United
States occur in infants younger than 6 months. During the period from
1997 through 2000, the case-fatality rate for infants younger than 6
months was 0.8%; 63% of these infants were hospitalized with frequent
complications, including pneumonia (11.8%), seizures (1.4%), and
encephalopathy (0.2%).142 From 2000 through 2004, 100 pertussis-related
deaths were reported; 90% were among infants younger than 4 months,
and 76% occurred in infants younger than 2 months.90
In 2014, 23,971 cases of pertussis were reported to the CDC; 9935
cases occurred during an outbreak in California to produce a rate of 26
cases per 100,000 people, with a rate of 1746 cases per 100,000 infants
younger than 12 months. Three deaths were attributed to this outbreak,
all were infants with an onset of illness at less than 5 weeks of age.691
Maintaining high rates of immunization in children beyond infancy,
with booster immunization for adolescents and adults, may reduce the
risk of infection in infants by decreasing the incidence of infection in
older family members and the resultant transmission of B. pertussis
within the household. Vaccination, including boosters, is essential because
the disease is highly infectious, and transmission often occurs before
adults seek medical care.
Preparations
Whole-cell pertussis vaccine was introduced in the United States in the
1920s. Not until the 1940s to 1950s, however, did pediatric whole-cell
pertussis vaccine become routinely recommended for children. This
vaccine, unavailable in the United States since 2002, consisted of a
suspension of inactivated B. pertussis combined with diphtheria and
tetanus toxoids (DTP).90
To reduce the incidence of local and systemic reactions caused by
whole-cell vaccines, less reactogenic pediatric acellular vaccines composed
of one or more purified components of B. pertussis combined with
diphtheria and tetanus toxoids (DTaP) were developed. Initially licensed
in 1991 for use as the fourth or fifth dose in the series, DTaP was licensed
in 1997 for all five doses in the series.
2574 PART V  Prevention of Infectious Diseases
TABLE 245.16  Acellular Pertussis Vaccines Licensed for Use in the United States
Trade Vaccine
Vaccine Name Manufacturer
DTaP Vaccines for Children Age <7 Years
DTaP Daptacel Sanofi Pasteur
DTaP Infanrix GlaxoSmithKline Biologicals
DTaP-IPV Kinrix GlaxoSmithKline Biologicals
DTaP-hepatitis B-IPV Pediarix GlaxoSmithKline Biologicals
DTaP-IPV/Hib Pentacel Sanofi Pasteur
DTaP-IPV Quadracel Sanofi Pasteur
Tdap Vaccines for Adolescents
Tdap Adacel Sanofi Pasteur
Tdap Boostrix GlaxoSmithKline Biologicals
DTaP, Diphtheria–tetanus–acellular pertussis; FHA, filamentous hemagglutinin; FIM, fimbriae; Hib, Haemophilus influenzae type b vaccine; IPV, inactivated poliovirus vaccine; PE, pertactin;
PT, pertussis toxin; Td, tetanus and reduced diphtheria toxoids; Tdap, tetanus–diphtheria–acellular pertussis.
Modified from American Academy of Pediatrics. Pertussis (whooping cough). In: Kimberlin DW, Brady MT, Jackson MA, Long SS, eds. Red Book: 2015 Report of the Committee on Infectious
Diseases. 30th ed. Elk Grove Village, IL: American Academy of Pediatrics; 2015:608–21.
Numerous acellular vaccines formulated from the different compo-
nents have been tested in children. All currently US licensed vaccines
contain detoxified or inactivated pertussis toxin (i.e., pertussis toxoid)
and filamentous hemagglutinin.231 Most vaccines include one or both
of the following B. pertussis antigens: pertactin (PRN, a 69-kd outer
membrane protein) and fimbriae proteins (FIM, agglutinogens). Various
vaccines have different amounts of each component. No pertussis-only
vaccine is available.
From 2001 until 2008, numerous changes were made to the list of
licensed acellular pertussis–containing vaccines available in the United
States. Several acellular vaccines are available for use in the primary
vaccination series for children younger than 7 years (Table 245.16).
For enhanced control of pertussis, routine revaccination of adolescents
and adults with an acellular pertussis vaccine is recommended to
minimize the morbidity associated with infection in these age groups
and to reduce the reservoir of infection. Tdap vaccines contain the
same pertussis antigen components as are in the pediatric vaccines
(some in reduced quantities). The tetanus and diphtheria components
are the same as for the current adult formations of Td, with reduced
diphtheria content as recommended for use in people 7 years of age
or older.
The ACIP recommends that whenever feasible, the same DTaP vaccine
product should be used for all doses of the vaccination series. If the
vaccine provider does not know or does not have available the type of
DTaP previously administered, any of the available licensed DTaP vaccines
can be used to complete the vaccination series.138
Immunogenicity
The Multicenter Acellular Pertussis Trial evaluated the immunogenicity
and safety of 13 acellular pertussis–containing vaccines compared with
whole-cell DTP administered to infants at 2, 4, and 6 months of age
in the United States.231 Serologic correlates of immunity to diphtheria
and tetanus toxoids, defined as antibody levels 0.1 IU/mL or greater,
were achieved after vaccination with acellular vaccines and were
comparable with those achieved with DTP vaccination. Pertussis
immunity, determined by at least a fourfold rise in antibody titer to
pertussis toxin and filamentous hemagglutinin, was equal to or greater
than results with DTP after immunization with either of the two DTaP
vaccines.253
Efficacy
For whole-cell and acellular vaccines, serologic correlates of immuno-
genicity have not been established for assessing efficacy. Field and other
No. of Pertussis Antigenic
Antigens Content Dose Series Approved
5 PT, FHA, PE, 2 All 5 doses
types of FIM
3 PT, FHA, PE All 5 doses
3 PT, FHA, PE Booster dose for 5th dose of DTaP and 4th dose
of IPV, children 4 through 6 years of age
3 PT, FHA, PE First 3 doses, children 6 wk–6 y of age
5 PT, FHA, PE, 2 First 4 doses, children 6 wk–4 y of age
types of FIM
5 PT, FHA, PE, 2 Booster dose for 5th dose of DTaP and 4th dose
types of FIM of IPV, children 4–6 y of age
5 PT, FHA, PE, 2 Single dose at 11–12 y of age instead of Td
types of FIM
3 PT, FHA, PE Single dose at 11–12 y of age instead of Td
epidemiologic studies must be performed to demonstrate efficacy. Studies
in the United States of household contacts exposed to pertussis indicate
that the efficacy of whole-cell vaccine was 80% or greater.123,188,513 Studies
reporting lower rates of vaccine efficacy often reflect the use of different
criteria for the diagnosis of pertussis and lesser effectiveness of the
vaccine in protecting against mild infection than against severe disease.268
Vaccine-induced immunity persists for at least 3 years and subsequently
diminishes with time.
Pertussis in individuals previously vaccinated is less severe and is
associated with fewer complications than in unvaccinated people. In a
case-control study of pertussis, immunization of both parents decreased
the incidence of disease by 51% among infants younger than 4 months.691
Vaccine effectiveness in pregnant women is 91%.50
In studies of the efficacy of eight acellular pertussis vaccines in
infants, rates of prevention of pertussis ranged from 58% to 93%.541
Comparing efficacy of the different products, however, often is not
possible because of differences in study design, vaccine schedule (i.e.,
number of doses and age of administration), case definitions of pertussis,
and other confounding variables. The acellular vaccines appear to be
similar in efficacy to most whole-cell vaccines. Whereas in two large
trials in Sweden and Italy, several acellular vaccines demonstrated
substantially greater efficacy than seen in the one US whole-cell vaccine
previously approved, other whole-cell vaccines studied appeared to be
slightly more effective than acellular vaccines in other trials.252 The
vaccines in the Swedish and Italian trials were given in a three-dose
schedule, in contrast to the four-dose primary schedule for vaccination
of young children in the United States.
Adverse Events
Local and febrile reactions to whole-cell vaccines occur in more than
one half of DTP recipients.200 These manifestations usually develop
within the first 24 hours and are brief in duration. More serious reactions
to whole-cell vaccines are uncommon. The reactions include prolonged
crying for 3 hours or longer occurring within the first 48 hours of
receiving vaccination (1% to 3% of DTP recipients) and a temperature
of 40.5°C or greater (≥104.9°F) within 48 hours (0.3%); a hypotonic-
hyporesponsive episode described as collapse or shock-like state within
48 hours and seizure within 3 days of vaccination was estimated to
occur once per 1750 doses.200 Episodes of inconsolable crying, high
fever, and hypotonic-hyporesponsive episodes after receipt of DTP
vaccine resolved without sequelae.
Most post-DTP seizures occurring within 48 hours of receipt of
vaccine are brief, self-limited, and generalized and occur in association

with fever. These seizures have not been demonstrated to result in the
subsequent development of epilepsy or other neurologic sequelae.
Predisposing factors include an underlying convulsive disorder, a personal
history of previous convulsion, and a family history of convulsions.128
A small increase in the risk of febrile seizure but no increased risk in
the development of epilepsy after immunization has been reported.627
The incidence of local and febrile reactions after the administration
of acellular vaccines is significantly lower.231,541 Comparison of rates of
adverse events with different acellular vaccines versus whole-cell vaccines
demonstrated similar safety profiles for each of the vaccines.193,585 The
most common adverse events include injection site reactions (e.g.,
erythema, induration, tenderness) and mild system symptoms, including
slight to moderate fever, drowsiness, irritability, and loss of appetite.
Rates of local reactions increase with each subsequent dose of DTaP
vaccine.537,642 Booster doses of acellular pertussis vaccine may be associated
with extensive local swelling (i.e., limb swelling), especially with vaccines
having a high diphtheria content.554 The pathogenesis of this reaction
is not understood, but it spontaneously resolves without sequelae and
is not associated with an increased risk of similar adverse events occurring
after receipt of the fifth dose.41 Severe reactions to acellular vaccines
such as prolonged crying of 3 hours or more, temperature greater than
or equal to 40.5°C (104.9°F), hypotonic-hyporesponsive episodes, and
seizures are rare.193,231,309,323,541,585,644 As with local and febrile reactions,
their occurrence with acellular pertussis vaccination is significantly less
frequent than that after whole-cell vaccination.
Syncope can occur after immunization with Tdap, is more common
among adolescents and young adults, and can result in serious injury
if a vaccine recipient falls. Vaccinees should be seated and observed for
15 minutes after immunization. If syncope occurs, patients should be
observed until symptoms resolve.41
When administered in the third trimester of pregnancy as recommended
by the ACIP, there has been no association with an increased risk of
maternal or neonatal death, preeclampsia, hemorrhage, uterine rupture,
caesarean section, renal failure, premature delivery, decreased birth weight,
or prolonged stay in a neonatal intensive care unit with administration
of Tdap. Increases in poor birth outcomes or maternal adverse events
have not been observed among women receiving multiple Tdap vaccines
during pregnancies spaced less than 5 years apart.243,488,625 This finding
was confirmed in a review of reported adverse events following the recom-
mendation that pregnant women received Tdap during the third trimester
of each pregnancy regardless of prior vaccine history.489
Serious Neurologic Illness
The National Childhood Encephalopathy Study (NCES), a large case-
control study from Great Britain that was published in 1985, estimated
that the occurrence of acute neurologic illness resulting in hospitalization
was 1 case per 140,000 DTP vaccinations.481 In a 10-year follow-up
study published in 1993, neurologic sequelae were found to be common
occurrences, but no more so than in children with unrelated, acute
neurologic illness in infancy,480 and reviews of the data have disputed
the conclusion that pertussis vaccine can cause neurologic sequelae.14,128,622
Later data from Canada evaluating more than 12,000 pediatric hospi-
talizations for serious neurologic illness between 1993 and 2002 found
no association after administration of more than 6.5 million doses
between development of encephalopathy and receipt of DTaP vaccina-
tion.41 Taken together, the data do not support a role for whole-cell
pertussis vaccine in causing brain damage.115
Indications
Vaccination against pertussis with DTaP is recommended routinely for
children at 2, 4, and 6 months of age, followed by a fourth dose at 12
to 18 months of age and a fifth dose at 4 to 6 years of age.21,41,90 Immuniza-
tion can be started when the child is as young as 6 weeks of age if pertussis
is prevalent in the community. The interval between administrations
of the three doses of the initial series can be as short as 4 weeks. The
AAP and ACIP recommend exclusive use of acellular pertussis vaccines
for all doses of the pertussis vaccine series.21,41,90 DTP is no longer available
in the United States. However, in many countries, including several in
Europe and developing countries, whole-cell vaccine remains the recom-
mended product.
CHAPTER 245  Active Immunizing Agents 2575
A single dose of Tdap is recommended universally for people 11
years or older, including adults, in place of the initial Td booster vaccine.
The preferred schedule is to administer Tdap at the preventive visit for
the 11- or 12- year-old children who have completed their primary
DTP/DTaP series.21,41,90 Adolescents and adults 11 years or older who
received Td but not Tdap should receive a single dose of Tdap to provide
protection against pertussis. Tdap can be administered regardless of
the time since receipt of the last tetanus- or diphtheria-containing
vaccine.41 Adolescents between the ages of 11 and 18 years who have
never been vaccinated against tetanus, diphtheria, or pertussis should
initially receive a single dose of Tdap followed by Td for the subsequent
two doses at 4 weeks or more and 6 to 12 months later.
No pertussis-containing vaccine is FDA approved for children between
the ages of 7 and 10 years. If pertussis vaccine is not contraindicated,
children 7 through 10 years of age who are not fully vaccinated (i.e.,
have not received five doses of DTaP or four doses of DTaP if the fourth
dose was administered on or after the fourth birthday) should receive
a single dose of Tdap to provide protection against pertussis. If additional
doses of tetanus and diphtheria toxoid–containing vaccines are needed
for children 7 through 10 years of age, Tdap vaccine is substituted as
the first dose. The subsequent two doses should be Td vaccine at 4
weeks or more and 6 to 12 months after the previous dose if indicated
for the catch-up series.29,90
Women should receive Tdap before becoming pregnant. Women
who have not been immunized previously with Tdap should receive
Tdap during pregnancy, preferably during the early third trimester (i.e.,
after 20 weeks’ gestation). If it is not administered during pregnancy,
Tdap should be administered in the immediate postpartum period.171,175
Additional immunization with Tdap should be administered in the
early third trimester of each additional pregnancy. Every 10 years
thereafter, booster vaccination should be provided by Td.
As further protection against transmission of pertussis to infants
who are at greatest risk for pertussis-related morbidity or mortality
compared with other age groups, the cocoon strategy is recommended
to immunize mothers, families, and close contacts against pertussis to
decrease their likelihood of acquisition and subsequent transmission
of B. pertussis to infants. Adolescents and adults (i.e., parents, siblings,
grandparents, child care providers, and health care personnel) who
have or anticipate having close contact with an infant younger than 12
months should receive a single dose of Tdap to protect against pertussis
if they have not previously received Tdap. Ideally, these people should
receive Tdap at least 2 weeks before beginning close contact with the
infant.41,171
Contraindications and Precautions
The contraindications and precautions for administering pertussis
vaccine are based on adverse reactions associated with whole-cell vaccine.
Although reactions occurring after the administration of DTaP are much
less common than are those associated with DTP, the contraindications
and precautions for DTaP are the same.21,41,90 Adverse events temporally
related to pertussis immunization that contraindicate further administra-
tion of DTaP are as follows:
• An immediate anaphylactic reaction. Subsequent immunization with
any of the three components of the vaccine should be avoided.
• Encephalopathy occurring within 7 days. Children who experienced
encephalopathy within 7 days after administration of a previous
dose of diphtheria and tetanus toxoids and pertussis vaccine (i.e.,
DTP, DTaP, or Tdap) not attributable to another identifiable cause
should not receive additional doses of a vaccine that contains pertussis.
Encephalopathy in this context is defined as a severe, acute, central
nervous system disorder (e.g., coma, prolonged seizures) unexplained
by another cause and may manifest as major alterations in conscious-
ness or generalized or focal seizures that persist for more than a few
hours without recovery within 24 hours. Additional doses of DT
(or Td) vaccine should be substituted for any pertussis-containing
vaccine.
Postvaccination reactions constituting precautions are as follows:
• Moderate or severe acute illness with or without a fever
• Guillain-Barré syndrome within 6 weeks after a previous dose of
tetanus toxoid–containing vaccine
2576 PART V  Prevention of Infectious Diseases
• A convulsion, with or without fever, occurring within 3 days of
receiving DTP or DTaP vaccination
• Persistent, severe, inconsolable screaming or crying for 3 hours or
more within 48 hours of DTP or DTaP vaccination
• Hypotonic-hyporesponsive episode occurring within 48 hours of
DTP or DTaP vaccination
• Temperature of 40.5°C (104.9°F) or greater that is unexplained by
another cause and occurs within 48 hours of DTP or DTaP
vaccination
With these adverse events occurring in temporal association with
DTaP vaccination, the decision to administer additional doses of pertussis
vaccine should be considered carefully. Children for whom vaccination
is deferred because of moderate or severe acute illness should be vac-
cinated when their condition improves. In circumstances such as a
pertussis outbreak in which the potential benefits of pertussis immuniza-
tion outweigh the possible risks, vaccination is indicated, particularly
because these events have not been proved to cause permanent sequelae.
The risk of these reactions occurring after receipt of DTaP is substantially
lower than after receipt of DTP.
For children with an evolving neurologic disorder in the first year
of life, pertussis immunization should be deferred until the nature and
cause of the disorder have been established. A personal history of having
a stable neurologic condition (i.e., previous convulsion unrelated to
DTaP vaccination, a history of seizure disorder, well-controlled seizures,
or cerebral palsy) or a family history of convulsions is not a contraindica-
tion, and pertussis immunization should be administered on
schedule.
Certain conditions after DTaP vaccine, such as temperature of 40.5°C
(104.9°F) or higher, collapse or shock-like state, persistent crying, or
convulsions with or without fever, are a precaution to subsequent doses
of DTaP. However, occurrence of one of these adverse reactions after
DTaP vaccine in childhood is not a contraindication or precaution to
administration of Tdap to an adolescent or adult. A history of severe
Arthus hypersensitivity reaction after a previous dose of a tetanus or
diphtheria toxoid–containing vaccine administered less than 10 years
earlier should lead to deferral of Tdap or Td immunization for 10 years
after administration of the tetanus or diphtheria toxoid–containing
vaccine.21,41,90
Pneumococcal Vaccine
S. pneumoniae is a leading bacterial pathogen, especially among young
children, elderly people, and people with predisposing conditions. In
children, it is the most common cause of otitis media, occult bacteremia,
and bacterial pneumonia requiring hospitalization. After the widespread
introduction of conjugate Hib vaccination and subsequent marked
decline in occurrence of Hib meningitis, S. pneumoniae became a leading
cause of bacterial meningitis in children in the United States.
In some populations, such as Alaska Natives, the incidence of
bacteremia is markedly higher than that reported in other geographic
areas of the United States.228 Groups considered at high risk for invasive
pneumococcal disease (IPD) include children with sickle cell disease,
asplenia, Hodgkin disease, congenital humoral immunodeficiency, HIV
infection, and nephrotic syndrome and recipients of organ transplants.
Children who have received cochlear implants are at particular risk for
developing meningitis.144,552 Other chronic diseases associated with an
increased risk of development of severe pneumococcal disease include
chronic cardiovascular and pulmonary diseases, diabetes mellitus, and
renal failure. The role of these chronic diseases in predisposing individuals
to pneumococcal infection has been demonstrated primarily in adults.
Mortality rates are highest among those who have bacteremia or
meningitis, elderly people, and patients with impaired humoral immunity
or certain chronic diseases.
The purified polysaccharide vaccine has been effective in reducing
severe disease in the adult population,99 but it has little impact in young
children because the vaccine is not immunogenic in children younger
than 2 years.42 The polysaccharide vaccine has not been effective in
preventing otitis media caused by S. pneumoniae.42 Several factors made
the development of new preventive strategies for pneumococcal disease
a high priority.212,214 Morbidity and mortality rates of pneumococcal
infection appear to be particularly high in developing countries. The
increasing incidence of antimicrobial-resistant pneumococci further
underscores the need for developing effective pneumococcal vaccines
for young children.88 Resistance of S. pneumoniae to multiple antibiotics
increased rapidly in the United States and even more rapidly in other
parts of the world.381 Children younger than 2 years have the highest
rate of IPD but do not develop an effective antibody response to
polysaccharide vaccine. Children 2 to 5 years of age may have relatively
poor responses to serotypes 6B, 14, 19F, and 23F, which are common
causes of pediatric infections and the most prevalent penicillin-resistant
serotypes.
These factors prompted the development of conjugated polysac-
charide–protein vaccines, two of which have been licensed in the United
States. These vaccines are similar in design to the licensed Hib conjugate
vaccines. Because of the large number of serotypes of S. pneumoniae that
cause disease, development of these conjugate pneumococcal vaccines
was more difficult than the development of similar vaccines for Hib.
Each pneumococcal antigen must be coupled to a protein carrier, and
the vaccine must be prepared to ensure that antigen is sufficient to induce
an immune response but insufficient to elicit an adverse reaction.
One potential problem with conjugate pneumococcal vaccines is
the need to immunize against many different serotypes of pneumococci.
Because of local reactions to the protein component, conjugate vaccines
that contain all implicated serotypes have proved difficult to produce.
Initial decisions for serotype inclusion need to be carefully planned for
specific groups. For instance, vaccine containing types 4, 6B, 9V, 14,
18C, 19F, and 23F (i.e., PCV7) is necessary for prevention of otitis
media in the United States, whereas types 1, 2, and 5 need to be added
to prevent pneumonia in developing countries.
The use of conjugate vaccines against limited serotypes has led to
emergence of pneumococcal serotypes (e.g., 19A) that were previously
less common but have proved equally concerning for IPD and emerging
resistance.102,161,364 Emergence of replacement serotypes led to the expan-
sion of the previous vaccine to the 13-valent pneumococcal conjugate
vaccine (PCV13) in the United States.162 Routine infant immunization
using these conjugate vaccines led to significant reductions in the
instances of S. pneumoniae disease.263 Since the widespread introduction
of PCV7 in infants in 2000, rates of IPD have decreased markedly in
the United States.263 The incidence of all IPDs has decreased by 80%
for children younger than 2 years and by up to 90% for infections
caused by vaccine and vaccine-related serotypes.42,161,686 An increase in
nonvaccine serotype disease has occurred, but it is small compared
with the overall reductions in vaccine-type disease.52,102,145,161
A decline in the incidence of vaccine-type disease among unvaccinated
children and adults has occurred since the introduction of routine
vaccination for infants in the United States.145 Rates of IPD among
infants younger than 2 months have decreased significantly, providing
evidence that vaccinating children 2 to 23 months of age has led to
changes in pneumococcal carriage in infants who were too young to
receive PCV7.543 In surveillance of children with sickle cell disease from
1998 to 2009, rates of IPD fell by 53%.528 As of 2012, PCVs are included
in national immunization programs in 86 of 194 WHO member states,
with similar expectations of IPD decrease.174
Herd immunity is estimated to prevent twice as many cases as do the
direct effects of vaccination alone.145,161 Although the exact mechanism
of herd immunity is uncertain, one hypothesis is that vaccinated children
are less likely to have nasal carriage of pneumococcus and therefore less
pneumococcal transmission to their contacts.222 Use of conjugate vaccines
has reduced nasopharyngeal carriage of vaccine serotypes with PCV7
and PCV13.201,223,224 Pneumococcal conjugate vaccination also has led to
increased nasopharyngeal colonization of children with nonvaccine
serotypes.293,479 In surveillance of IPD cases among children younger than
5 years, the introduction of PCV7 decreased penicillin-nonsusceptible
cases by 64%, with serotypes not in PCV7 causing 78% to 97% of penicillin-
nonsusceptible IPD.331 This underscores the need for ongoing surveillance
of emerging nonvaccine serotypes with respect to nasopharyngeal coloniza-
tion, antibiotic nonsusceptibility and of rates of IPD.613
Preparations
Two pneumococcal vaccines are available for use in children in the
United States. The first is a 13-valent vaccine (PCV13) licensed in 2010

(Prevnar, Wyeth Vaccines), which contains the capsular polysaccharides
from serotypes contained in the previous PCV7 (i.e., 4, 6B, 9V, 14, 18C,
19F, and 23F) and six additional serotypes (i.e., 1, 3, 5, 6A, 7F, and 19A)
conjugated to mutant diphtheria toxin (CRM197).42 Serotypes included
in PCV7 and potentially cross-reactive serotypes (i.e., 6A, 9A, 9L, 18B,
and 18F) accounted for 86% of cases of bacteremia, 83% of cases of
meningitis, and 65% of AOM cases occurring in children younger than
6 years in the United States during 1978 to 1994.509 In 2007, the Active
Bacterial Core surveillance estimated 4600 cases of IPD among children
younger than 5 years in the United States, with 2900 attributable to
serotypes covered by PCV13 versus 60 cases covered by PCV7.161 The
incidence of IPD from PCV13 or nonPCV7 serotypes was reduced by
64% and 93%, respectively, among children younger than 5 years by
2013, driven mostly by reductions of serotypes 19A and 7F.487
The second vaccine (i.e., PPV23 [Pneumovax]) is composed of
purified, capsular polysaccharide antigens of 23 pneumococcal serotypes.
Although 90 different serotypes have been identified, vaccine serotypes
in the 23-valent vaccine are historically responsible for 85% to 90% of
adult infections and almost 100% of invasive disease and 85% of otitis
media cases in children.112,294 Each vaccine is recommended in a dose
of 0.5 mL that is given intramuscularly.
Immunogenicity and Efficacy
The immunogenicity of the conjugate polysaccharide vaccine appears
to be determined by the pneumococcal polysaccharide serotype, rather
than by the carrier protein. Some serotypes (i.e., 14, 18C, and 19F) are
excellent immunogens because they elicit antibody protection after a
single dose, whereas others (i.e., 6B and 23F) require three doses of
vaccine.259 Conjugate vaccine elicits immunologic memory.259 The
antibody concentrations achieved after the initial series of three doses
usually are sustained for only a few months and then decline to almost
preimmunization levels. A dose of pneumococcal vaccine (i.e., polysac-
charide or conjugate) given in the second year of life elicits an amnestic-
type response.
Prelicensure clinical efficacy of PCV7 was studied in a large, prospec-
tive, placebo-controlled efficacy trial in northern California involving
38,000 children. The vaccine was 89% effective in preventing invasive
disease caused by any pneumococcal serotype and 97% effective
against disease caused by the seven vaccine serotypes.80 For noninvasive
disease, a decrease of 7% in the number of cases of otitis media and
23% in doctor visits for recurrent otitis (i.e., six or more visits per year)
occurred for vaccinated children. The study also demonstrated an 11%
decrease in the number of clinical cases of pneumonia and efficacy of
26% against a first episode of radiograph-confirmed pneumonia in
vaccinees.333,600
Prelicensure immunogenicity of PCV13 was studied in a randomized,
double-blind, active-controlled trial in which 663 US infants received
at least one dose of PCV7 or PCV13. The study was powered for
noninferiority of immunoglobulin antibody response measured by
enzyme immunoassay and included subset analysis of functional antibody
responses measured by opsonophagocytosis assay (OPA).25,707 The
noninferiority criterion (i.e., immunoglobulin geometric mean concentra-
tions) was met for all shared serotypes; although slightly lower in the
PCV13 group, the functional OPA response was similar, suggesting
PCV13 has similar efficacy as PCV7 against shared serotypes. After a
fourth dose of PCV13, the additional six serotypes also produced a
functional OPA response in 97% to 100%.
The ability of PCV7 to protect children against AOM was evaluated
in an efficacy trial conducted in Finland.260 For prevention of AOM
caused by pneumococci of any serotype, efficacy was estimated to be
34%, whereas efficacy against AOM irrespective of cause was 6%. Efficacy
against AOM caused by vaccine-related serotypes was 57%, but an
increase of 33% in the rate of AOM episodes caused by nonvaccine
serotypes occurred in the group receiving the heptavalent vaccine
compared with controls. Despite of the increase in disease caused by
nonvaccine serotypes, the net effect on pneumococcal AOM was a
reduction of 34%.
RCTs enrolling African children and using a nine-valent pneumococcal
conjugate vaccine demonstrated efficacy in the prevention of radiologi-
cally confirmed pneumonia and vaccine-type IPD.220,398 The vaccine
CHAPTER 245  Active Immunizing Agents 2577
was efficacious in preventing vaccine-type invasive disease in HIV-infected
children.398 One of the trials demonstrated a reduction in the all-cause
mortality rate for vaccine recipients.220 These data make a compelling
case for extending the benefits of pneumococcal conjugate vaccination
to developing countries.
Vaccination with purified polysaccharide vaccine results in serologic
type-specific antibody in most healthy adults and older children.
Immunocompromised patients may respond less well. In children younger
than 2 years, the antibody response is poor to most serotypes, including
those most likely to cause infection, such as types 6A and 14.130,112,294
Patients with AIDS have impaired antibody responses to vaccination,
but asymptomatic HIV-infected adults do respond.130,112
Vaccine efficacy in preventing serious pneumococcal infection has
been demonstrated for the purified polysaccharide vaccine primarily
in immunocompetent adults, including elderly people and those with
chronic diseases such as chronic pulmonary and cardiac disorders and
diabetes mellitus, which predispose these patients to development of
pneumococcal infections. Efficacy against vaccine serotypes ranges from
61% to 75% in adults.99,594 Investigations in adults in whom vaccine
protection against pneumococcal infection has been substantially less
have been criticized for methodologic problems.130,112 Efficacy in the
limited studies of children has been consistent with that for adults. In
children with sickle cell disease or anatomic asplenia, an octavalent
vaccine was highly effective in preventing bacteremic infection.51
Adverse Events
Pneumococcal conjugate vaccines appear to be safe, and in 13 clinical
trials, the safety profile of PCV13 was comparable to that of PCV7.25,42,509
The reactions most commonly reported have been local reactions at
the injection site, but they occur at a lower frequency than do local
reactions with other childhood vaccines such as DTP.80
Local reactions at the injection site, such as erythema and pain, are
reported for approximately 50% of recipients of the purified polysac-
charide vaccine.42 However, more severe local and systemic reactions,
such as fever and myalgia, are rare events that occur in less than 1%
of vaccine recipients. Severe systemic reactions such as anaphylaxis
rarely have been reported.692 Preterm infants show safety results com-
parable with those for term infants.463 In adults who were revaccinated
within 1 to 2 years in early studies, local reactions occurred more
commonly than did those after initial immunization.130,112 However,
subsequent investigations, including studies of children, indicated no
increase in the incidence or severity of local or systemic reactions on
revaccination after longer intervals.401,557
Indications
Recommendations for the use of PCV13 have been issued by the AAP
and the ACIP.25,509 The AAP and ACIP recommend universal use of
PCV13 in children 59 months or younger. For children to whom no
prior PCV7 or PCV13 has been administered before they reach 7 months
of age, four doses of PCV13 are recommended. Doses should be
administered routinely at 2, 4, 6, and 12 to 15 months of age. For
children younger than 24 months who have not received their recom-
mended four doses of PCV7, a dose of PCV13 should be administered
at the next scheduled vaccination; the total number of doses is based
on the child’s age and described elsewhere.25,42,509
A single supplemental dose of PCV13 is recommended for all children
14 months to 59 months who have previously received all four doses
of PCV7. A single dose of PCV13 is recommended for children 60
months to 18 years of age who are fully immunized with PCV7 and
have underlying medical conditions that increase their risk of IPD. For
children 6 through 18 years of age, PCV13 should be given regardless
of previous PCV7 or PPSV23 administration.87 If not previously
administered, children 24 months to 18 years of age should receive the
PPV23 to expand serotype coverage.
The AAP recommends PPV23 for children 24 months or older and
PCV13 for all children 59 months of age or older who belong to one
or more of the following risk groups:
• Immunocompetent children with chronic heart disease, chronic lung
disease, diabetes mellitus, cerebrospinal fluid leaks, or cochlear
implants
2578 PART V  Prevention of Infectious Diseases
• Children with functional or anatomic asplenia, including sickle cell
disease or other hemoglobinopathies, congenital or acquired asplenia,
or splenic dysfunction
• Children with immunocompromising conditions, including HIV
infection; chronic renal failure and nephrotic syndrome; diseases
associated with treatment with immunosuppressive drugs or radiation
therapy, including malignant neoplasms, leukemias, lymphomas,
and Hodgkin disease; or solid organ transplantation and congenital
immunodeficiency
For previously vaccinated children 18 years or younger who are at
high risk for severe pneumococcal infection, revaccination with PPV23
after 5 years is recommended.25,87,509 For children between the ages of
6 and 18 years who have not received PCV13 but have received at
least one PPSV23 dose, a single PCV13 dose should be given at least
8 weeks after the last PPSV23 dose, regardless of previously given
PCV7.176 This includes children who have functional (e.g., sickle cell
disease) or anatomic asplenia, children and adolescents with HIV
infection, and those who have a rapid antibody decline (i.e., nephrotic
syndrome, renal failure, or organ transplantation).295 Revaccination with
PPV23 should be considered for high-risk older children and adults
who were vaccinated 6 years or more earlier, but no more than two
total PPV23 doses are necessary. The interval between polysaccharide
and conjugate vaccines should be at least 8 weeks, regardless of the
order given.399
Contraindications
No contraindications to initial vaccination exist.25,509 The safety of
pneumococcal vaccine in pregnant women has not been evaluated, but
adverse consequences for the fetus have not been observed in neonates
whose mothers were vaccinated inadvertently during pregnancy. Ideally,
women at high risk for pneumococcal disease should be vaccinated
before pregnancy. For people who have had a severe reaction, such as
anaphylaxis or a localized, severe hypersensitivity response, revaccination
should be avoided.
Poliovirus Vaccine
The widespread implementation of poliovirus vaccine programs resulted
in a dramatic reduction in the incidence of paralytic poliomyelitis
throughout the world. In contrast to the prevaccine era, when more
than 18,000 cases of paralytic disease occurred in the United States
annually, the last known case in this country caused by indigenous
wild-type virus occurred in 1979.178 Other than rare imported cases,
the only cases of paralytic poliomyelitis in the United States since then
have been vaccine related.
The effectiveness of polio vaccination led the WHO to launch the
Global Polio Eradication Initiative in 1988, when approximately 350,000
people succumbed to polio each year. The initiative initially made rapid
gains; the number of new wild poliovirus cases decreased by 99% between
1988 and 2005. However, ongoing transmission threatened the success
of the polio eradication program, and the Polio Eradication and Endgame
Strategic Plan 2013–18 was developed under the auspices of the WHO
to eradicate wild poliovirus, vaccine-associated paralytic polio (VAPP),
and circulating vaccine-derived poliovirus (VDPV).701 The phased plan
was implemented in places where OPV was used routinely. At least one
dose of inactivated polio vaccine (IPV) was introduced in 2015, and
bivalent OPV (bOPV, types 1 and 3) replaced trivalent OPV (tOPV)
starting in 2016. The type 2 component of tOPV is being removed
because it causes more than 90% of all cVDPV cases and approximately
40% of vaccine-associated paralytic polio cases, it interferes with the
immune response to the other two types, and wild poliovirus type 2
has been eradicated since 1999.
As of 2016, four of the six regions of the WHO have been certified
polio-free: the Americas (1994), Western Pacific (2000), Europe (2002),
and South East Asia, including India (2014). Eighty percent of the world’s
population currently lives in polio-free areas. However, Afghanistan,
Nigeria, and Pakistan are the three remaining reservoirs of endemic
disease, largely because regional conflicts and poor health care infra-
structures hinder widespread immunization campaigns. Countries with
ongoing outbreaks of cVDPV include Guinea, Lao People’s Democratic
Republic, Madagascar, Myanmar, Nigeria, and Ukraine.516,539,701
The elimination of poliovirus infection has been achieved primarily
through the use of OPV (i.e., Sabin strain). This product had been the
vaccine of choice for children in the United States since the early 1960s
because it induced optimal intestinal immunity, was painless to
administer, and secondarily immunized some contacts by fecal-oral
spread of the vaccine virus and contributed to the immunity of the
population.105 Because 8 to 10 cases of vaccine-associated paralytic polio
occurred annually and the risk of exposure to wild poliovirus had been
markedly reduced or eliminated in the United States, expanded use of
IPV (i.e., Salk strain) was recommended by the CDC and the AAP
beginning in 1997.16,129
In 1999, as a result of progress in the global eradication of polio-
myelitis, the need for further reduction in the risk of acquiring vaccine-
associated paralytic polio, and the acceptance of IPV by parents and
physicians,131 IPV was recommended for the first two doses of poliovirus
vaccine for routine childhood vaccination.18,134 To eliminate the risk of
vaccine-associated paralytic polio completely, an all-IPV schedule was
recommended in January of 2000 for routine childhood vaccination
in the United States.19,137,134 IPV is the only vaccine used in developed
countries.
Since 2000, there have been ongoing outbreaks of paralytic polio-
myelitis caused by circulating VDPVs that are neurovirulent polioviruses
derived from the Sabin OPV vaccine strain. The epidemics have occurred
among underimmunized children living in certain economically deprived
regions. The low immunization rates in these areas have permitted
these viruses to circulate for long periods and, by continuous mutation,
to acquire biologic properties that are indistinguishable from naturally
occurring wild polioviruses. Interruptions in OPV administration and
the previous eradication of the corresponding serotype of indigenous
wild poliovirus were the critical risk factors for all VDPV outbreaks.387
Circulation of VDPVs underscores the critical importance of eliminating
the last pockets of wild poliovirus, maintaining universally high levels
of polio vaccine coverage (>90% of young children), withdrawing all
OPVs as soon as wild poliovirus has been eradicated globally, and
continuing poliovirus surveillance into the foreseeable future.
Preparations
Trivalent IPV is the only vaccine available for routine infant and child-
hood immunization in the United States. IPV is prepared by inactivation
of naturally occurring polioviruses by treatment with formaldehyde.
Five trivalent IPV vaccines are available in the United States: IPOL
(single-component vaccine [Sanofi Pasteur]), Pediarix (in combination
with DTaP vaccine and HBV vaccine [GlaxoSmithKline]), Pentacel (in
combination with DTaP and Hib vaccines [Sanofi Pasteur]), Quadracel
(in combination with DTaP vaccine [Sanofi Pasteur]), and Kinrix (in
combination with DTaP vaccine [GlaxoSmithKline]). These vaccines
are produced in monkey kidney (Vero) cells except for Pentacel, which
is grown in human diploid cells, and each contains 40, 8, and 32 D-antigen
units of poliovirus types 1, 2, and 3, respectively. The single-component
vaccine is the only IPV preparation that contains preservative.
The trivalent OPV formulations contain approximately 106.5 50%
tissue culture infectious doses (TCID50), 105.5 TCID50, and 106.2 TCID50
of poliovirus types 1, 2, and 3, respectively, in a 10 : 1 : 3 ratio. The
unequal contribution of each type to the trivalent preparation represents
a balanced formulation designed to account for the more efficient
replication of type 2 OPV virus in the gastrointestinal tract and to
avoid interference with the replication of the two latter types. The live
oral OPV strains are grown in Vero cells and do not contain a preservative.
OPV is no longer available in the United States.
Monovalent OPV (mOPV) vaccines (types 1 and 3) are recommended
for use in supplementary immunization campaigns where only wild
poliovirus type 1 or type 3 alone is circulating, with the purpose of
controlling outbreaks. Two doses of mOPV administered within
2 weeks is used as part of the short-interval additional dose approach,
which is intended to rapidly boost population immunity in certain
settings.670
Immunogenicity and Efficacy
Neutralizing antibodies are detectable to all three poliovirus types in
99% of recipients of IPV after two doses and in 100% after the third

dose.468,606 Detectable antibody persists at protective levels for at least
5 years, although geometric mean titers decline considerably.630 A
meta-analysis revealed that vaccine efficacy of the currently licensed
enhanced-potency IPV formulations ranges from 33% to 47% after
one dose and 79% to 90% after two doses in infants older than 10
weeks.308
An optimal immune response to trivalent OPV requires multiple
doses. In developed countries, three doses given at least 2 months apart
are sufficient, with antibody prevalence to all three types being approxi-
mately 96% after the third dose.468 Detectable serum antibody to all
three types persists in 84% to 98% of vaccinees 5 years after receiving
primary immunization.411
OPV efficacy was directly evaluated during a type 1 poliovirus
outbreak in Taiwan in the early 1980s. During this outbreak, vaccine
efficacy was estimated to be 82%, 96%, and 98% for one, two, and three
or more doses, respectively.390 In tropical countries, the series of OPV
at 6, 10, and 14 weeks of age recommended by the WHO EPI fails to
produce active immunity in a significant proportion of infants. Low
seroconversion rates have been documented in many locations, averaging
73%, 90%, and 70% for types 1, 2, and 3, respectively.526 Diarrheal
disease at the time of immunization is a major factor.496 The impact of
diarrhea on seroconversion persists despite the administration of three
or four OPV doses.
The monovalent OPV vaccines have higher type-specific seroconver-
sion rates than does the trivalent vaccine and are considered more
effective when used in response to an outbreak caused by one poliovirus
type.103
Adverse Events
No serious adverse events have been associated with use of the currently
available IPV vaccine.19,43,134 Because IPV vaccine contains trace amounts
of streptomycin, neomycin, and polymyxin B, allergic reactions are
possible in recipients with hypersensitivity to one or more of these
antibiotics.
The OPV vaccine can cause vaccine-associated paralytic polio, the
overall risk for which is approximately one case per 2.4 million doses
distributed. The rate after the first dose is approximately one case per
750,000 doses, including vaccine recipient and contact cases. Immu-
nodeficiency-related VDPV excretion by people with primary immu-
nodeficiencies is a rare complication of OPV use and is associated with
chronic excretion and fatal disease.98
Indications
The polio vaccination series in the United States consists of four doses
of IPV administered subcutaneously or intramuscularly.19,43,134 The first
and second doses are administered at 2 and 4 months of age, respectively.
The third dose is usually given at 6 to 18 months of age, and a fourth
dose is given routinely at 4 to 6 years of age, before school entry.
Administration of a fourth dose is not necessary if the third dose was
given on or after the child’s fourth birthday. IPV is a component of
Pediarix, Pentacel, Quadracel, and Kinrix. Pediarix may be given from
6 weeks through 6 years of age. Pentacel may be used 6 weeks through
4 years of age, and Quadracel and Kinrix may be used for children 4
to 6 years of age.
The WHO continues to recommend OPV as the vaccine of choice
for global eradication of wild poliovirus in endemic areas and during
epidemics. Since 2015, at least one additional dose of IPV is recommended
from 14 weeks of age, with or without a concurrent OPV dose, in
preparation for withdrawing all OPV after global eradication has been
certified. Since 2016, trivalent OPV has been switched to bivalent OPV
(i.e., types 1 and 3). In the immunization schedule of the WHO EPI,
doses of OPV are recommended at birth and when the child is 6, 10,
and 14 weeks of age.29 In geographic areas with endemic polio, a dose
may be given when the neonate is discharged from the hospital (i.e.,
the zero dose). Supplementary doses often are given during mass com-
munity programs in these areas. Breastfeeding does not interfere with
successful immunization with OPV.
Routine poliovirus vaccination is not necessary in adults residing
in the United States. These individuals are at minimal risk for exposure,
and most are adequately protected because of vaccination during
CHAPTER 245  Active Immunizing Agents 2579
childhood. However, vaccination is recommended for individuals who
have an increased risk of exposure, including people traveling to countries
where poliomyelitis is epidemic or endemic, members of communities
of specific population groups experiencing wild poliovirus disease, health
care workers in close contact with patients who may be excreting wild
poliovirus, and laboratory workers in contact with specimens that may
contain wild-type poliovirus. Previously immunized adults who are at
increased risk for exposure to poliomyelitis, such as those traveling to
countries where poliomyelitis is still endemic, should receive a single
dose of IPV. Available data do not indicate the need for more than a
single lifetime booster dose of IPV. Adults who are unvaccinated or
whose vaccination status is not documented should receive a primary
vaccination series with IPV. This consists of two doses of IPV at 4- to
8-week intervals and a third dose 6 to 12 months after the second dose.
Precautions and Contraindications
IPV is contraindicated in people who have ha an anaphylactic reaction
after receiving a previous dose of IPV or an anaphylactic reaction to
one of the antibiotics in the vaccine preparation (i.e., streptomycin,
polymyxin B, or neomycin).19,43,134 Poliomyelitis vaccination usually is
contraindicated in pregnant women because of the theoretical risk of
harm to the fetus. However, no deleterious effects from IPV administered
during pregnancy have been demonstrated; and if immediate protection
against poliomyelitis is needed, IPV may be given.
Rotavirus Vaccine
Rotavirus infection is the most common cause of severe diarrhea disease
in infants and young children worldwide and continues to have a major
global impact on childhood morbidity and mortality, causing an estimated
527,000 deaths of children younger than 5 years each year or approximately
5% of all childhood deaths worldwide.521 In the United States before the
introduction of vaccine in 2006, an estimated 3 million rotavirus infections
occurred every year, and 95% of children had at least one rotavirus
infection by 5 years of age. Rotavirus infection was responsible for more
than 400,000 physician visits, more than 200,000 emergency department
(ED) visits, 55,000 to 70,000 hospitalizations, and 20 to 60 deaths each
year of children younger than 5 years.298,688 In the prevaccine era, rotavirus
accounted for 30% to 50% of all hospitalizations for gastroenteritis
among US children younger than 5 years.217
Rotavirus gastroenteritis is preventable with live oral rotavirus
vaccines. In 1998, the only approved rotavirus vaccine, a tetravalent
rhesus-based rotavirus vaccine (RRV-TV) (Rotashield, Wyeth Labora-
tories), was withdrawn from the market in the United States because
of an association with intussusception among vaccinated infants.495 In
2006, a bovine-based pentavalent rotavirus vaccine (RotaTeq, Merck &
Co.) was licensed by the FDA for use in infants in the United States.
The ACIP of the CDC and the AAP have recommended universal
vaccination of US infants against rotavirus.24,217 In 2008, a live attenuated
human rotavirus vaccine (Rotarix, GlaxoSmithKline) was licensed in
the United States.
The epidemiology of rotavirus disease in the United States has changed
dramatically since rotavirus vaccines became available in 2006. National
declines in rotavirus detection have been reported, ranging from 58%
to 90% in each of the seven postvaccine years compared with all seven
prevaccine years combined. A biennial pattern of rotavirus activity
emerged in the postvaccine era, with years of low activity and highly
erratic seasonality alternating with years of moderately increased activity
and seasonality similar to that seen in the prevaccine era.9 Other US
studies show the large public health impact of routine rotavirus vaccination
in reducing the circulation of rotavirus among US children. Declines in
laboratory-confirmed rotavirus hospitalization632 and reductions in
outpatient visits, emergency room visits, acute gastroenteritis, and
rotavirus-coded hospitalizations have been reported.215 From 2007 through
2011, more than 176,000 hospitalizations, 242,000 emergency department
visits, and 1.1 million outpatients visits due to diarrhea were averted,
resulting in costs savings of $924 million over the 4-year period.427
Preparations
Two rotavirus vaccines are licensed for use in the United States. The
pentavalent rotavirus vaccine (RV5) is an oral vaccine that contains
2580 PART V  Prevention of Infectious Diseases
five live reassortant rotaviruses. The rotavirus parent strains of the
reassortants were isolated from human and bovine hosts. Four reassortant
rotaviruses express one of the outer capsid proteins (i.e., G1, G2, G3,
or G4) from the human rotavirus parent strain and the attachment
protein (i.e., P7[5]) from the bovine rotavirus parent strain. The fifth
reassortant virus expresses the attachment protein (i.e., P1A[8]) from
the human rotavirus parent strain and the outer capsid protein (i.e.,
G6) from the bovine rotavirus parent strain. The reassortants are
propagated in Vero cells using standard tissue culture techniques.
RV5 vaccine is provided in a squeezable plastic dosing tube with a
twist-off cap designed to allow for the vaccine to be administered directly
to infants by mouth. Each tube contains a single 2-mL dose of the
vaccine as a buffered-stabilized liquid solution.
The human rotavirus vaccine (RV1) is a G1 P1A[8] virus attenuated
by passage in cell culture. RV1 is provided as a lyophilized powder that
is reconstituted with a supplied diluent before administration.
Both rotavirus vaccines must be stored at refrigerator temperatures
(2°C–8°C [35°F–46°F]) and protected from light. RV1 diluent may be
stored at room temperature. The vaccines must not be frozen. The shelf
life of properly stored vaccine is 24 months. RV5 should be administered
as soon as possible after being removed from refrigeration. RV1 should
be administered within 24 hours of reconstitution. Reconstituted RV1
may be stored at refrigerator or room temperature.
No studies have addressed the interchangeability of the rotavirus
vaccines.
Immunogenicity and Efficacy
The immune correlates of protection from rotavirus infection and disease
are not fully understood. In a large phase III clinical trial of RV5, an
increase in titer of rotavirus group-specific serum IgA antibodies was
used as one of the measures of the immunogenicity. Serum samples
were obtained from a subset of study participants before they were
immunized and approximately 2 weeks after they received the third
dose. Seroconversion was defined as a threefold or greater increase in
antibody titer from baseline. Seroconversion rates for IgA antibody to
rotavirus were 95% among vaccine recipients and 14% among recipients
of the placebo.660
The efficacy of RV5 was evaluated in two phase III trials.83,660 In
these trials, the efficacy of RV5 after completion of a three-dose regimen
against rotavirus gastroenteritis of any severity was 74%, and against
severe rotavirus gastroenteritis, it was 98 percent. Efficacy was observed
against all G1 to G4 and G9 serotypes, but relatively few non-G1 rotavirus
cases were reported. RV5 reduced the incidence of office visits by 86%,
emergency department visits by 94%, and hospitalizations for rotavirus
gastroenteritis by 96%. The efficacy of RV5 in the second rotavirus
season after immunization was 63% against rotavirus gastroenteritis
of any severity and 88% against severe rotavirus gastroenteritis.
Neither breastfeeding nor concurrent administration of other child-
hood vaccines appears to diminish the efficacy of a three-dose series
of RV5. The efficacy of RV5 between doses of a three-dose series and
with less than three doses (i.e., incomplete regimen) was explored in
post hoc analyses of the large efficacy study of RV5. The vaccine reduced
the rates of combined hospitalizations and ED visits for G1 through
G4 rotavirus gastroenteritis by 100% between doses 1 and 2 and 91%
between doses 2 and 3. RV5 reduced the rates of rotavirus gastroenteritis
regardless of serotype by 82% between doses 1 and 2 and 84% between
doses 2 and 3.237
Phase III clinical trials of RV1 efficacy have involved more than
21,000 infants 6 through 12 weeks of age, primarily in two studies in
Latin America and Europe.569,658 After completion of a two-dose RV1
regimen, the efficacy of rotavirus vaccine against severe rotavirus
gastroenteritis (i.e., Latin American study) was 85%, and against any
rotavirus gastroenteritis (i.e., European study), it was 87%. RV1 reduced
hospitalization for rotavirus gastroenteritis by 85% to 100%, depending
on the study. The efficacy of fewer than two doses is not known.
Adverse Events
Safety with respect to intussusception was evaluated for 71,725 subjects
enrolled in phase III efficacy trials of RV5.83,660 For the prespecified
42-day postimmunization end point, six cases of intussusception were
observed in the RV5 group versus five cases of intussusception in the
placebo group (multiplicity-adjusted relative risk, 1.6). The data did
not suggest an increased risk of intussusception relative to placebo.
Among vaccine recipients, no confirmed cases of intussusception occurred
within the 42-day period after administration of the first dose, which
was the period of highest risk for the previously licensed RRV-TV vaccine.
No evidence of clustering of cases of intussusception was observed
within a 7- or 14-day window after immunization for any dose. For
the 1-year follow-up period after administration of the first dose, 13
cases of intussusception were observed in the RV5 group versus 15
cases of intussusception in the placebo group (multiplicity-adjusted
relative risk = 0.9).
Some studies performed outside the United States detected a low
level of increased risk of intussusception after rotavirus immunization
shortly after the first dose. The level of risk observed in these postmarket-
ing studies is substantially lower than the risk of intussusception after
immunization with RotaShield, the previous rotavirus vaccine.100,524,655
US postmarketing studies have also identified a small increased risk of
intussusception with RV5 and RV1, usually within a week after the first
or second vaccine dose. This additional risk is estimated to range from
about one case per 20,000 to 100,000 US infants who receive rotavirus
vaccine.73,325,601,679,708
Both vaccines are well tolerated and have a low reactogenicity profile
when given alone. They do not cause clinically significant increases in
reactogenicity when coadministered with other routine childhood
vaccines.234,563 For both vaccines, the incidence of fever, vomiting, diarrhea,
and irritability were measured in the clinical trials. For RV5, no significant
difference versus placebo was observed in the incidence of fever or
severe fever and irritability or severe irritability. A 3% increase in the
incidence of diarrhea and vomiting was observed with RV5, but these
symptoms were mild and did not require treatment.83,236,660 For RV1,
no difference versus placebo was observed in the incidence of diarrhea,
fever or severe fever, vomiting or severe vomiting, and irritability or
severe irritability within 14 days of immunization with any dose.235,535,657,659
There was no statistically significant increased risk of death or other
serious adverse events with either vaccine compared with placebo.
Vaccine virus shedding in stool has been documented for both
rotavirus vaccines. Rotavirus shedding occurs in approximately 9% of
RV5 recipients after the first dose but rarely after subsequent doses.236
For RV1, live rotavirus shedding in stool occurs in approximately 25%
of recipients, with peak excretion occurring about day 7 after the first
dose. With the use of more sensitive real-time PCR tests for rotavirus
shedding, detection rates for viral shedding were demonstrated in 20%
to 30% in recipients of RV5 and in 80% to 90% of those receiving
RV1.355,611 Both vaccines have been transmitted from vaccine recipients
to unvaccinated siblings, but no significant gastrointestinal symptoms
were seen in the unvaccinated sibling after transmission.527,559 Shedding
and transmission are not considered significant safety concerns because
of the attenuated nature of the rotavirus vaccine strains and the lack
of severe gastrointestinal symptoms after transmission.
In 2010, porcine circovirus or porcine circovirus DNA was detected
in both rotavirus vaccines.68,297,413,469 There is no evidence that this virus
is a safety risk or causes illness in humans.412
Indications
Infants should receive three doses of RV5 administered orally at 2, 4,
and 6 months of age or two doses of the RV1 at 2 and 4 months of
age.24,217 The first dose should be administered when the child is between
6 and 14 weeks of age (i.e., on or before 14 weeks, 0 days of age).
Subsequent doses should be administered at a minimum of 4-week
intervals, and all doses of vaccine should be administered by the time
the child is 32 weeks of age (i.e., on or before 32 weeks, 0 days).
Immunization should not be initiated for infants older than 14
weeks because of insufficient data on the safety of the first dose of
rotavirus vaccine in older infants. Vaccine should not be administered
after 8 months of age because of insufficient data on the safety and
efficacy of rotavirus vaccine in infants after this age. For infants for
whom the first dose of rotavirus vaccine is inadvertently administered
off-label at 15 weeks or older, the rest of the rotavirus immunization
series should be completed according to the schedule defined earlier

because timing of the first dose should not affect the safety and efficacy
of the second and third doses.
The rotavirus vaccine series should be completed with the same
product whenever possible. However, vaccination should not be deferred
if the product used for a prior dose or doses is not available or is not
known. In this situation, the provider should continue or complete the
series with the product that is available. If any dose in the series was
RV5 (RotaTeq) or the vaccine brand used for any prior dose in the
series is not known, a total of three doses of rotavirus vaccine should
be administered. Infants documented to have had rotavirus gastroenteritis
before receiving the full course of rotavirus immunizations should still
start or complete the three-dose schedule because the initial infection
frequently provides only partial immunity.
Infants who are being breastfed can receive rotavirus vaccine. Like
other childhood vaccines, rotavirus vaccine can be administered to
infants with transient, mild illnesses, with or without low-grade fever.408
Rotavirus vaccine can be administered together with DTaP, Hib, IPV,
hepatitis B, and pneumococcal conjugate vaccines.
The AAP and ACIP support immunization of preterm infants under
the following conditions. The infant is at least 6 weeks of age, the infant
is clinically stable, and the first dose of vaccine is given at the time of
discharge or after the infant has been discharged from the hospital
nursery.
Infants living in households with people who have or are suspected
of having an immunodeficiency disorder or impaired immune status
or with a pregnant woman can be immunized. To minimize potential
virus transmission, all members of the household should employ
measures such as good handwashing after contact with the feces of the
immunized infant (e.g., after changing a diaper) for at least 1 week
after the first dose of rotavirus vaccine has been given.
An infant who regurgitates, spits out, or vomits during or after
receiving a dose of rotavirus vaccine should not have that dose re-
administered. The infant can receive the remaining recommended doses
of rotavirus vaccine at appropriate intervals. If a recently immunized
child is hospitalized for any reason, no precautions other than standard
precautions need be taken to prevent the spread of vaccine virus in the
hospital setting.
Contraindications and Precautions
Rotavirus vaccine should not be administered to infants who have severe
hypersensitivity to any component of the vaccine or individuals who
have experienced a serious allergic reaction to a previous dose of rotavirus
vaccine.24,217 The RV1 oral applicator contains latex rubber. RV5 may
be preferred for children at high risk for latex sensitization.
Practitioners should consider the potential risks and benefits of
administering rotavirus vaccine to infants with known or suspected
altered immunocompetence. Children and adults who are immuno-
compromised because of congenital immunodeficiency, bone marrow
transplantation, or solid organ transplantation sometimes experience
severe, prolonged, and even fatal rotavirus gastroenteritis. However,
no safety or efficacy data are available for the administration of
rotavirus vaccine to infants who are potentially immunocompromised
with the exception of infants with severe combined immune
deficiency (SCID). SCID is a contraindication for the use of both rotavirus
vaccines.157 Gastroenteritis, including severe diarrhea and prolonged
shedding of vaccine virus, has been reported in infants who were
administered live oral rotavirus vaccines and later identified as having
SCID.61
Rotavirus vaccine should not be administered to infants with acute,
moderate to severe gastroenteritis until the condition improves. Rotavirus
vaccine has not been studied among infants with concurrent acute
gastroenteritis, in whom its immunogenicity and efficacy theoretically
can be compromised. Infants with moderate to severe illness should
be immunized as soon as they have recovered from the acute phase of
the illness.
Infants with preexisting chronic gastrointestinal conditions and who
are not undergoing immunosuppressive therapy should benefit from
rotavirus vaccine immunization, and the benefits outweigh the theoretical
risks. However, the safety and efficacy of rotavirus vaccine have
not been established for infants with these preexisting conditions (e.g.,
CHAPTER 245  Active Immunizing Agents 2581
congenital malabsorption syndromes, Hirschsprung disease, short-gut
syndrome, persistent vomiting of unknown cause).
A history of intussusception is a contraindication for the use of
both rotavirus vaccines.165 Some data suggest that infants with a history
of intussusception may be at higher risk for a repeat episode than other
infants.
Rubella Vaccine
Rubella is a viral disease that usually manifests as a mild febrile rash
illness in adults and children; however, 20% to 50% of infected people
are asymptomatic. Rubella can have severe adverse effects on the fetuses
of pregnant women who contract the disease during the first trimester
of pregnancy. It causes a wide range of congenital defects known as
congenital rubella syndrome (CRS). The primary objective of the rubella
vaccination program is to prevent intrauterine rubella infection. The
primary strategies for rubella control in the United States are universal
childhood vaccination, prenatal screening of pregnant women for rubella
immunity, and vaccination of rubella-susceptible women after
delivery.
In the prevaccine era, epidemics of rubella occurred every 6 to 9
years, with the last major epidemic in the United States taking place in
1964 through 1965.694 The incidence of reported cases of rubella fell
sharply after routine rubella immunization of young children was initiated
in the United States in 1969. From the estimated 2 million cases per
year in the prevaccine era, fewer than 1000 cases were reported in 1983.
During 1989 through 1991, a resurgence of rubella occurred, primarily
because of outbreaks among unvaccinated adolescents and young adults
who initially were not recommended for vaccination and in religious
communities with low rubella vaccination coverage.107 As a result of
the rubella outbreaks, two clusters of approximately 20 CRS cases
occurred.424,475 Outbreaks during the mid-1990s occurred in settings
where young adults congregated and involved unvaccinated people who
belonged to specific racial or ethnic groups.121 Further declines occurred
as rubella vaccination efforts increased in other countries in the WHO
Region of the Americas. From 2001 through 2004, reported rubella and
CRS cases were at an all-time low, with an average of 14 reported rubella
cases a year, four CRS cases, and one rubella outbreak (defined as three
or more cases linked in time or place).550
In October 2004, 35 years after initiation of the rubella immunization
program, an independent panel of international experts was convened
by the CDC to assess progress toward elimination of rubella and CRS.
Based on data showing fewer than 25 cases of rubella reported each
year since 2001, at least 95% vaccination coverage among school-aged
children, an estimated 91% population immunity, adequate surveillance
to detect rubella outbreaks, and a pattern of virus genotypes consistent
with virus originating in other parts of the world, panel members
concluded unanimously that rubella was no longer is endemic in the
United States.549
Rubella continues to be endemic in many parts of the world.
Internationally imported rubella cases may give rise to indigenous
transmission. From 2005 through 2011, a median of 11 rubella cases
was reported each year in the United States (range, 4–18). Two rubella
outbreaks involving three cases and four total CRS cases were reported.
Among the 67 rubella cases reported from 2005 through 2011, a total
of 28 cases (42%) were known importations.551 In 2011, an expert panel
reviewed available data and unanimously agreed that rubella elimination
had been maintained in the United States.520
From 2012 through 2015 a total of 29 rubella cases (range, 5–9
cases/year) and 6 CRS cases (range, 1–3 cases/year) have been reported
in the United States. The United States needs to continue its vigilance
against rubella and CRS by maintaining high vaccination rates among
children; ensuring vaccination among women of childbearing age,
especially women born outside the United States; continuing surveillance
of rubella and CRS; and responding rapidly to any outbreak.146
Preparations
Since 1979, RA 27/3 (Rubella abortus, 27th specimen, third extract)
vaccine, prepared in human diploid tissue culture, has been the only
vaccine available in the United States; it replaced the earlier HPV-77
and Cendehill vaccines. RA 27/3 induces higher antibody titers and
2582 PART V  Prevention of Infectious Diseases
more closely parallels the immune response after natural infection than
did previous vaccines.314,420,425,515,676 Two rubella-containing vaccines,
MMR and MMRV, are available. Both vaccines should be kept at 2°C
to 8°C (35.6°F–46.4°F) or colder during storage and should be protected
from light to avoid inactivation of the virus. After reconstitution, the
vaccine should be used within 8 hours.
Immunogenicity and Efficacy
Immunization with rubella vaccine induces humoral and cell-mediated
immunity. At least 95% of susceptible vaccinees 12 months or older
develop antibody titers that are protective after a single dose of
vaccine.275,281,288,607,639,676 After a second dose of rubella vaccine, approxi-
mately 99% had detectable rubella antibody and approximately 60%
had a fourfold increase in titer.372,404,423
Follow-up studies indicate that one dose of rubella vaccine can
provide long-lasting immunity. Vaccine-induced rubella antibodies have
persisted in more than 90% of vaccinees 16 years after receiving a single
dose of vaccine, but antibody levels decreased over time.190,345,353,421,540
Although levels of vaccine-induced rubella antibodies can decrease over
time, data from surveillance of rubella and CRS suggest that waning
immunity with increased susceptibility to rubella disease does not occur.
Among people receiving two doses, approximately 91% to 100% had
detectable antibodies 12 to 15 years after receiving the second dose.227,423
Outbreaks of rubella in vaccinated populations are rare. Studies
demonstrate rubella vaccine is approximately 97% effective in preventing
clinical disease after a single dose (range, 94–100%).69,225,283
Lifelong protection against clinical reinfection or asymptomatic
viremia, or both, usually results from a single dose of vaccine given
early in childhood. In some cases, vaccinees exposed to natural rubella
developed a rise in antibody titer unassociated with clinical symptoms.
Reinfection is associated only rarely with viremia. Significant pharyngeal
shedding also is observed infrequently. Person-to-person transmission,
however, has not been reported. Reinfection caused by wild-type rubella
virus also may be observed in individuals with previous natural rubella
infection. The risk of CRS developing from rubella reinfection during
pregnancy is extremely low.561
Adverse Events
Rubella vaccines usually are well tolerated. The most frequent complaints
after vaccination are fever, lymphadenopathy, or rash, which occur in
5% to 15% of children 5 to 12 days after receiving vaccination.44 Transient
peripheral neuritis (i.e., paresthesia and pain in the arms and legs) has
been observed uncommonly, primarily in older age groups.580
Approximately 3% of children have transient joint manifestations,
including arthralgia and, less commonly, arthritis 1 to 3 weeks after
being immunized. Although 25% of women report having joint pain
after being vaccinated, arthritis with objective clinical findings lasting
less than 10 days occurs in 13% to 15%. Cases of persistent or recurrent
joint symptoms have been reported but are rare events. In 1992, the
IOM reviewed the existing data on rubella and adverse joint events and
concluded that the evidence available was consistent with a causal
relationship between rubella vaccination and chronic arthritis in women,
although data on current vaccine strains are limited.354 The incidence
of joint manifestations after immunization is lower than that after natural
infection at the corresponding age.
Rubella revaccination is well tolerated, even among college-aged
and older vaccinees, and it is associated with a much lower incidence
of adverse reactions than primary rubella immunization of young
adult populations. Reported rates of joint-related complaints of 4% to
18% after revaccination are lower than those reported after primary
vaccination.186,590
Indications
Live virus rubella vaccine usually is recommended for all children 12
months or older. It is given as MMR or MMRV when children are 12
to 15 months of age.44,471 A second dose of rubella vaccine administered
as MMR or MMRV is given at the time they enter school, usually 4 to
6 years of age, according to recommendations for routine measles
immunization. The vaccine should be provided to previously unim-
munized preschool-aged children or older schoolchildren despite a
history of having clinical rubella, unless serologic tests confirm
immunity.
Emphasis should be placed on the immunization of the postpubertal
male and female population, especially college students and those in
the military. Rubella vaccine also should be administered to adolescent
girls and women of childbearing age who lack a history of previous
vaccination. Other opportunities for immunization include premarital
screening, routine gynecologic examinations, visits for neonatal and
well-child care, or other medical visits. The immediate postpartum
period is an excellent time for giving immunizations. Rubella vaccine
can be given after administration of anti-Rho(D) immune globulin,
but serologic testing to determine whether seroconversion has occurred
should be performed at least 8 weeks after vaccination. When practical,
potential vaccinees may be screened for susceptibility. However, vaccina-
tion of girls and women of childbearing age is justifiable and may be
preferable, without previous serologic testing of women not known to
be pregnant.
Adults in the United States who were born in countries where rubella
vaccination was not offered are at higher risk for contracting rubella
and having infants with CRS. Health care practitioners who treat foreign-
born adults should document the rubella immunity of these patients
with a written record of rubella-containing vaccine or by serologic
testing. Susceptible adults, especially women of childbearing age, should
be vaccinated. During rubella outbreaks, all susceptible people who
have no contraindications to rubella vaccine should be identified and
vaccinated.
Precautions and Contraindications
Specific contraindications to the administration of live rubella vaccine
include pregnancy; severe febrile illness; known history of anaphylactic
reaction to rubella vaccine, gelatin, or neomycin, which are contained
in the vaccine; and immunodeficiency conditions (i.e., malignancy,
primary immunodeficiency disease, immunosuppressive or corticosteroid
therapy, and radiation therapy).44,471 People with mild immunosuppres-
sion, such as those with asymptomatic HIV infection or those taking
short-term or low-dose corticosteroids, may be vaccinated.
Postpubertal women of childbearing age who are known to be
pregnant or who are attempting to become pregnant should not be
vaccinated. Vaccinated women should be counseled about the need to
avoid pregnancy for 28 days after receiving vaccination.471 Although
pregnancy is a contraindication to administering rubella vaccination,
the maximal theoretical risk to the fetus is estimated to be 2.6%.545
From 1979 until 1989, the CDC registered 321 susceptible women who
inadvertently had received RA 27/3 rubella vaccine within 3 months
before or after conception and carried their pregnancies to term. None
of their infants had defects compatible with CRS, although 2% had
serologic evidence of intrauterine infection.113 Because rubella virus
has been isolated from the products of conception of women vaccinated
during pregnancy, continued caution with respect to vaccination during
pregnancy is advised. However, the evidence available indicates that
rubella vaccination inadvertently given during pregnancy ordinarily
does not represent a reason to consider interruption of pregnancy.
Although vaccine virus may be isolated from the pharynx, vaccinees
do not transmit rubella to others, except in the case of a vaccinated
breastfeeding mother. In this situation, the infant may be infected through
breast milk, and a mild rash illness may develop, but serious adverse
effects have not been noted. Infants infected through breastfeeding
respond normally to rubella vaccination at 15 months of age. Breastfeed-
ing is not a contraindication to receiving rubella vaccination.
Concern about potential transmission of disease from immunized
children to susceptible contacts, including pregnant women, has not
been supported by studies of susceptible household contacts. Susceptible
children whose household contacts are pregnant may be vaccinated.
People with a history of thrombocytopenia may experience throm-
bocytopenia after receipt of MMR vaccine. The decision to vaccinate
should depend on the benefits of immunity compared with the risk of
recurrence or exacerbation of thrombocytopenia after vaccination or
during natural infection with measles or rubella.
Rubella vaccine should not be given during an interval beginning
2 weeks before and extending 3 months after the administration of

immune globulin or blood transfusion. Because rubella vaccine usually
is given as MMR or MMRV, and evidence suggests that high doses of
immune globulin preparations can inhibit the immune response to
measles vaccine for 3 or more months, depending on the dosage, rubella
vaccination with MMR or MMRV necessitates deferral for longer periods
(see Measles Vaccine).44,471,603
Tetanus Toxoid
The efficacy of active immunization against tetanus was demonstrated
most dramatically in military personnel during World War II, when tetanus
toxoid virtually eliminated tetanus in injured servicemen. Since the 1940s,
routine immunization of civilians in the United States with tetanus toxoid
has been successful in almost eliminating tetanus. In most cases, disease
has been reported in unimmunized or inadequately immunized individu-
als.114 The primary three-dose series of a tetanus toxoid–containing vaccine
confers protective immunity for 10 years or longer.90,405
Without a tetanus booster, immunity wanes over time. The potential
for occurrence of tetanus is indicated by the significant number of
adults in the United States who lack protective concentrations of serum
antibody.289 Between 2001 and 2008, 233 cases of tetanus were reported
in the United States with a case-fatality rate of 13%. In 22 of these
cases, the children were between the ages of 5 and 19 years, and 16 had
received one or no tetanus immunizations. There were no deaths in
this age group.168
Neonatal tetanus also has been almost eliminated in the United
States. However, it is a leading cause of morbidity in neonates in
developing countries. As a result, global elimination of neonatal tetanus
remains a goal of the WHO. Because the spores of tetanus are distributed
widely in the environment, the risk of infection among the unimmunized
is constant. This is a fact not necessarily appreciated by parents who
refuse immunization in the belief that widespread immunization in
the general population will confer some protection on the unimmunized,
as was demonstrated by two cases of tetanus in children in Oklahoma
in 2012.246,375
Preparations
Tetanus toxoid is prepared by formaldehyde treatment of Clostridium
tetani toxin.90,405 It has been prepared in fluid and aluminum salt-adsorbed
preparations, but in the United States, only the latter is available. Fluid
toxoid preparations result in a significantly shorter duration of immunity
than that induced by aluminum-adsorbed antigens; therefore, adsorbed
antigens are recommended.
Tetanus toxoid is available in combination with diphtheria toxoid
and acellular pertussis vaccine (DTaP) for routine administration to
infants and children younger than 7 years and for adolescents and adults
11 years or older as a single booster (Tdap). For all people for whom
pertussis vaccine is contraindicated, tetanus toxoid is combined with
diphtheria toxoid as DT or Td (see Diphtheria Toxoid).
The first two Tdap vaccines approved for use in adolescents and
adults in the United States—Boostrix (GlaxoSmithKline Biologicals)
and Adacel (Sanofi Pasteur)—were licensed in 2005. Preparations of
DT, Td, and Tdap are identical in the amounts of tetanus toxoid they
contain, but they differ in the quantity of diphtheria toxoid. The dose
of Tdap is the same as that of DT or Td (0.5 mL) and is administered
intramuscularly.
Immunogenicity and Efficacy
Adequate primary immunization provides sufficient protective titers
of antitoxin for at least 10 years and ensures prompt, anamnestic
responses to subsequent booster injections. Immune response to
tetanus toxoid was measured after administration of each adult Tdap
vaccine and compared with that elaborated after Td vaccine. Seroprotec-
tive anti-tetanus antibody concentrations, defined as a titer 0.1 IU/mL
or greater, and booster response rates to tetanus were determined to
be noninferior after vaccination with Tdap compared with Td
vaccination.90,405
Adverse Events
Local reactions of pain, swelling, and induration can occur, but these
reactions in children usually are attributable to the pertussis component
CHAPTER 245  Active Immunizing Agents 2583
contained in the vaccine rather than to response to tetanus toxoid.47
Hypersensitivity reactions can occur in adolescents and adults but rarely
are severe. Neurologic reactions occurring after the administration of
tetanus toxoid are rare events. Reactions include brachial neuritis and
Guillain-Barré syndrome.
Regarding adverse reactions reported after Tdap, vaccination with
Boostrix was associated with a statistically higher rate of moderate to
severe headache compared with Td, and that with Adacel was associated
with higher rates of mild injection site pain and low-grade fever compared
with the Td vaccine. No serious adverse events have been reported for
Boostrix. Two cases of serious adverse advents (both characterized as
neuropathic reactions) in adults possibly related to having received
Adacel (none reported in adolescents) have been reported, and in both
cases, symptoms resolved completely within several days.90,405
Indications
Preexposure indications.  For primary immunization, doses of tetanus
toxoid provided as DTaP should be administered when the child is 2,
4, and 6 months of age.21,47,90 A fourth dose is given 6 to 12 months
after the third dose (i.e., at 12 to 18 months of age) to maintain adequate
serum antibody concentrations for the ensuing preschool years. For
children younger than 7 years not immunized in infancy, an initial dose
of DTaP is given with subsequent doses 2, 4, and 10 to 16 months later,
followed by a single booster dose at age 4 to 6 years, just before school
entry.
In 2005, the FDA licensed two Tdap vaccines for routine use in
adolescents and adults. Adacel (Sanofi Pasteur) is approved for people
11 to 64 years of age, and Boostrix (GlaxoSmithKline Biologicals) is
approved for children and adolescents 10 years or older. These vaccines
are approved for one-time use only in individuals who have previously
completed their primary vaccination series with DTP or DTaP as a
substitute for their next Td booster.171 The preferred age for Tdap
vaccination is 11 to 12 years. Catch-up vaccination with Tdap is encour-
aged for adolescents 13 to 18 years old who completed their primary
series with DTP or DTaP and have not received a Td or Tdap booster.
Adolescents 11 through 18 years of age who received Td but not
Tdap are encouraged to receive a single dose of Tdap to provide protec-
tion against pertussis if they have completed the recommended childhood
DTP/DTaP immunization series. Tdap should be administered regardless
of the interval since the last tetanus or diphtheria toxoid–containing
vaccine. Although longer intervals between Td and Tdap may decrease
the occurrence of local reactions, the benefits of protection against
pertussis outweigh the potential risk of adverse events.47,171 Every 10
years thereafter, tetanus booster should be provided by Td.
Adolescents between the ages of 11 and 18 years who have never
been vaccinated against tetanus, diphtheria, or pertussis should receive
Tdap initially, followed by Td for the subsequent two doses 4 or more
weeks and then 6 to 12 months later. For children between the ages of
7 and 10 years who have not been vaccinated previously, Tdap vaccine
should substitute an initial dose of Td in the catch-up series, followed
by two subsequent doses of Td vaccine at 4 or more weeks, and 6 to
12 months after the previous dose.47,171 Interruption of the recommended
schedule or delay in administering subsequent doses during primary
immunization does not reduce immunity.
Antepartum indications.  In areas of the world where the risk of acquiring
neonatal tetanus is significant, previously unimmunized, pregnant women
should receive two antepartum doses of a tetanus toxoid–containing
vaccine spaced at least 4 weeks apart. The second dose should be given
at least 2 weeks before delivery. The woman should complete the three-
dose series in 6 to 12 months.318,405 Tdap should be substituted for the
first Td dose if Tdap has not been administered previously. In the
United States, immunization with Tdap is recommended during each
pregnancy, preferably in the early third trimester.171,175 If vaccination is
not provided before delivery or during pregnancy, women who have
not received Tdap vaccine previously should receive a single dose of
Tdap in the immediate postpartum period, preferably before being
discharged from their hospital or birthing center.
Postexposure wound management.  The potential need for immuno-
prophylaxis is an integral aspect of wound management at the time
of trauma or injury. The recommended use of tetanus toxoid in
2584 PART V  Prevention of Infectious Diseases
TABLE 245.17  Recommended Tetanus
Prophylaxis in Wound Management
CLEAN, MINOR ALL OTHER
WOUNDS WOUNDSa
History of Td or Td or
Tetanus Toxoid Tdapb TIG Tdapb TIG
<3 doses or unknown Yes No Yes Yes
≥3 doses Noc No Nod No
a
Including wounds contaminated with dirt, feces, soil, and saliva; puncture wounds;
avulsions; and wounds resulting from missiles, crushing, burns, and frostbite.
b
For children <7 y; diphtheria–tetanus–acellular pertussis (DTaP) or diphtheria-tetanus (DT)
(depending on vaccine status of patient) is preferred to tetanus toxoid (TT) alone. Tdap is
preferred over Td for underimmunized children ≥7 y who have not received Tdap
previously.47 Td is preferred to TT for adolescents who received Tdap previously or when
Tdap is not available.
c
Yes if ≥10 y since last tetanus-containing vaccine dose.
d
Yes if ≥5 y since last tetanus-containing vaccine dose. More frequent boosters are not
needed and can accentuate side effects.
Td, Tetanus-diphtheria; Tdap, tetanus–diphtheria–acellular pertussis; TIG, tetanus
immune globulin.
addition to tetanus immune globulin at the time of injury is given in
Table 245.17. To ensure adequate immunity, children and adults receiving
tetanus toxoid for wound management should be given age-appropriate
preparations of vaccines containing diphtheria and pertussis, unless
contraindicated, and tetanus toxoid. Tdap is preferred over Td if the
person has not received Tdap previously.47,171 Specific recommendations
depend on the individual’s immunization status, the nature of the wound,
and the duration of time between when the injury occurred and evalu-
ation and treatment were undertaken.
After prophylaxis is provided, primary immunization should be
completed subsequently in those lacking the recommended number of
doses. This conservative approach to the frequent administration of
booster doses of tetanus toxoid in wound management for previously
immunized people is supported by the prolonged immunity from tetanus
vaccination and the increased incidence of hypersensitivity reactions
associated with receipt of frequent booster injections.529 Patients con-
valescing from tetanus infection should complete active immunization
because infection often does not confer immunity.
Precautions and Contraindications
A history of having an immediate, severe hypersensitivity reaction to
tetanus toxoid–containing preparations that is severe or anaphylactic
in type is a contraindication to receiving further vaccination.21,47,90,405
People who experience Arthus-type hypersensitivity reactions after
receiving tetanus toxoid or temperature greater than 39.4°C (103°F)
after a previous dose of a tetanus toxoid–containing preparation usually
have high serum tetanus antitoxin concentrations and should not be
given doses of Td more frequently than every 10 years, even if they
have a tetanus-prone wound.47 If an anaphylactic reaction to a previous
dose of tetanus toxoid is suspected, intradermal skin testing may be
helpful in determining whether to discontinue tetanus toxoid
vaccination.367
Because tetanus toxoid administration has been associated with
recurrence of Guillain-Barré syndrome in rare cases,359 the decision to
give additional doses in people with a history of this syndrome within
6 weeks after receipt of tetanus toxoid should be based on consideration
of the benefit of revaccination and the comparative risk of recurrence
of Guillain-Barré syndrome.128 No physician-diagnosed cases of ana-
phylaxis, Arthus reactions, or Guillain-Barré syndrome in any adolescent
or adult after either Tdap vaccine have been reported.
Varicella Vaccine
In the prevaccine era, varicella was endemic in the United States and
virtually all people acquired varicella by the time they reached adulthood.
Varicella infection was responsible for an estimated 4 million cases,
11,000 hospitalizations, and 100 deaths each year in the United States.133
Approximately 90% of cases were children, with the highest incidence
for children 1 to 6 years old.
After introduction and routine use of varicella vaccine in 1995, the
incidence of varicella fell by 90%, deaths from varicella declined by
66%, and rates of hospitalization for varicella decreased by 80%.322,504,715
However, a high frequency of breakthrough varicella (i.e., chickenpox
occurring in a previously vaccinated person) in immunized children
and continuing outbreaks of varicella in schools and in childcare centers
occurred, despite high rates of vaccination.292 Studies showed that over
time the vaccine’s effectiveness was less than 90%,592 and in one study
of healthy children, the rate of seroconversion after one dose of the
vaccine was only 76%.477 In June 2006, the CDC and AAP recommended
a routine two-dose varicella vaccination policy for children (i.e., first
dose at 12 to 15 months and second dose at 4 to 6 years) and catch-up
vaccinations for children, adolescents, and adults who previously had
received only one dose.23,451
Since recommendation of a routine second dose of vaccine in 2006,
the incidence of varicella has declined further among children. Data
show that administration of two doses of varicella vaccine is associated
with higher antibody titers, presumably offering better protection from
varicella.415 Results from a controlled study of the effectiveness of two
doses of varicella vaccine indicated that administration of two doses
was highly effective in preventing varicella in the first 2.5 years after
implementation of the two-dose schedule to prevent disease.595 Odds
of developing varicella were 95% lower for children who received two
doses compared with one dose of varicella vaccine.
Preparations
Three varicella-containing vaccines are approved for use in the United
States: varicella vaccine (Varivax), combination MMRV vaccine
(ProQuad), and herpes zoster vaccine (Zostavax). Varicella vaccine was
licensed in the United States in 1995. It is a preparation of the Oka
strain of varicella-zoster virus (VZV) obtained from the vesicle fluid
of a healthy child with varicella that has been attenuated by serial
propagation in human embryo lung fibroblasts, guinea pig embryonic
cells, and human diploid cell cultures. The vaccine contains trace amounts
of neomycin, fetal bovine serum, sucrose, residual components of human
diploid (MRC-5) cells, and gelatin. The vaccine does not contain
preservatives.
Varicella vaccine is lyophilized and stored frozen at −15°C or colder
until reconstituted. Any freezer that reliably maintains an average
temperature of −15°C and has a separate sealed freezer door is acceptable
for storing vaccine. The vaccine also may be stored at refrigerator
temperature (2°C–8°C) for as long as 72 hours before reconstitution.
Vaccine stored at 2°C to 8°C that is not used within 72 hours should
be discarded. Reconstituted vaccine should be stored at room temperature
and discarded if it is not used within 30 minutes.
In September 2005, a combined live attenuated MMRV vaccine was
licensed for use in children 12 months through 12 years of age.148 The
attenuated measles, mumps, and rubella vaccine viruses in MMRV are
identical and of equal titer to those in the MMR vaccine. The titer of
Oka/Merck VZV is higher in MMRV vaccine than in single-antigen
varicella vaccine. Each 0.5-mL dose contains a small quantity of
hydrolyzed gelatin, human albumin, residual components of MRC-5
cells, neomycin, bovine calf serum, and other buffer and media ingre-
dients. Unlike single-antigen varicella vaccine, MMRV vaccine cannot
be stored at refrigerator temperature. MMRV vaccine must be stored
frozen at an average temperature of −15°C or lower for up to 18 months.
After reconstitution, the vaccine should be used immediately to minimize
loss of potency and should be discarded if it is not used within 30
minutes. The diluent should be stored separately at room temperature
or in the refrigerator. MMRV vaccine contains no preservative.
In May 2006, the FDA approved herpes zoster vaccine for use in
people 60 years or older. No indications for use of this vaccine in children
exist.
Immunogenicity and Efficacy
Varicella vaccine is highly immunogenic in susceptible children.
Seroconversion has occurred in more than 96% of children 12 months
to 12 years of age after one dose of vaccine.685 Preexisting antibody, if

present at 12 months of age, does not appear to interfere with antibody
response. As with other viral vaccines, the antibody response after
immunization is lower than that from natural disease. Adolescents and
adults have age-related decreases in the ability to develop a primary
response to varicella virus.291 Seroconversion rates of 78% to 82% after
one dose and 99% after two doses have been reported in those older
than 12 years.291,685
In studies in the United States and Japan, serum antibodies to varicella
have been detected for as long as 10 to 20 years after immunization in
more than 95% of immunized children.59,376 Antibody concentrations
have persisted for at least 1 year in 97% of adults and adolescents who
were administered two doses of vaccine 4 to 8 weeks apart.291 Cell-
mediated immunity to VZV has been detected in 87% of children and
94% of adults 5 years after vaccination.714
MMRV vaccine was licensed on the basis of equivalence of immu-
nogenicity of the antigenic components, rather than clinical efficacy.
Clinical studies involving healthy children 12 to 23 months of age
indicated that those who received a single dose of MMRV vaccine
developed levels of antibody to measles, mumps, rubella, and varicella
similar to those of children who received MMR and varicella vaccines
concomitantly at separate injection sites.414
Varicella vaccine has been demonstrated to be highly effective in
preventing varicella in children and in reducing the severity of infection
if they do become infected. In prelicensure clinical trials, vaccine was
70% to 90% effective in preventing varicella and more than 95% effective
in preventing severe disease.416,674 Several postlicensure studies have
shown similar results, with vaccine effectiveness ranging from 83% to
100% in preventing varicella and 87% to 100% in preventing severe
disease.195,365,654 In follow-up studies, chickenpox developed in 0.2% to
2.3% of vaccinated children per year after exposure to wild-type varicella
virus, a rate that does not seem to increase with length of time after
immunization.661 These vaccine failure cases are mild, with fewer skin
lesions, lower rates of fever, and faster recovery, and they are less
contagious than are moderate to severe cases of varicella.75,593,661,671 These
infections have been called breakthrough varicella.
Although findings of some studies have suggested otherwise, most
investigations have not identified time since vaccination as a risk factor
for breakthrough varicella. Some investigations have identified asthma,
use of corticosteroids, and vaccination at younger than 15 months as
risk factors for breakthrough varicella.251,286,365,646,656 Breakthrough varicella
infection can result from several factors, including interference of vaccine
virus replication by circulating antibody, impotent vaccine resulting
from storage or handling errors, or inaccurate record keeping. Interference
from live viral vaccine administered before varicella vaccine can reduce
vaccine effectiveness.
A study of 115,000 children in two health maintenance organizations
from 1995 to 1999 found that children who received varicella vaccine
less than 30 days after MMR vaccination had a 2.5-fold increased
risk of breakthrough varicella compared with those who received
varicella vaccine before, simultaneously with, or more than 30 days
after receiving MMR.656 Inactivated vaccines (i.e., DTaP, Hib, IPV, and
hepatitis B) and OPV did not increase the risk of breakthrough varicella
if they were administered less than 30 days before administration of
varicella vaccine.
For adults and adolescents who have seroconverted, varicella vaccine
provides protective efficacy rates of approximately 70% after household
exposure. In the remaining 30%, attenuated disease with fewer skin
lesions and little or no systemic toxicity develops, as in children.291
Adverse Events
Varicella vaccine produces relatively few adverse reactions.596,693 The
most common adverse reactions that occur after receipt of varicella
vaccine are local reactions, such as pain, soreness, erythema, and swelling.
Based on information from the manufacturer’s clinical trials of varicella
vaccine, local reactions after receiving the first dose are reported by
19% of children and by 24% of adolescents and adults.596,693 These local
adverse reactions usually are mild and self-limited.
A varicella-like rash at the site of injection is reported by 3% of
children and by 1% of adolescents and adults after receipt of the second
dose. In both circumstances, a median of two lesions has occurred.
CHAPTER 245  Active Immunizing Agents 2585
These lesions usually occur within 2 weeks and usually are maculopapular
rather than vesicular.596,693
In postlicensure studies, the adverse event most frequently reported
is a mild vesicular rash that occurs in approximately 5% of vaccinees.133,290
Most of these generalized rashes occur within 3 weeks, and most are
maculopapular. In one study, vesicular rashes that occurred within 2
weeks of vaccination were more likely to be caused by wild-type varicella,
whereas rashes that occurred more than 2 weeks after vaccination were
more likely to be caused by the Oka vaccine strain.596
Systemic reactions can occur. Fever within 42 days of vaccination
is reported by 15% of children and 10% of adolescents and adults.
Most of these episodes of fever have been attributed to concurrent
illness rather than to the vaccine.
Clinical trials of MMRV that compared events that occurred within
42 days of receiving MMRV or MMR and varicella vaccine separately
in different anatomic sites found the frequencies of local reactions and
generalized varicella-like rash similar to those described for varicella
vaccine.414 A temperature of 38.9°C (102°F) or higher within 42 days
of vaccination was more common in the MMRV group (22%) than in
the group that received MMR and varicella vaccine at different sites
(15%). A measles-like rash also occurred more frequently in MMRV
recipients (3%) than in those receiving separate injections (2%). Fever
and measles-like rash usually occurred 5 to 12 days after receipt of
vaccination. In a postlicensure study, an increased risk of seizure was
seen among children 12 to 23 months of age receiving MMRV vaccine
compared with those who received MMR and varicella vaccines given
separately in the 7- to 10-day postvaccination period.394
Varicella vaccine is a live virus vaccine and may result in a latent
infection, similar to that caused by wild-type varicella virus. Consequently,
zoster caused by the vaccine virus has been reported, mostly among
vaccinated children. Based on reports to VAERS, the rate of herpes
zoster after varicella vaccination is 2.6 cases per 100,000 vaccine doses
distributed.133 The incidence of herpes zoster after natural varicella
infection in healthy people younger than 20 years is 68 cases per 100,000
person-years,320 and for all ages, it is 215 cases per 100,000 person-years.242
However, the latter rates should be compared cautiously because they
are based on populations monitored for longer periods than the vaccinees
were monitored.
Cases of herpes zoster have been confirmed by PCR to be caused
by vaccine virus and wild-type virus, a finding suggesting that some
herpes zoster disease in vaccinees may result from antecedent natural
varicella infection.133,330 Most cases of herpes zoster that occur after
administration of vaccine have been mild and have not been associated
with complications such as postherpetic neuralgia.
Transmission of the vaccine virus occurs rarely and most often from
immunocompromised vaccinees. Of the 15 million doses of varicella
vaccine distributed, on only three occasions has transmission from
immunocompetent people been documented by PCR analysis.418,574 All
three cases resulted in mild disease without complications. In one case,
a child 12 months old transmitted the vaccine virus to his pregnant
mother.437,574 The mother elected to terminate the pregnancy, but fetal
tissue tested by PCR was negative for varicella vaccine virus. The other
two documented cases involved transmission from healthy children 1
year of age to a healthy sibling 4.5 months of age and to a healthy
father.133 Transmission also has occurred from a person with herpes
zoster caused by vaccine strain virus.94 Transmission has not been
documented in the absence of a vesicular rash after vaccination. No
evidence indicates reversion to virulence of the vaccine strain during
transmission; siblings of leukemic vaccine recipients who acquired
vaccine virus had mild rash in 75% of cases and symptomless seroconver-
sion in 25%.55
Indications
Monovalent varicella vaccine and MMRV have been licensed for use
for healthy children 12 months through 12 years of age.26,23,49,155,450,451
Children in this age group should receive two 0.5-mL doses of varicella
vaccine administered subcutaneously, separated by at least 3 months.
The recommendation for at least a 3-month interval between doses is
based on the design of the studies evaluating two doses in this age
group; if the second dose inadvertently is administered between 28 days
2586 PART V  Prevention of Infectious Diseases
and 3 months after the first dose, the second dose does not need to be
repeated.
All healthy children routinely should receive the first dose of varicella-
containing vaccine at 12 through 15 months of age. The second dose
of vaccine is recommended routinely when children are 4 through 6
years of age (i.e., before a child enters kindergarten or first grade) but
can be administered at an earlier age. Because of the minimal potential
for increased febrile seizures after the first dose of MMRV vaccine in
children 12 through 15 months of age, the AAP and ACIP recommend
a choice of MMR plus monovalent varicella vaccine or MMRV for
toddlers receiving their first immunization of this kind.26,450 Parents
should be counseled about the rare possibility of their child developing
a febrile seizure 1 to 2 weeks after immunization with MMRV for the
first immunizing dose. For the second dose at 4 through 6 years of age,
MMRV usually is preferred over MMR plus monovalent varicella to
minimize the number of injections. Varicella vaccine should be admin-
istered to all children in this age range unless there is evidence of
immunity to varicella or a contraindication to administration of the
vaccine.
A catch-up second dose of varicella vaccine should be offered to all
children 7 years and older who have received only one dose. A routine
health maintenance visit at 11 through 12 years of age is recommended
for all adolescents to evaluate immunization status and administer
necessary vaccines, including the varicella vaccine.
Individuals 13 years or older without evidence of immunity should
receive two 0.5-mL doses of varicella vaccine separated by at least 28
days. The recommendation for at least a 28-day interval between doses
is based on the design of the studies evaluating two doses in this age
group. For people who previously received only one dose of varicella
vaccine, a second dose is necessary. Only monovalent varicella vaccine
is licensed for use in this age group.
Women should be assessed prenatally for evidence of varicella
immunity. On completion or termination of their pregnancies, women
who do not have evidence of varicella immunity should receive the
first dose of varicella vaccine before discharge from the health care
facility. The second dose should be administered 4 to 8 weeks later at
the postpartum or other health care visit. To ensure administration of
varicella vaccine, standing orders are recommended for health care
settings where completion or termination of pregnancy occurs.
Postexposure prophylaxis.  Data from the United States and Japan in
a variety of settings indicate that varicella vaccine is 70% to 100%
effective in preventing illness or modifying the severity of illness if it
is used within 3 days and possibly up to 5 days after exposure.573,672 The
ACIP recommends administration of varicella vaccine to people without
evidence of immunity 12 months or older, including adults, as soon as
possible within 72 hours and possibly up to 120 hours after varicella
exposure.451 Varicella vaccine may prevent or modify disease and should
be considered in these circumstances if there are no contraindications
to its use. A second dose should be given at the age-appropriate interval
after the first dose. Physicians should advise parents and their children
that the vaccine may not protect against disease in all cases because
some children might have been exposed at the same time as the index
case. However, if exposure to varicella does not cause infection, post-
exposure immunization with varicella vaccine will result in protection
against subsequent exposure. There is no evidence that administration
of varicella vaccine during the presymptomatic or prodromal stage of
illness increases the risk of vaccine-associated adverse events or more
severe natural disease.
In 2006, the ACIP approved a revised definition for evidence of
immunity to varicella.451 Revised criteria for evidence of immunity to
varicella include any of the following:
• Documentation of age-appropriate vaccination
• Preschool-aged children 12 months or older: one dose
• School-age children, adolescents, and adults: two doses
• Laboratory evidence of immunity or laboratory confirmation of
disease
• Birth in the United States before 1980
• Diagnosis of varicella or verification of history of varicella disease
by a health care provider
• History of herpes zoster based on health care provider diagnosis
Precautions and Contraindications
Varicella-containing vaccines are contraindicated for pregnancy, severe
febrile illness, known history of anaphylactic reaction to vaccine
components, and immunodeficiency states (i.e., malignancy, primary
immunodeficiency disease, immunosuppressive or corticosteroid therapy,
and radiation therapy).26,23,49,155,450,451
Varicella vaccine should not be administered to people who have
had an anaphylactic-type reaction to any component of the vaccine,
including gelatin and neomycin. Most people with allergy to neomycin
have resulting contact dermatitis, a reaction that is not a contraindication
to immunization. Monovalent varicella vaccine does not contain preserva-
tives or egg protein, and although the measles and mumps vaccines
included in MMRV vaccine are produced in chick embryo culture, the
amounts of egg cross-reacting proteins are not significant. Children
with egg allergy routinely can be given MMRV without previous skin
testing.
Varicella vaccine should not be administered routinely to children
who have congenital or acquired T-lymphocyte immunodeficiency,
including those with leukemia, lymphoma, and other malignant neo-
plasms affecting the bone marrow or lymphatic systems, and children
receiving long-term immunosuppressive therapy. An exception includes
certain children infected with HIV (discussed later). Children with
impaired humoral immunity can be immunized.
Immunodeficiency should be excluded before immunization of
children with a family history of hereditary immunodeficiency. An
immunodeficient or HIV-seropositive household family member does
not contraindicate vaccine use in other family members.
In people with possible altered immunity, immunization against
chickenpox should use only monovalent varicella vaccine. The Oka vaccine
strain remains susceptible to acyclovir. If a high-risk patient develops
vaccine-related varicella, acyclovir should be used as treatment.
Before routine immunization of healthy children against varicella
was instituted in the United States in 1995, many young children with
leukemia were susceptible to chickenpox. Considering the variation in
intensity of chemotherapy regimens and the decreasing incidence of
varicella in the United States, these high-risk children should not be
immunized routinely. Immunization of susceptible leukemic children
without evidence of immunity in remission should be undertaken only
with expert guidance and with availability of antiviral therapy in case
complications occur.
Live virus vaccines usually are withheld for an interval of at least 3
months after immunosuppressive cancer chemotherapy has been dis-
continued. However, the interval until immune reconstruction varies
with the intensity and type of immunosuppressive therapy, radiation
therapy, underlying disease, and other factors. It often is not possible
to make a definitive recommendation for an interval after cessation of
immunosuppressive therapy when live virus vaccines can be administered
safely and effectively.
Screening for HIV infection is not indicated before routine VZV
immunization. Varicella vaccine should be considered for nonimmune
HIV-infected children with a CD4+ T-lymphocyte percentage of 15%
or greater, especially if they are receiving antiretroviral therapy.482 Eligible
children should receive two doses of monovalent varicella vaccine with
a 3-month interval between doses and return for evaluation if they
experience a postimmunization varicella-like rash. Hundreds of HIV-
infected children have been safely immunized in the United States, and
the vaccine is tolerated much as it is in healthy immunized children.
Varicella vaccine has protected these children against varicella and herpes
zoster by preventing infection with wild-type VZV.
Varicella vaccine should not be administered to people who are
receiving high doses of systemic corticosteroids (i.e., 2 mg/kg per day
or more of prednisone or its equivalent or 20 mg/day of prednisone
or its equivalent) for 14 days or more. The recommended interval
between discontinuation of corticosteroid therapy and immunization
with varicella vaccine is at least 1 month. Varicella vaccine may be
administered to people receiving inhaled, nasal, and topical corticosteroids.
The results of one small study indicate that two doses of the varicella
vaccine in 29 children with nephrotic syndrome between 12 months
and 18 years of age usually were well tolerated and immunogenic,
including children receiving low-dose, alternate-day prednisone.

Household contacts of immunocompromised people should be
immunized if they have no evidence of immunity to decrease the
likelihood that wild-type VZV will be introduced in the household.
Transmission of vaccine-strain VZV from healthy people has been
documented in seven instances, resulting in eight secondary cases. Even
in families with immunocompromised people, including people with
HIV infection, no precautions are needed after immunization of healthy
children in whom a rash does not develop. Immunized people in whom
a rash develops should avoid direct contact with immunocompromised
hosts without evidence of immunity for the duration of the rash.
Receipt of antibody-containing blood products (i.e., whole blood,
plasma, or parenteral immune globulin) may interfere with seroconver-
sion to varicella vaccine. The length of time that such passively acquired
antibody persists depends on the concentration and quantity of the
blood product received408 (see Table 245.11).
Although no direct evidence demonstrates that varicella vaccine is
harmful to a pregnant woman or her fetus, the vaccine should not be
administered to women known to be pregnant or considering becoming
pregnant within the month because of the theoretical risk of fetal
infection associated with a live virus vaccine. Vaccinated women should
avoid conception for 1 month after receiving vaccination.
The manufacturer established a Varicella Vaccination in Pregnancy
Registry to monitor the maternal-fetal outcomes of pregnant women
inadvertently given varicella vaccine. The registry was closed in October
2013 because the low rate of exposure of varicella-susceptible women
of childbearing age to VZV-containing vaccines, in addition to the rarity
of the outcome, contributed to the low feasibility of the registry providing
more robust data on the risk of congenital varicella syndrome within
a reasonable timeframe.453 A summary of 18 years of registry data found
no cases of congenital varicella syndrome and no increased prevalence
for other birth defects after exposure to VZV-containing vaccines during
pregnancy. However, the number of exposures was insufficient to exclude
a very low risk of congenital varicella syndrome in varicella-susceptible
women exposed during the high-risk period.689
A study of nursing mothers and their infants showed no evidence
of excretion of vaccine strain in human milk or of transmission to
infants who are breastfeeding. Varicella vaccine should be administered
to nursing mothers who lack evidence of immunity.
Reye syndrome has occurred in children infected with varicella who
receive salicylates. Whether varicella vaccine may induce Reye syndrome
is not known, but the vaccine manufacturer recommends that salicylates
not be given within at least 6 weeks after administration of varicella
vaccine.
Diseases for Which Combination Vaccines Are Available
Many new and improved vaccines have been introduced over the past
20 years. Incorporation of these vaccines into already complex childhood
immunization schedules has posed a challenge. In the 2016 Recommended
TABLE 245.18  Combination Vaccines Licensed in the United Statesa
Vaccineb Trade Name (year licensed)
DTaP-HepB-IPV Pediarix (2002)
DTaP-IPV/Hib Pentacel (2008)
DTaP-IPV Kinrix (2008)
DTaP-IPV Quadracel (2015)
HepA-HepB Twinrix (2001)
Hib-MenCY MenHibrix (2012)
MMRV ProQuad (2005)
a
Excludes measles-mumps-rubella (MMR), DTaP, Tdap, Td, and IPV vaccines, for which individual components are not available. DTaP/Hib (TriHIBit) and Hib/HepB (Comvax) are no longer
manufactured.
b
A hyphen (-) between vaccine products indicates that products are supplied in their final form by the manufacturer and do not require mixing or reconstitution by the user. A slash (/)
indicates that the products must be mixed or reconstituted by the user.
DTaP, Diphtheria–tetanus–acellular pertussis; HepA, hepatitis A; HepB, hepatitis B; Hib, Haemophilus influenzae type b; IPV, inactivated poliovirus; MenCY, meningococcal group CY; MMRV,
measles-mumps-rubella-varicella.
Modified from American Academy of Pediatrics. Combination vaccines. In: Kimberlin DW, Brady MT, Jackson MA, Long SS, eds. Red Book: 2015 Report of the Committee on Infectious
Diseases. 30th ed. Elk Grove Village, IL: American Academy of Pediatrics; 2015:36–7.
CHAPTER 245  Active Immunizing Agents 2587
Immunization Schedule in the United States, a minimum of 22 separate
injections are needed to immunize a child from birth to 2 years of
age.210,560 At some visits, the administration of three to five separate
injections can be indicated.
Combination vaccines represent one solution to the problem of
increased numbers of injections. These vaccines incorporate into a single
product antigens that prevent several diseases. Combinations licensed
in recent years in the United States are shown in Table 245.18.
Licensed combination vaccines can be used when any components
of the combination are indicated and its other components are not
contraindicated and if licensed by the FDA for that dose in the series.408
Use of combination vaccines can reduce the number of injections patients
receive and alleviate parental concerns about the number of injections.
Potential advantages of combination vaccines include improved vaccine
coverage rates, timely vaccination coverage for children who need
catch-up vaccination, reduced shipping and stocking costs, reduced
costs for extra health care visits necessitated by deferral of vaccination,
and facilitation of adding new vaccines into vaccination programs.
Potential disadvantages of combination vaccines include adverse
events that may occur more frequently after administration of a combina-
tion vaccine compared with administration of separate antigens at the
same visit, such as those that occur with the MMRV vaccine and
combination DTaP-hepatitis B-IPV vaccine450,637; confusion and uncer-
tainty about selection of vaccine combinations and schedules for
subsequent doses, especially when vaccinations are given by multiple
providers who might be using different products; reduced immunogenic-
ity of one or more components238; extra doses of certain antigens in
the fixed product (e.g., a provider who uses DTaP-hepatitis B-IPV vaccine
will give an extra dose of hepatitis B component); and a shorter shelf-life
than the individual component vaccines. The economic impact of the
use of combination vaccines is unclear because combination products
have the potential for increased or decreased costs compared with
single-antigen component vaccines.
The minimum age for administration of a combination vaccine is
the oldest minimum age for any of the individual components; the
minimum interval between doses is equal to the greatest minimum
interval of any of the individual components. When patients have received
the recommended immunizations for some of the components in a
combination vaccine, administering the extra antigens in the combination
vaccine is permissible if they are not contraindicated and doing so will
reduce the number of injections required. However, excessive doses of
toxoid vaccines (i.e., diphtheria and tetanus) can result in extensive
local reactions.
Only combination vaccines licensed by the FDA should be used.
Separate vaccines should not be combined into the same syringe for
administration together unless mixing is indicated for the patient’s age
and is explicitly specified on the FDA-approved product label inserts.
Only one combination vaccine (i.e., DTaP-IPV/Hib vaccine [Pentacel])
Age Range Routinely Recommended Ages
6 wk–6 y Three-dose series at 2, 4 and 6 mo
6 wk–4 y Four-dose series at 2, 4, 6, and 15–18 mo
4–6 y Fifth dose of DTaP and fourth dose of IPV
4–6 y Fifth dose of DTaP and fourth or fifth dose of IPV
≥18 y Three doses on a schedule of 0, 1, and 6 mo
2 –23 mo Four-dose series at 2, 4, 6, and 15–18 mo
12 mo–12 y Two doses, the first at 12–15 mo, the second at 4–6 y
2588 PART V  Prevention of Infectious Diseases
contains separate antigen components for which FDA approves mixing
by the user. The safety, immunogenicity, and efficacy of unlicensed
combinations are unknown.
Licensure of a combination vaccine by the FDA is based on studies
demonstrating that the product’s immunogenicity (or efficacy) and
safety are comparable or equivalent to monovalent or combination
products licensed previously. FDA licensure also indicates that a
combination vaccine may be used interchangeably with monovalent
formulations and other combination products with similar component
antigens produced by the same manufacturer to continue the vaccination
series. For example, DTaP, DTaP/Hib, and future DTaP vaccines
that contain similar acellular pertussis antigens from the same manu-
facturer may be used interchangeably if licensed and indicated for the
patient’s age.152
Licensure of a vaccine by the FDA does not necessarily indicate that
the vaccine is interchangeable with products from other manufacturers.
Data are readily available for diseases with known serologic correlates
of protective immunity. For diseases without surrogate laboratory
markers, prelicensure field vaccine efficacy (phase III) trials or postli-
censure surveillance usually are required to determine protection.478
The ACIP prefers that doses of vaccine in a series come from the same
manufacturer; however, if this is not possible or if the manufacturer
of doses of vaccine given previously is unknown, providers should
administer the vaccine that they have available.
VACCINES WITH SELECTIVE INDICATIONS FOR
CHILDREN AND ADOLESCENTS
Bacille Calmette-Guérin Vaccine
Effective control of tuberculosis in the United States has been achieved
by the early identification and treatment of cases, followed by surveillance
of household and other close contacts and institution of appropriate
preventive measures for those at high risk for disease development. In
the United States, the mainstay of preventive therapy is isoniazid
chemoprophylaxis, which is used in asymptomatically infected people
to prevent the progression of infection to disease. In selected instances,
however, the potential for acquiring disease, poor compliance by contacts
instructed to take chemoprophylaxis, or failure of chemoprophylaxis
may justify the use of immunoprophylaxis.127
Bacille Calmette-Guérin (BCG) is not usually recommended for
immunoprophylaxis in the United States because of the low risk of
infection with Mycobacterium tuberculosis, the unpredictable effectiveness
of the vaccine against adult pulmonary tuberculosis, and the vaccine’s
potential interference with tuberculin skin test reactivity. Elsewhere in
the world, BCG vaccine is used in more than 100 countries and is recom-
mended routinely at birth by the WHO696 (http://www.who.int/
immunization/policy/Immunization_routine_table2.pdf?ua=1). Of
primary concern to pediatricians is the risk to an infant born to a
mother with tuberculosis or living within a household with other
identified individuals with tuberculosis.48
Preparations
BCG is the only approved vaccine against tuberculosis. BCG is a live
attenuated strain derived from Mycobacterium bovis. All currently
available BCG vaccines are derived from the original strain at the Pasteur
Institute in Paris, but they have been propagated by different methods
in many laboratories and therefore vary in their immunogenic and
reactogenic properties. BCG (Merck) is the only vaccine licensed in the
United States. Comparative evaluations of this preparation and other
BCG vaccines have not been performed.
BCG is administered only percutaneously using a sterile multiple-
puncture device. The standard dose of BCG vaccine is 0.2 to 0.3 mL
of reconstituted lyophilized BCG. At least 10 new potential vaccines to
prevent tuberculosis are in clinical development.274 Nevertheless, BCG
will remain in use in the foreseeable future and may continue to be
used as a prime vaccine in a prime-boost immunization schedule in
conjunction with new tuberculosis vaccines.383 BCG preparations instilled
in the treatment of bladder cancer are not intended to be used as
vaccines.127
Immunogenicity and Efficacy
BCG is used primarily in young infants in an attempt to prevent dis-
seminated and other life-threatening manifestations of M. tuberculosis
disease. However, BCG does not prevent infection with M. tuberculosis.
The efficacy of different BCG vaccines seems to vary broadly. Two
meta-analyses of published clinical trials and case-control studies
concerning the efficacy of BCG vaccines concluded that BCG has relatively
high protective efficacy (approximately 80%) against meningeal and
miliary tuberculosis in children.207,562 The protective efficacy against
pulmonary tuberculosis, however, differed significantly among the studies,
precluding a specific conclusion. Protection afforded by BCG in one
meta-analysis was estimated to be 50%.207
Adverse Events
Four billion doses of BCG have been administered with a proven safety
record.383 BCG vaccination usually results in scarring at the site of
injection. However, the vaccine has been associated uncommonly (1–2%
of vaccinations) with local adverse reactions such as subcutaneous
abscess and lymphadenopathy, which are not usually serious.
Osteitis affecting the epiphyses of long bones is a rare complication
that develops in 1 of 1 million vaccinees and may occur as long as
several years after receiving BCG immunization. The rate may be higher
among neonates. Disseminated fatal disease occurs rarely (0.1–1 case/1
million vaccinees), primarily in people with severely impaired immune
systems.127,409,438,621
Antituberculosis therapy, except for pyrazinamide, is recommended
to treat osteitis and disseminated disease caused by BCG. Some experts
also recommend treatment of chronic suppurative lymphadenitis caused
by BCG. People with complications caused by BCG should be referred
to a tuberculosis expert for management.
Indications
In the United States, administration of BCG should be considered only
in limited and select circumstances, such as unavoidable risk of exposure
to M. tuberculosis and failure or unfeasibility of other methods of control
of tuberculosis. The ACIP and AAP have published recommendations
for the use of BCG to control tuberculosis in children.33,169 Healthy
infants from birth to 2 months of age may be given BCG without
tuberculin skin testing; thereafter, BCG is given only to children with
a negative tuberculin skin test result. BCG immunization should be
considered for infants and children who are not infected with HIV in
the following circumstances:
• The child is exposed continually to a person or people with contagious
pulmonary tuberculosis resistant to isoniazid and rifampin, and the
child cannot be removed from this exposure.
• The child is exposed continually to a person or people with untreated
or ineffectively treated contagious pulmonary tuberculosis, and the
child cannot be removed from the exposure or given antituberculosis
therapy.
Careful assessment of the potential risks and benefits of BCG vaccine
and consultation with personnel in local area control programs for
tuberculosis are strongly recommended before the use of BCG. When
BCG vaccine is given, care should be taken to observe the precautions
and directions for administration on the product label. Other childhood
vaccines can be administered concurrently with BCG.
Skin Test Reactivity
Recipients of BCG should have repeat tuberculin skin tests 2 to 3 months
after immunization to establish that tuberculin cellular reactivity has
developed. Failure to react dictates the need for repeat BCG vaccination
followed by repeat tuberculin testing.127 The tuberculin reaction to the
BCG vaccine available in the United States usually results in 7 to 15 mm
of induration after vaccination and diminishes gradually during sub-
sequent years. Without revaccination or repeated exposure to M.
tuberculosis, reactivity usually disappears within 10 years.127 The size of
the area of induration may be correlated with the number of doses of
BCG.357 However, tuberculin skin test sensitivity does not correlate with
BCG efficacy.337 In BCG recipients, differentiating between a tuberculin
reaction representing acquired tuberculous infection and persistent
postvaccination reactivity is difficult.

Because the degree and duration of protection against tuberculous
disease afforded by BCG are uncertain, a positive tuberculin reaction
may be indicative of disease. BCG recipients with a positive tuberculin
skin test result should be carefully evaluated with risk assessment,
radiography, and other diagnostic tests, including an interferon-γ release
assay (IGRA), which does not produce cross-reactions after sensitization
by BCG.467
Precautions and Contraindications
BCG vaccine should not be administered to individuals with burns, skin
infections, and certain primary or secondary immunodeficiencies,
including HIV infection, because of the risk of disseminated BCG disease.
The use of BCG vaccine also is contraindicated in people receiving
immunosuppressive medications, including high-dose corticosteroids.
In the United States, where the risk of acquiring tuberculosis is low,
BCG vaccine should not be administered to children with known or
suspected asymptomatic HIV infection.127,510 However, in countries
where the risk of contracting tuberculosis is high and HIV surveillance
of pregnant women and infants is limited, the WHO has recommended
that asymptomatic HIV-infected children receive BCG vaccine at birth
or shortly thereafter.696,695 However, the WHO recommends that BCG
should not be administered to infants known to be infected with HIV
even in resource-poor regions because the risk of disseminated BCG
in these infants is significantly high, approaching 1%.698,699 Although
no harmful effects of BCG vaccine on the fetus have been documented,
women should avoid receiving vaccination during pregnancy.
Cholera Vaccine
The global burden of cholera is difficult to estimate due to underreport-
ing, but experts place the annual number of cases at 2.9 million with
95,000 deaths.8 In 2009, 45 countries reported 221,226 cholera cases
with 4946 deaths to the WHO, with 98% of cases and 99% of deaths
reported from Africa.566 In, 2010, an outbreak of cholera occurred in
Haiti with more than one-half million cases and more than 7000
confirmed deaths. It was the first epidemic in the Western Hemisphere
since the 1991 epidemic in Peru.6 After it emerged in Haiti, cholera
spread to other countries, including the Dominican Republic and Cuba.
From 2001 through 2013, 123 confirmed cases of cholera in the
United States were acquired abroad; of these, 63 were associated with
the epidemic in Hispaniola.436 Most cases of disease have occurred in
travelers to cholera-affected areas or people who have eaten contaminated
food brought or imported from these areas.122 Although cholera remains
a significant public health concern in African, Asian, and South American
countries, even in these countries the risk to US travelers is low. People
following the usual tourist itinerary that use standard accommodations
in countries reporting cholera are at very low risk for infection.566
Preparations
There are two major types of oral vaccines against cholera: killed whole
cell-based and genetically attenuated live vaccines.345 A single cholera
vaccine CVD 103-HgR (Vaxchora; PaxVax, Redwood City, CA) is available
in the United States. This vaccine is an attenuated live oral genetically
modified V. cholerae O1 strain (CVD 103-HgR) and was licensed by
FDA in 2016 for United States travelers 18 to 64 years of age visiting
endemic countries.
Two other vaccines are prequalified by WHO and are available in
many countries outside the United States: WC/rBS (Dukoral; Crucell,
the Netherlands) and Modified WC-only (Shanchol; Shantha Biotechnics,
Medchal, Hyderabad, India). The WC/rBS vaccine is a whole, killed
cell–based vaccine that contains Vibrio cholerae O1 with purified
recombinant B subunit of cholera toxoid. The modified WC-only vaccine
is also a whole, killed cell-based vaccine but lacks the B subunit. The
WC-only vaccine was originally manufactured by the government of
Vietnam. Although inexpensive to produce, it did not elicit antitoxic
immunity. In 2007, the WC-only vaccine was modified with international
efforts to create a low-cost vaccine that is produced in India572,599
Immunogenicity and Efficacy
In a randomized, placebo-controlled, double-blind trial of the CVD
103-HgR vaccine with an oral cholera challenge in 197 health human
CHAPTER 245  Active Immunizing Agents 2589
volunteers, vaccine efficacy was found to be 90% at 10 days and 80%
3 months after a single vaccine dose.184 Although the CVD 103-HrG
vaccine provides protective vibriocidal antibodies in 90% of vaccinees,
it is specific to V. cholerae serogroup 01 and does not confer protection
to O139 or other non-O1 serogroups.184 CVD 103-HrG vaccines have
the benefit of being efficacious with a onetime dose instead of the two
spaced doses required of the killed, whole cell vaccines.
WC/rBS vaccine confers protection specific to V. cholerae serogroup
O1.345 Immunization does not protect against V. cholerae serogroup
O139 or other species of Vibrio. Field trials in Bangladesh, Peru, and
Sweden have shown that the WC/rBS vaccine confers 85% to 90%
protection for 6 months in all age groups after administration of two
doses 1 week apart. In Bangladesh, protection declined rapidly after 6
months in young children, but it was still approximately 60% effective
in older children and adults after 2 years. Because of the limited duration
of protection, the WC/rBS vaccine is not recommended to be used in
children younger than 2 years.
The modified killed, whole cell–only vaccine had been studied in
several trials and found to be safe and highly effective, with seroconversion
rates of vibriocidal antibodies ranging from 53% to 91%.54,572,599,628 Limited
data on the safety and immunogenicity of the modified whole-cell–based
vaccine in children at least 1 year of age appear promising.572
Adverse Events
In clinical trials of the newly licensed CVD 103-HgR vaccine, there was
no difference between placebo and vaccine recipients with respect to
diarrhea, asthenia, headache, abdominal pain, anorexia, nausea and
vomiting, or fever.184
Millions of doses of WC/rBS vaccine have been supplied worldwide.345
According to manufacturer information from clinical trials and post-
marketing surveillance, mild gastrointestinal symptoms (e.g., abdominal
pain, cramping, diarrhea, nausea) are most commonly reported, occurring
at a frequency of 0.1% to 1%. Serious adverse events, including a flulike
syndrome, rash, arthralgia, and paresthesias, are rare, occurring in less
than one of 10,000 doses distributed. In several RCTs, the modified,
killed, whole cell–only vaccine also demonstrated a low frequency of
mild symptoms and no major adverse events.54,572,628
Indications
In June 2016, the ACIP voted to recommend cholera vaccine (CVD
103-HgR, Vaxchora) for adult (18–64 years old) travelers to an area of
active toxigenic V. cholerae O1 transmission. Special consideration should
be given for those at higher than average risk, such as health care profes-
sionals in endemic areas, aid workers in refugee camps, and those traveling
to remote areas where cholera epidemics are occurring and access to
medical care is limited. No country requires proof of cholera immuniza-
tion as a condition for entry, and the WHO recommends against such
a requirement. Some local authorities, however, may require immuniza-
tion; to determine local requirements, travelers should consult the
embassies of the countries to which they will be traveling.
Precautions and Contraindications
Oral cholera vaccine should not be administered to people with a
hypersensitivity reaction to any of the vaccine components. Administra-
tion of oral cholera vaccine should be postponed for people with acute
gastrointestinal illness or acute febrile illness.
Japanese Encephalitis Virus Vaccine
Japanese encephalitis (JE) virus, the most important cause of epidemic
mosquito-borne arboviral encephalitis in Asia, has a wide clinical
spectrum, ranging from asymptomatic infection to permanent neurologic
sequelae associated with a high rate of disability (i.e., 709,000 disability-
adjusted life-years), and a high case-fatality rate of 20% to 30% or even
higher among children younger than 10 years. The annual incidence
of JE among 3 billion people at risk in 24 countries in Southeast Asia
and the Western Pacific is 1.8 case per 100,000 people despite the
availability of effective vaccines in many regions.700
The JE virus is a zoonotic flavivirus that cannot be eliminated because
its animal reservoirs are widespread. However, human infection could
be controlled by universal human immunization in endemic areas. The
2590 PART V  Prevention of Infectious Diseases
envelope glycoprotein of the JE virus contains the major epitopes that
are targeted by neutralizing antibodies.
Historically, an inactivated mouse brain–derived vaccine (JE-VAX)
controlled JE virus infection successfully among human populations
in Japan, Korea, and Taiwan since 1968.517 This vaccine is no longer
available in the United States and is being phased out elsewhere because
of greater reactogenicity, higher cost, and larger number of doses
compared with the newer-generation vaccines.
Preparations
The 15 JE vaccines in use in Asia are classified in four categories:
inactivated mouse brain–derived vaccines, inactivated Vero cell–derived
vaccines, live attenuated vaccines, and live recombinant (chimeric)
vaccines. In the United States, the inactivated Vero cell–derived, alum-
adjuvanted vaccine, JE-VC (Ixiaro, Intercell Biomedical, United Kingdom,
distributed by Novartis Vaccines and Diagnostics in the United States)
is indicated for use in individuals 2 months and older.177 It is derived
from the attenuated SA 14-14-2 JEV strain.
The primary vaccination series for JE-VC is two intramuscular doses
administered 28 days apart. The dose for children younger than 3 years
is 0.25 mL, and 0.5 mL is given to children 3 years or older.177 The
vaccine does not contain stabilizers, antibiotics, or thimerosal and should
be stored at 2°C to 8°C (35°F–46°F) and protected from light.
A primary hamster kidney cell—derived, live attenuated vaccine
(CD.JEVAX) has been used widely in China since 1988 and is used
widely in Asia now. It is based on the SA 14-14-2 JEV strain. Primary
immunization consists of a single 0.5- mL subcutaneous dose in children
8 months or older. It contains gelatin, human serum albumin, and
other stabilizers.
A live attenuated, recombinant (chimeric) JE virus vaccine (IMOJEV,
JE-CV, ChimeriVax-JE) was licensed in Australia in 2010 and is used
widely in Asia. The premembrane and envelope coding sequences derived
from the SA 14-14-2 JEV strain were engineered to replace the homolo-
gous sequences of the live attenuated yellow fever vaccine virus, which
is used as a vector. This vaccine is propagated in Vero cells. Primary
immunization is a single dose of 0.5 mL given subcutaneously at 9
months or older, and a booster dose is indicated for children.
Immunogenicity and Efficacy
The JE-VC vaccine was licensed in the United States on the basis of its
ability to induce JE virus–neutralizing antibodies as a surrogate for
protection and safety evaluations in approximately 5000 adults.587 The
accepted immunologic surrogate of protection is a serum neutralizing
antibody titer of at least 1 : 10 as determined by a 50% plaque reduction
neutralization assay (PRNT50) result.700
Vaccine effectiveness for the inactivated JE-VC vaccine is at least
93%, 80% to 99% for the live attenuated JE vaccines, and at least 90%
for the live recombinant vaccines. Long-term immunogenicity data are
limited. A booster vaccine is recommended 2 years after the primary
series to induce a robust anamnestic response.700
Mass immunization campaigns with live attenuated and inactivated
mouse brain–derived JE vaccines significantly reduce JE disease in a
community. No data are available for the inactivated Vero cell–derived
and live recombinant vaccines.
Adverse Reactions
The inactivated Vero cell–derived vaccines, live attenuated vaccines,
and live recombinant vaccines all have acceptable safety profiles. The
most common local reactions to JE-VC are rash, fever, headache, myalgia,
and fatigue, but severe reactions occur in 1.6 of 100,000 administered
doses,177,700 as described on the CDC website (http://www.cdc.gov/
vaccines/acip/recs/grade/je-child.html). Severe adverse events include
febrile convulsions, thrombocytopenic purpura, and encephalitis.247 The
other vaccine preparations are associated with similar reactogenicity
and tolerability as that of JE-VC.
Indications
The risk of JE for most travelers to Asia is low but varies on the basis
of destination, duration, season, and activities. All travelers to countries
with endemic JE should be informed of the risks of JE and use personal
protective measures (i.e., bed nets and mosquito repellants) to reduce
the risk of mosquito bites. For some travelers who will be in high-risk
settings, JE vaccine can further reduce the risk of infection. The CDC
recommends JE vaccine for travelers who plan to spend a month or
longer in areas with endemic infection during the JE virus transmission
season.30,271 JE vaccine should be considered for shorter-term travelers
if they plan to travel away from an urban area and have an itinerary
or activities that increase the risk of JE virus exposure. Information on
the location of JE virus transmission and detailed information on vaccine
recommendations and adverse events can be obtained from the CDC
website (https://wwwnc.cdc.gov/travel).
Primary immunization with JE-VC should be completed at least 1
week before potential exposure to JE virus. If the primary series was
administered more than 1 year earlier, a booster dose is recommended
for individuals older than 16 years before potential reexposure.248 Data
on the response to a booster dose administered more than 2 years after
the primary series and the need for and timing of additional booster
doses are not available. There is no information about the utility of
booster doses for children. The sparse available data suggest that the
different JE vaccines are interchangeable without causing adverse reactions
or compromising immunogenicity.
Precautions and Contraindications
A severe allergic reaction after a previous dose of JE-VC is a contraindica-
tion to administration of subsequent doses.271 JE-VC contains protamine
sulfate, a compound known to cause hypersensitivity reactions in some
people.
Practitioners should use caution when considering the use of JE
vaccine in pregnant women. Vaccination with JE vaccines usually should
be deferred because of a theoretical risk to the developing fetus. However,
pregnant women who must travel to an area in which the risk of JE
exposure is high should be vaccinated with an inactivated JE vaccine
if the benefits outweigh the risks of vaccination for the mother and
developing fetus.
Breastfeeding is not a contraindication to vaccination with inactivated
JE vaccine. However, whether JE-VC is excreted in human milk is not
known. Because many drugs are excreted in human milk, practitioners
should use caution when considering the use of inactivated JE vaccine
in breastfeeding women.
No data exist on the use of JE-VC in immunocompromised people
or patients receiving immunosuppressive therapies.
Rabies Vaccine
Rabies is a viral zoonosis transmitted in saliva and other tissue of infected
mammals. The virus enters the central nervous system of the host and
causes an acute, progressive encephalomyelitis that is almost universally
fatal. Postexposure prophylaxis is possible because of the long incubation
period, usually weeks to months, of this infection. The time of incubation
correlates with the length of the axon along which the virus migrates
to eventually infect the central nervous system. Children are at particular
risk of exposure to rabies from an infected dog, cat, or other animal
because they are less likely to take aversive measures if attacked and
are more likely to sustain an injury to the head or neck. Accordingly,
children are likely to have shorter incubation periods especially with
an exposure injury on the head or neck.
In this century, the number of human deaths in the United States
attributed to rabies has declined from 100 or more each year to an
average of 2 or 3 each year. Two programs have been responsible for
this decline. First, animal control and vaccination programs begun in
the 1940s and oral rabies vaccination programs in the 2000s have
eliminated domestic dogs as reservoirs of rabies in the United States.
Second, effective human rabies vaccines and immunoglobulins have
been developed.
Wild animals are the most important source of infection for humans
and domestic animals. Insectivorous bats carrying variants of the rabies
virus have been responsible for most human cases of rabies in the
continental United States in recent years. Transmission has occurred
from minor and unrecognized bites from infected bats. Wild carnivores,
especially raccoons, skunks, and foxes, are the terrestrial animals most
often infected with rabies. Wildlife rabies occurs throughout the

continental United States; only Hawaii remains consistently free of rabies.
Domestic animals, including dogs, cats, and ferrets, can be infected,
with three times as many reports of rabies annually in cats compared
with dogs.
Human exposure to rabies from a domestic animal in the United
States is a rare occurrence. In most other countries (e.g., Asia, Africa,
and Latin America), dogs remain the most important potential source
of infection. International travelers in areas where canine rabies is
endemic are at increased risk for exposure to rabies.
Rabies was diagnosed in a total of 37 people in the United States
since 2003.485 Seventy percent of them acquired the disease in the United
States or Puerto Rico. Organ or tissue transplantation was identified
as the source of infection for 19% of individuals. Bats were implicated
as the source of infection in 65%, with a bat bite reported in
seven cases bat contact without a reported bite in six cases and a rabies
virus associated with bats without a known exposure identified in four
cases. Thirty percent of human rabies deaths reported to the CDC since
2003 appear to have been related to rabid animals outside the United
States.
Preparations
Two rabies vaccines are available for preexposure and postexposure
prophylaxis in the United States: human diploid cell vaccine (HDCV)
and purified chicken embryo cell (PCEC). Both vaccines are licensed
for intramuscular administration. HDCV (Imovax Rabies, Sanofi Pasteur)
is derived from the Pitman-Moore strain grown in human diploid cell
culture. PCEC (RabAvert, Chiron Corporation-Novartis) is prepared
from the fixed rabies virus strain Flury LEP grown in primary culture
of chicken fibroblasts. The HDCV and PCEC vaccines each contain the
WHO-recommended standard of at least 2.5 IU of rabies virus antigen
per 1.0-mL intramuscular dose. Although not licensed for use in the
United States, two intradermal rabies vaccines are recommended by
the WHO and used in countries where the two tissue culture vaccines
(i.e., HDCV and PCEC) are prohibitively expensive.132
Immunogenicity and Efficacy
Viral neutralizing antibodies are produced within 7 to 10 days, and
protective immunity usually persists for 2 years or longer. Although a
definitive protective titer has not been identified, the WHO and CDC
adhere to working guidelines for an acceptable response to immuniza-
tion.118 The CDC specifies complete viral neutralization at a 1 : 5 or
greater titer by the rapid fluorescent-focus inhibition test as acceptable;
the WHO specifies 0.5 IU/mL or more as acceptable.
Given the essentially universal fatal prognosis of infection after
symptoms develop, no randomized, placebo-controlled human trials
have documented the efficacy of vaccine for preexposure or postexposure
prophylaxis. However, substantial field experience and direct evidence
from controlled animal studies demonstrate a protective effect. The
paucity of human cases attests to the efficacy of postexposure prophylaxis
with the currently recommended vaccine and immune globulin
preparations.
Rabies has not been reported in the United States in any patient
who received the recommended postexposure measures. Cases of human
rabies occurring after postexposure prophylaxis have resulted from
failure to adhere to established guidelines, such as those of the CDC
or the WHO.117,250,272,598,673
Adverse Events
Reactions occurring after administration of HDCV or PCEC vaccine
are less serious and less common than those associated with the previously
available vaccines.132 Local reactions at the injection site occur in 30%
to 74% of injections, and mild systemic reactions such as fever, headache,
nausea, abdominal pain, muscle aches, and dizziness occur in 5%to
40% of vaccine recipients. In one report, approximately 6% of people
had an immune complex–like reaction 2 to 21 days after receipt of the
booster dose of HDCV.108 This systemic hypersensitivity reaction occurred
less frequently in people receiving primary vaccination. The reactions
have been associated with the presence of β-propiolactone–altered
human albumin in HDCV and the development of IgE antibodies to
this allergen.273
CHAPTER 245  Active Immunizing Agents 2591
Indications and Precautions
When used as indicated, both types of rabies vaccine are considered
equally safe and effective for preexposure and postexposure prophylaxis
as described in the ACIP recommendations.448,570 Usually, an immuniza-
tion series is initiated and completed with one vaccine product. No
clinical studies have been conducted that documented a change in efficacy
or the frequency of adverse reactions when the series is completed with
a second vaccine product. Ideally, an immunization series should be
completed with the same product unless serious allergic reactions occur.
Corticosteroids, immunosuppressive conditions, and concurrent
administration of antimalarial agents can interfere with the adequate
development of an active immune response. Postvaccination titers should
be checked in these circumstances or if a significant interruption in
vaccine schedule has occurred, especially in the context of a more
significant exposure, and in consultation with local public health
authorities.
For adults, rabies vaccination always should be administered in the
deltoid area. For children, the anterolateral aspect of the thigh also is
acceptable. The gluteal area never should be used for HDCV or PCEC
injections because administration of HDCV in this area results in lower
neutralizing antibody titers and decreased immunogenicity.272
Postexposure prophylaxis.  The essential components of rabies post-
exposure prophylaxis are wound treatment and, for previously unvac-
cinated people, concurrent administration of human rabies immune
globulin (HRIG) and vaccine (Table 245.19).448,570 The combination of
active and passive immunization is indicated for the treatment of all
bite and all non-bite exposures inflicted by animals suspected or proven
to be rabid. Recommendations for the management of people with
possible exposure to rabies include giving meticulous attention to
thorough cleansing of the wound with soap and water. The decision
to give rabies immunoprophylaxis depends on the circumstances
precipitating the exposure, the species and condition of the animal
inflicting the wound, and the prevalence of rabies in local animal
populations. Bite and nonbite exposures, including scratches, abrasions,
open wounds, and mucous membranes contaminated with saliva, are
considered significant. Because the need for preventive measures is
based on these specific circumstances, the local department of health
should be consulted promptly concerning the necessity for initiating
postexposure prophylaxis.
When possible, the brains of wild animals (i.e., skunks, foxes, coyotes,
raccoons, and bats), stray dogs or cats, or symptomatic animals implicated
in an exposure should be examined in certified laboratories for evidence
of rabies. Immunization always should be initiated promptly and
discontinued only if laboratory results are negative. Individuals exposed
to healthy dogs or cats that are available for observation do not require
immediate prophylactic treatment. Implicated healthy domestic dogs
or cats should be quarantined and observed for at least 10 days. If
symptoms develop that suggest rabies, the exposed individual should
begin postexposure prophylaxis, and the brain of the animal should be
examined. An unknown or unavailable animal must be regarded as
potentially rabid.
Studies conducted in the United States by the CDC have documented
that a regimen of one dose of HRIG and five doses of rabies vaccine
(1.0 mL for each dose) given on days 0, 3, 7, 14 and 28 was safe and
induced an excellent antibody response in all recipients.448 In March
2010, the ACIP changed recommendations to one dose of HRIG with
four doses of rabies vaccine (1.0 mL for each dose) given on days 0, 3,
7, and 14. The number of doses recommended for people with altered
immunocompetence has not changed; they should be administered a
five-dose vaccination regimen (days 0, 3, 7, 14, and 28) along with one
dose of HRIG.570 If anatomically feasible, the full dose of HRIG (20 IU/
kg) should be infiltrated thoroughly in the area around and into the
wounds. Any remaining volume should be injected intramuscularly at
a site distant from that of vaccine administration. The dose of HRIG
should not exceed that recommended and should not be given beyond
the seventh day because HRIG can partially suppress active antibody
production.
People previously fully vaccinated do not require HRIG and should
receive only vaccine (two doses 3 days apart) because an amnestic
response will occur after the administration of a booster regardless of
2592 PART V  Prevention of Infectious Diseases
TABLE 245.19  Rabies Postexposure Prophylaxis for Individuals Not Previously Immunized
Evaluation and Disposition
Animal Type of the Animal
Wild
Skunks, raccoons, foxes, and most other Regard as rabid unless animal proven
carnivores; bats negative by laboratory testsa
Domestic
Dogs, cats, and ferrets Healthy and available for 10 days
observation
Rabid or suspected rabid
Escaped (unknown)
Other
Livestock, small rodents, large rodents Consider individually
(woodchucks and beavers), lagomorphs
(rabbits and hares), and other mammals
a
The animal should be euthanized and tested as soon as possible. Holding for observation is not recommended. Discontinue vaccine if immunofluorescence test results of the animal are
negative.
b
During the 10-day observation period, begin postexposure prophylaxis at the first sign of rabies in a dog, cat, or ferret that has bitten someone. If the animal exhibits clinical signs of rabies,
it should be euthanized immediately and tested.
Modified from Manning SE, Rupprecht CE, Fishbein D, et al. Human rabies prevention—United States, 2008: recommendations of the Advisory Committee on Immunization Practices.
MMWR Recomm Rep. 2008;57(RR-3):1–28.
the antibody titer.448 Serum for antibody testing should be obtained
from people whose prophylaxis history or immune status is uncertain,
and the course of postexposure active and passive immunoprophylaxis
as described for nonimmune individuals should be initiated immediately.
If serologic testing demonstrates adequate anti-rabies antibody, post-
exposure prophylaxis can be discontinued.
Once initiated, rabies prophylaxis should not be interrupted or
discontinued because of local or mild systemic adverse reactions to
rabies vaccine. Usually, the reactions can be successfully managed with
antiinflammatory and antipyretic agents such as ibuprofen or acet-
aminophen. When a person with a history of serious hypersensitivity
to rabies vaccine must be revaccinated, antihistamines can be admin-
istered. Epinephrine should be readily available to counteract any
anaphylactic reactions, and the person should be observed carefully
immediately after receiving vaccination.
Preexposure prophylaxis.  Active immunization should be considered
for high-risk groups (i.e., veterinarians, animal handlers and control
officers, selected laboratory workers, people visiting countries where
rabies is hyperendemic, and people whose pursuits may involve frequent
contact with rabid animals, such as spelunkers). People whose risk of
exposure is less but whose access to immediate competent medical care
is restricted also should be considered for preexposure prophylaxis.
The primary series consists of three doses (1.0 mL/dose) administered
on days 0, 7, and 21 or 28, given intramuscularly in the deltoid area.
The three-dose series provides long-term protective immunity, and
routine serologic testing for rabies antibody after primary immunization
is not necessary. For individuals who may be immunosuppressed,
measurement of anti-rabies antibodies should be performed. In the
case of continued or frequent exposure, serum samples should be tested
every 2 years and a booster dose of rabies vaccine provided when the
antibody titer falls below the minimum accepted level.448
Precautions and Contraindications
Because of the potential consequences of inadequately treated rabies
exposure and because no indication exists that fetal abnormalities have
been associated with rabies vaccination, pregnancy is not considered a
contraindication to postexposure prophylaxis.448 If the risk of exposure
to rabies is substantial, preexposure prophylaxis also can be indicated
during pregnancy.
People who have a history of serious hypersensitivity to rabies vaccine
should be revaccinated with caution. Although serious systemic, ana-
phylactic, or neuroparalytic reactions are rare events during and after
the administration of rabies vaccines, the reactions pose a serious
dilemma for the patient and the attending physician. A patient’s risk
Postexposure Prophylaxis Recommendations
Consider immediate vaccination and if not previously vaccinated, use
rabies immune globulin
Persons should not begin prophylaxis unless animal develops clinical
signs of rabiesb
Immediately vaccinate
Consult public health officials
Consult public health officials
Bites of squirrels, hamsters, guinea pigs, gerbils, chipmunks, rats,
mice, other small rodents, rabbits, and hares rarely require antirabies
prophylaxis
of acquiring rabies must be carefully considered before deciding to
discontinue vaccination. Advice and assistance on the management of
serious adverse reactions for people receiving rabies vaccines may be
sought from the state health department or the CDC.
Typhoid Vaccine
Typhoid fever, an acute, life-threatening febrile illness caused by the
bacterium Salmonella enterica serovar typhi (S. typhi), remains a serious
public health problem throughout the developing world. Although
disease prevalence varies greatly depending on the specific population
studied, current global estimates suggest that 27 million cases of typhoid
and 270,000 deaths occur annually.97 In the United States and much of
the developed world, typhoid fever has virtually disappeared.97 Approxi-
mately 400 cases of typhoid fever, mostly among travelers, are reported
to the CDC each year. Most reported cases in the United States are
acquired during travel to developing countries.374 The primary indication
for typhoid vaccination in the United States is international travel to
an endemic area.373 In developing countries without safe water and
sanitation, mass immunization is a potentially effective strategy to limit
the severity and impact of typhoid fever.3
The changing epidemiology of typhoid fever underscores the
importance of vaccination of international travelers and high-risk
populations in endemic regions. Studies report that the highest incidence
rate is found among children younger than 5 years and results in more
severe disease than in earlier periods.604,609 S. typhi is increasingly resistant
to ampicillin, chloramphenicol, and cotrimoxazole; even quinolone
resistance is reported in many parts of the world.97,366 Case-fatality rates,
which had decreased from 10% to 1% with appropriate antibiotic therapy,
could rise again without safe, effective, and affordable vaccination
strategies, especially as rates of resistance increase across the globe.
Preparations
The three types of typhoid vaccines are inactivated, whole-cell vaccines;
live attenuated bacterial vaccines; and subunit vaccines.503 The parenteral,
heat-phenol–inactivated, whole-cell vaccine widely used for many years
was highly immunogenic but also was highly reactogenic and no longer
is available in the United States. It is the only vaccine approved for use
in children as young as 6 months and is still available in several developing
countries because of its affordability, although the manufacture of this
vaccine may not be up to international standards.
Two vaccines are licensed for use in the United States: an oral live,
attenuated vaccine (TY21a, Vivotif Berna) and a purified Vi (virulence)
capsular polysaccharide of S. typhi vaccine (ViCPS) (Typhim Vi, Aventis
Pasteur) for intramuscular use. Table 245.20 provides information on

TABLE 245.20  Dosage and Schedule for Typhoid Fever Vaccination
Vaccination Age (y) Dose/Route of Administration
Oral Live Attenuated TY21a Vaccine
Primary series ≥6 1 capsulea/oral
Booster ≥6 1 capsulea/oral
Vi Capsular Polysaccharide Vaccine
Primary series ≥2 0.50 mL/IM
Booster ≥2 0.50 mL/IM
a
Administer with cool liquid no warmer than 37°C (98.6°F).
NA, Not applicable.
Modified from Jackson BR, Iqbal S, Mahon B, et al. Updated recommendations for the use of typhoid vaccine—Advisory Committee on Immunization Practices, United States, 2015. MMWR
Morb Mortal Wkly Rep. 2015;64:305–8.
vaccine dosage and administration. The time required for primary
vaccination is different for the two vaccines, as are the lower age limits
for use in children.
Ty21a is an oral, live attenuated vaccine consisting of a stable mutant,
Ty21a, developed by chemical mutagenesis of a pathogenic S. typhi
strain. This vaccine was licensed in the United States in 1989 for use
in adults and children 6 years or older and is available as an enteric-coated
capsule (i.e., must be swallowed whole). The four-dose primary vaccine
series in the United States and Canada (three-dose series in other parts
of the world) is administered as one capsule every other day, taken 1
hour before a meal, for a total of four capsules. The capsules should
be kept refrigerated (not frozen), and all four doses must be taken to
achieve maximum efficacy. Each capsule should be taken with cool
liquid no warmer than 37°C (98.6°F) approximately 1 hour before a
meal. This regimen should be completed 1 week before potential exposure.
The vaccine manufacturer recommends that Ty21a not be administered
to infants or children younger than 6 years.
A parenteral subunit vaccine, ViCPS, was licensed in 1994 for use
in adults and children as young as 2 years of age. Primary vaccination
with ViCPS consists of one 0.5-mL (25-µg) dose administered intra-
muscularly and should be given at least 2 weeks before potential exposure.
The manufacturer does not recommend the vaccine for children younger
than 2 years.
Various protein conjugated Vi polysaccharide vaccines have been
developed and are used in countries other than the United States, Two
were recently licensed in India for use in children 3 months or older.366,631
In circumstances of continued or repeated exposure to S. typhi,
booster doses are recommended to maintain immunity after primary
immunization. The optimal booster schedule for either vaccine has not
been determined. Current recommendations for revaccination with
either vaccine are provided in Table 245.20. No data have been reported
comparing the use of one vaccine as a booster after primary immunization
with the other.
Efficacy
Although field trials have demonstrated approximately 80% efficacy of
typhoid vaccines in US travelers,446 no comparative studies have been
performed.366 For the heat-phenol–inactivated, whole-cell vaccine,
efficacy ranged from 51% to 88% and lasted for as long as 7 years. The
oral, live attenuated Ty21a vaccine stimulates humoral (i.e., serum IgG
and mucosal IgA antibodies) and cell-mediated immune responses. In
trials of the Ty21a vaccine, efficacy ranged from 42% to 96% after
administration of the initial series of three doses, with the lower effica-
cies seen in trials from areas with highly endemic disease.429,605 The
optimal schedule for booster immunizations has not been determined
for this vaccine. Protective immunity persisted for at least 7 years in
field trials in endemic countries where herd immunity may have
an effect.324 Revaccination is recommended with the same four-capsule
regimen every 5 years for as long as continued exposure is likely
to occur.
Immunization with ViCPS results in seroconversion, defined as a
fourfold rise in serum anti-Vi antibody, in 80% of vaccinees within 2
weeks in endemic and nonendemic areas.324,342,397 Because the vaccine
CHAPTER 245  Active Immunizing Agents 2593
No. of Doses Dosing Schedule Boosting Interval
4 Days 0, 2, 4, 6 NA
4 Days 0, 2, 4, 6 Every 5 y
1 NA NA
1 NA Every 2 y
is administered parenterally, mucosal immunity does not develop. The
efficacy of ViCPS vaccine in clinical trials was 72% at 17 months2 and
64% at 21 months397 after administration of a single dose. A cluster-
randomized trial in India enrolling 37,673 children 2 years or older
demonstrated 61% effectiveness.629 Polysaccharide vaccines do not
stimulate T cells and cannot establish immunologic memory. Additional
doses of ViCPS therefore do not elicit a booster effect. Revaccination
with a single dose is recommended every 2 years for people who remain
at risk.
Conjugate Vi vaccines trials have used various carrier proteins, and
one study of more than 12,000 children 2 to 5 years old demonstrated
90% efficacy over a trial period of 4 years using recombinant exoprotein
A of Pseudomonas aeruginosa (Vi-rEPA).434 Anti-Vi IgG titers were higher
and longer lasting with conjugate Vi vaccines compared with Vi alone
in adults and children from endemic areas.631
None of the typhoid vaccines approaches 100% efficacy, and a large
inoculum of S. typhi can overcome vaccine-induced immunity. Vaccines
do not substitute for proper hygiene and appropriate food handling
practices.
Adverse Events
Reactions to the oral Ty21a vaccine usually are mild and consist of
transient gastrointestinal upset, fever, headache, and an occasionally
rash. These reactions occur in less than 5% of recipients.366 Adverse
systemic effects are reported in less than 1% of vaccinees, and neither
the development of bacteremia nor person-to-person transmission has
been reported.324
Reactions to the ViCPS vaccine also occur infrequently and are
reported in approximately 7% of recipients366 These reactions include
tenderness at the injection site, erythema and induration, fever, and
rarely, rashes. Systemic complaints occur in less than 2%.324 In contrast,
reactions to the inactivated, whole-cell vaccine occur more commonly
and are more severe; they include fever in as many as 24% of recipients,
headache, and severe local pain or swelling in as many as 35% of vac-
cinees. Between 13% and 24% of vaccinees have missed school or work
because of adverse reactions.430
Reactions to the conjugate Vi vaccines were mild and limited to
fever and mild erythema. There were no serious adverse events.434,631
Indications
Typhoid vaccination in the United States is recommended only for the
following groups366,503:
• Travelers in areas where typhoid fever is endemic and for whom
the risk of exposure is recognized; risk of exposure is greatest with
travel to the Indian subcontinent, Latin America, Asia, the Middle
East, and Africa
• People with intimate exposure to a documented S. typhi carrier, as
occurs with continuing household contact
• Laboratory workers who have frequent contact with S. typhi and
people living in areas outside the United States with endemic typhoid
infection
Vaccination is not recommended for people attending summer camp
or for those in areas of natural disaster or for control of common-source
2594 PART V  Prevention of Infectious Diseases
outbreaks. Doses and schedules for the different typhoid vaccines are
given in the recommendations of the CDC.366,503
Contraindications
Ty21a is a live attenuated vaccine and should not be given to immuno-
compromised patients, including those receiving high doses of
corticosteroids and people with HIV infection.366,503 Ty21a vaccine also
should not be administered during a gastrointestinal illness or concurrent
with certain antibiotics. The 2015 Red Book recommends avoiding
antimicrobial therapy for at least 24 hours before the first dose of oral
typhoid vaccine through 7 days after the last dose.45 Reports are conflicting
regarding the use of the antimalarial agents atovaquone and proguanil;
however, chloroquine and mefloquine do not appear to interfere with
the immune response to oral Ty21a. Neither of the available typhoid
vaccines should be given to anyone with a history of severe local or
systemic reactions after receiving a previous dose of vaccine.
Ty21a is not approved for children younger than 6 years, and ViCPS
is not approved for children younger than 2 years. The whole-cell,
inactivated vaccine available outside of the United States is approved
for use in children between 6 months and 2 years of age.
Information is not available on the safety of these vaccines when
they are used during pregnancy. It is prudent on theoretical grounds
to avoid vaccinating pregnant women.
Yellow Fever Vaccine
Yellow fever occurs only in sub-Saharan Africa and tropical South
America, where it causes an estimated 200,000 cases and 30,000 deaths
annually.564 During the past 2 decades, 90% of all yellow fever cases
were reported from countries in West Africa, where travelers are thought
to be at the highest risk of travel-associated yellow fever.617 Clinical
disease ranges from a mild, nonspecific febrile illness to severe disease
with jaundice and hemorrhage.
Yellow fever is an important vaccine-preventable disease among
travelers to areas where yellow fever occurs. The yellow fever epidemic
zones include Bolivia, Brazil, Colombia, Ecuador, French Guiana, Guyana,
Paraguay, Peru, Suriname, Venezuela, and much of sub-Saharan Africa.
From 1970 to 2013, 10 cases of yellow fever were reported in unvaccinated
travelers from the United States and Europe who traveled to West Africa
(five cases) or South America (five cases). The unvaccinated traveler’s
risk of acquiring yellow fever probably is increasing because potential
zones of transmission of yellow fever are expanding to include urban
areas with large populations of susceptible humans and abundant
competent mosquito vectors. Vaccination is the most effective preventive
measure against yellow fever, a disease that has no specific treatment
and may cause the death of 20% to 50% of patients.484
Preparations
Yellow fever vaccines are derived from the original 17D yellow fever
vaccine strain. The live attenuated 17D-204 and 17DD yellow fever
strains are the yellow fever vaccines most commonly used.484 The only
yellow fever vaccine licensed in the United States is the 17D-204 vaccine,
which is prepared in chick embryos (YF-Vax, Sanofi Pasteur).618
Primary immunization consists of a single, subcutaneous injection
of 0.5 mL of reconstituted, freeze-dried vaccine for adults and children.
The vaccine should be stored at 2°C to 8°C. Because the vaccine does
not contain a preservative, reconstituted vaccine that remains unused
after 1 hour must be properly disposed.
Immunogenicity and Efficacy
Seroconversion rates of 93% have been documented for young children
receiving yellow fever vaccine.710 Thirteen observational studies showed
a seropositivity rate of 92% at least 10 years after receiving the vaccine
and 80% at least 20 years after vaccination.617 Immunity develops by
the tenth day after primary vaccination. The titer of virus-neutralizing
antibodies in the sera of vaccinees is used as a surrogate for vaccine
effectiveness.
No human efficacy studies have been performed with yellow fever
vaccine. However, the number of yellow fever cases was substantially
reduced after the introduction of the vaccine, supporting its protective
role in humans. Worldwide, only 18 cases of yellow fever have been
reported in vaccine recipients after the administration of more than
540 million doses; 16 (89%) had received a vaccine dose within the
previous 10 years.617
Adverse Events
The 17D-204 and 17DD yellow fever vaccines are among the safest and
most effective viral vaccines.484 Since 1965, approximately 8 million
doses of 17D-derived yellow fever vaccine have been administered to
US travelers, and approximately 300 million doses have been administered
to people in areas where yellow fever is endemic. Although 10% to 30%
of people who receive vaccine report headaches, myalgia, and low-grade
fever that begin within a few days after vaccination and last 5 to 10
days, less than 1% report temporarily curtailing their usual activities.
Historically, yellow fever vaccine–associated adverse events were seen
primarily among infants and manifested as encephalitis. However, with
the current yellow fever vaccine, serious adverse events associated with
vaccine rarely occur. A systematic review found that no serious adverse
events were reported in four RCTs of infants and children (n = 1866).636
Three well-characterized serious adverse events may occur after
yellow fever vaccine administration: immediate hypersensitivity or
anaphylactic reactions, yellow fever vaccine–associated neurologic disease
(YEL-AND), and yellow fever vaccine–associated viscerotropic disease
(YEL-AVD). Immediate hypersensitivity reactions, characterized by rash,
urticaria, or bronchospasm, or a combination of these features is
uncommon (1.8 cases/100,000 doses). Unrecognized allergy to eggs or
chicken or to the hydrolyzed gelatin used to stabilize the vaccine may
be responsible for hypersensitivity reactions.
YEL-AND is a serious but rarely fatal adverse event that occurs
among people of all ages. YEL-AND manifests as several distinct clinical
syndromes, including meningoencephalitis (i.e., neurotropic disease),
Guillain-Barré syndrome, acute disseminated encephalomyelitis (ADEM),
and bulbar palsy, starting 3 to 28 days after vaccination, usually in
first-time recipients.140 Meningoencephalitis occurs as a result of direct
yellow fever vaccine viral invasion of the central nervous system (CNS)
with infection of the meninges or the brain, or both. The other neurologic
syndromes (e.g., Guillain-Barré syndrome, ADEM) represent autoimmune
manifestations in which antibodies or T cells produced in response to
the vaccine cross-react with neuronal epitopes and lead to central or
peripheral nerve damage. The incidence of YEL-AND in the United
States is 0.8 case per 100,000 doses.
In 2001, a previously unrecognized, potentially fatal adverse reaction
among recipients of YF vaccine was first described. This syndrome
previously was reported as febrile multiple organ dysfunction or failure
and now is called yellow fever vaccine–associated viscerotropic disease.
YEL-AVD mimics naturally acquired wild-type yellow fever disease,
with the vaccine virus proliferating and disseminating throughout the
host’s tissues. Since it was initially described, more than 65 confirmed
or suspected cases have been reported globally. On the basis of an
analysis of cases for which information is available, YEL-AVD has
occurred only after a recipient’s first yellow fever vaccination; no cases
of YEL-AVD occurring in people receiving booster doses of the vaccine
have been reported. The median time from vaccination to disease onset
is approximately 4 days. The case-fatality ratio for reported cases is
approximately 60%. The incidence of YEL-AVD in the United States is
0.4 case per 100,000 doses.
Several risk estimates for YEL-AVD have been published. On the
basis of VAERS data, the reporting rate of YEL-AVD is 3 to 4 cases per
1 million doses distributed.435,462
The recognition of these adverse events may be challenging because
the neurologic syndromes (e.g., encephalitis, myelitis) can be difficult
to distinguish from bacterial meningitis, encephalitis, or malaria, and
the viscerotropic syndrome can be difficult to distinguish from hemor-
rhagic fevers, viral hepatitis, and many other causes of multisystem
failure.
Indications
Yellow fever vaccine is recommended for people 9 months or older
traveling to or residing in areas where yellow fever is endemic.618 Because
of the increased risk of neurologic complications, infants 6 to 8 months
of age should be considered for vaccination only when travel to high-risk

areas is unavoidable and high-level protection against mosquito exposure
is not feasible. Infants younger than 6 months have a substantially
increased risk of neurologic disease, and vaccination should not be
given to this age group. Vaccination for international travel to certain
destinations is required.
Yellow fever vaccination requirements for specific countries are
available on the CDC Traveler’s Health website (http://wwwnc.cdc.gov/
travel/yellowbook/2016/infectious-diseases-related-to-travel/yellow-
fever). To obtain an international certificate of vaccination, a yellow
fever vaccine approved by the WHO and administered at a designated
yellow fever vaccine center is required. Yellow fever vaccine centers in
the United States can be identified by contacting state or local health
departments or visiting the CDC website (http://wwwnc.cdc.gov/travel/
yellow-fever-vaccination-clinics/search). If the risks of potential serious
adverse events caused by the yellow fever vaccine are considered greater
than the potential benefits for exposed individuals, a medical waiver
letter can be provided, and guidance is provided on the CDC website
(http://wwwnc.cdc.gov/travel/yellowbook/2016/infectious-diseases-
related-to-travel/yellow-fever#4731).
Historically, the WHO international health regulations required
revaccination at 10-year intervals. However, evidence from several studies
indicated that yellow fever immunity persists for many decades. In
2015, the CDC’s ACIP issued a recommendation that only a single dose
of yellow fever vaccine is required to provide long-lasting protection
for most travelers except for pregnant women, hematopoietic stem cell
transplant recipients and HIV-infected people. The WHO has removed
the booster requirement from the international health regulations as
of 2016.617
Yellow fever vaccines can be administered at the same time as
inactivated vaccines and other live attenuated viral vaccines, except for
the MMR vaccine, because the immune responses against yellow fever,
mumps, and rubella are inhibited.408 These vaccines should be given
30 days apart.
Precautions and Contraindications
The risk of having adverse reactions appears to be age related.618 Infants
younger than 9 months should not receive yellow fever vaccine because
of the increased risk of vaccine-associated neurotropic disease developing
in this age group.30 Immunization should be delayed until an infant is
at least 9 months of age. In unusual circumstances, physicians considering
vaccinating infants 6 to 8 months of age should contact the applicable
division of the CDC for advice (i.e., CDC Division of Vector-Borne
Infectious Diseases or the CDC Division of Global Migration and
Quarantine: 800-232-4636).
No major adverse effects of yellow fever vaccine on the developing
fetus have been demonstrated. A slight increased risk was observed for
minor, mostly skin, malformations in infants. A higher rate of spontane-
ous abortions in pregnant women receiving the vaccine was reported
but not substantiated. Vaccine administration to pregnant women usually
is not indicated because the vaccine is a live virus. Pregnant women
should be considered for vaccination only when travel to high-risk
areas is required and protection against mosquito exposure is not feasible.
Considering that immune responses to vaccination during pregnancy
may vary, serologic testing can be considered to document a protective
immune response to the vaccine.
Three YEL-AND cases have been reported in exclusively breastfed
infants whose mothers were vaccinated with yellow fever vaccine. All
three infants were younger than 1 month and diagnosed with encephalitis.
Until more data are available, yellow fever vaccine should be avoided
in breastfeeding women. However, when travel of breastfeeding mothers
to a yellow fever–endemic area cannot be avoided, these women should
be vaccinated.
Yellow fever vaccine, which is a live attenuated virus vaccine, poses
a risk of developing encephalitis or other serious adverse events for
patients with conditions that commonly result in immunosuppression
(i.e. AIDS or symptomatic HIV infection, primary immunodeficiencies,
thymic disease with abnormal immune function such as thymoma or
myasthenia gravis, malignancy, transplantation, and radiation therapy).
The vaccine should be avoided by these people. Although not specifically
tested, the vaccine is presumed to pose risks for patients receiving
CHAPTER 245  Active Immunizing Agents 2595
immunosuppressive or immunomodulatory therapies (e.g., high-dose
systemic corticosteroids, alkylating drugs, antimetabolites, tumor necrosis
factor-α inhibitors, interleukin-1 and interleukin-6 blocking agents,
other monoclonal antibodies such as rituximab and alemtuzumab) and
should be avoided in most cases according to the drug manufacturers.
A history of thymectomy or indirect radiation therapy is not considered
a contraindication.
Family members of immunosuppressed people, who themselves have
no contraindications, may receive yellow fever vaccine. If travel to an
epidemic or endemic area is necessary, the patient should be instructed
in ways to avoid mosquitoes and given a vaccine waiver letter.
People with a history of systemic anaphylaxis to eggs or chicken
should not be vaccinated because the vaccines contain egg proteins and
on rare occasion may induce immediate allergic reactions. People may
also develop allergies to the vaccine because it contains gelatin and
latex from the vial stopper. Less severe or local manifestations of allergy
to eggs or to feathers are not contraindications to yellow fever vaccine
administration and do not warrant performing vaccine skin testing.36
If international quarantine regulations are the only reason to immunize
a patient known to be hypersensitive to eggs, a medical waiver letter
should be provided. If immunization of an individual with a questionable
history of egg hypersensitivity is considered essential because of the
high risk of exposure, an intradermal skin test can be given as directed
in the vaccine package insert.618
Vaccines Related to Bioterrorism
Anthrax and smallpox vaccines are potentially available to protect children
against bioterrorist attacks with Bacillus anthracis and variola. Anthrax
vaccine is not approved by the FDA for use in children. The AAP updated
its recommendations on exposure to anthrax through bioterrorism in
2014.86 Until there are sufficient data to support FDA approval, anthrax
vaccine will be made available for children at the time of an event as
an investigational vaccine through an expedited process that requires
institutional review board approval, including the use of appropriate
consent documents. Information on the process required for use of
anthrax vaccine in children will be available on the CDC website at the
time of an event (https://www.cdc.gov/anthrax/).703
The only smallpox vaccine licensed in the United States is ACAM2000,
a live virus vaccine.153 In the absence of a smallpox outbreak, preexposure
smallpox immunization is not recommended for children.46 Anthrax
and smallpox vaccines are reviewed in the relevant disease-specific
chapters of this textbook.
Investigational Vaccines
Routine immunizations for children have virtually eliminated many
infectious diseases from the United States. These successes have encour-
aged research to develop vaccines to prevent other serious viral and
bacterial diseases affecting children. A 1985 report by the IOM of the
National Academy of Sciences reviewed the benefits that would be
associated with the development and use of new and improved vaccines
in the United States.212 The report listed 14 diseases for which vaccines
were desirable. A 1999 study by the IOM observed that considerable
progress had been made since the 1985 study.213 Seven of 14 vaccines
listed in the 1985 study as domestic priorities for development are now
licensed. They include acellular pertussis vaccine, LAIV, and vaccines
against hepatitis A and B, Hib, varicella, and rotavirus.
The 1999 IOM report used a new quantitative model to compare
the cost and health benefits of developing candidate vaccines.213 This
model can be used to evaluate the potential impact of a new vaccine
on public health. In the 1999 report, the model was used to evaluate
diseases for which candidate vaccines were being developed. The report
divided 26 candidate vaccines into four groups, arranged from most
to least favorable for development. The four vaccines in the top tier
include a cytomegalovirus vaccine given to adolescents, a universal
influenza vaccine, a group B Streptococcus vaccine for high-risk adults
and pregnant women, and an S. pneumoniae vaccine for infants and
seniors. Other diseases for which vaccines would be desirable included
Chlamydia trachomatis, enterotoxigenic E. coli, Epstein-Barr virus,
Helicobacter pylori, hepatitis C virus, herpes simplex virus, human
papilloma virus (HPV), M. tuberculosis, Neisseria gonorrhoeae, respiratory
2596 PART V  Prevention of Infectious Diseases
BOX 245.2  Pathogens With Important Public
Health Implications That Have No Licensed Vaccines
Campylobacter jejuni
Chikungunya virus
Dengue virus
Enterotoxigenic Escherichia coli
Enterovirus 71 (EV71)
Group B Streptococcus (GBS)
Herpes simplex virus
Human immunodeficiency virus type 1 (HIV-1)
Influenza virus (i.e., no universal vaccine)
Leishmania spp. (i.e., leishmaniasis)
Mycobacterium tuberculosis (i.e., tuberculosis)
Necator americanus and Ancylostoma duodenale (i.e., human hookworm
disease)
Nipah virus
Nontyphoidal Salmonella spp. (i.e., salmonellosis)
Norovirus
Plasmodium spp. (i.e., malaria)
Respiratory syncytial virus (RSV)
Salmonella enterica subspecies (i.e., paratyphoid fever)
Schistosoma mansoni, S. haematobium, and S. japonicum (i.e.,
schistosomiasis)
Shigella spp. (i.e., shigellosis)
Staphylococcus aureus
Streptococcus pneumoniae
Streptococcus pyogenes
Trypanosoma cruzi (i.e., Chagas disease)
Zika virus
syncytial virus, parainfluenza virus, Shigella, and groups A and B
streptococci. Two vaccines listed in the 1999 study are now licensed:
pneumococcal conjugate vaccine for infants and seniors and HPV vaccine.
Progress in vaccine development is periodically reviewed and
published by National Institute of Allergy and Infectious Diseases
(NIAID) scientists in The Jordan Report.497 The 2012 report discusses
progress in vaccine development and states that we now have licensed
vaccines against Hib and pneumococcal types that cause high childhood
morbidity and mortality rates, against hepatitis A and B, against
rotaviruses, and against varicella. We also have improved vaccines against
such diseases as influenza and pertussis.
Advances in biotechnology, increased understanding of the virulence
factors of infectious agents, and knowledge of the host immune response
have led to new approaches for vaccine development.256 Technological
advances in making vaccines, including protein conjugation of bacterial
polysaccharides, DNA vaccines, viral chimeras, viral vectors, and other
novel platforms have been developed. Vaccines are being developed by
the application of these newer technologies to numerous infectious
agents for which effective vaccines are not currently available. The
development of vaccines for these pathogens requires solution of several
immunologic problems, including pathogen variability, short effector
memory, evoking functional responses, and identification of antigens
that generate protective responses.539
The 2012 Jordan Report states that many challenges remain. Progress
on vaccines to prevent some high-burden diseases has been frustratingly
slow, although there is a growing pipeline of novel vaccines against
dengue, malaria, tuberculosis, and others. The Report lists approximately
600 vaccine candidates in development against an estimated 110
pathogens. Considering the resource constraints in vaccine development,
approaches that are most likely to produce high-priority vaccines need
to be identified.
A special issue of Vaccine published in June 2016 focuses on the
research and development pipeline of vaccines against 25 pathogens
for which no licensed vaccines currently exist but for which there is
high public health importance, as identified by the WHO Product
Development for Vaccines Advisory Committee (PDVAC).687 PDVAC
is a body of independent experts that was established in 2014 to guide
the WHO and the vaccine development community along the pathway
toward the goal of licensure and deployment in countries with the
highest disease burden. These vaccines are listed in Box 245.2.
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CHAPTER 245  Active Immunizing Agents 2601.e1
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