Small pox eradicated in 1977 EPI coverage of > 80% by 1990 Certification for polio eradication by 2005 Over

3 million lives saved globally, annually

Vaccination: Process of inoculating the vaccine or the antigen Immunization: Process of inducing immune response, humoral or cell mediated. Seroconversion: Change from antibody negative state to antibody positive state. Seroprotection: The state of protection (from disease) due to presence of humoral immunity or antibody detectable in serum

Vaccination is a method of giving antigen to stimulate the immune response through active immunization.

A vaccine is an immuno-biological substance designed to produce specific protection against a given disease. A vaccine is antigenic but not pathogenic.

The greatest triumph of immunology has been the successful use of immunization procedures in the control of potentially fatal infectious diseases. The concept of immunization rose from the observation that individuals who recover from certain diseases are protected for life from recurrences. Modern vaccine biology is now targeting not only infectious diseases but also autoimmune and malignant disease.

The introduction of small quantities of fluid from active smallpox pustules into uninfected persons (variolation) was an effort at mimicking natural infection. These experiments were done in 1721 in an age when ethical clearance was not required! Jenner introduced vaccination in 1796 using cowpox to protect against smallpox. This was the first documented use of live attenuated vaccination and the beginning of modern immunization.

Specific defenses Immunity

Active immunity

Passive immunity

Following clinical infection

natural

Transfer of maternal Antibodies Through placenta Transfer of maternal Antibodies Through milk Following administration of Immunoglobulin or antiserum

Following subclinical infection

acquired
Following vaccination

Resistance developed in response to stimulus by an antigen (infecting agent or vaccine) and is characterized by the production of antibodies by the host.

Immunity conferred by an antibody produced in another host. It may be acquired naturally or artificially (through an antibody-containing preparation).

Temporary protection against infection can be established by giving preformed antibody from another individual of the same or a different species. The advantage of this form of therapy is that humoral immunity is acquired immediately. The disadvantage is that the administered antibodies are rapidly utilised by combination with antigen or catabolised in the normal way. Therefore protection is quite quickly lost and memory is not conferred.

An additional problem with passive immunotherapy is the potential transmission of infectious agents present in donor serum.

The first exposure to an antigen evokes a primary response. Immediately after introduction of immunogen little or no antibody is detected. This is called the inductive or latent period.

During this period, the immunogen is recognised as foreign and processed. The duration of this period is variable and depends on the type of antigen used, species of animal and route of immunization.

During the logarithmic phase, antibody concentration increases logarithmically for 410 days, until it reaches a peak. This peak antibody level usually takes 4 to 5 days for erythrocytes, 8-12 days for soluble proteins and 2 to 3 months for the toxoid of Corynebacterium diphtheriae.

The early primary response is characterized by a predominance of IgM over IgG, IgM production is transient and within 2 weeks of initiation of the response, IgG predominates.

The secondary immune response occurs upon second exposure to the same immunogen, weeks, months or even years later. The secondary immune response is accompanied by an accelerated response from already committed B lymphocytes in the memory pool.

Rapid proliferation and differentiation into plasma cells yields a higher antibody output. The secondary response is characterized by an initial negative phase, which is due to the immediate reaction of pre existing antibody with new immunogen.

Immunizing agents

vaccines

immunuglobulins

antisera

There are 5 major classes: IgM, IgA, IgG, IgE, IgD. Two types of immunoglobulin preparations are available for passive immunization:
Normal human immunoglobulin Specific (hyper-immune) human immunoglobulin

Human normal Human specific Non human ig immunoglobulin immunoglobulin (antisera) Hepatitis A Measles Rabies Tetanus Mumps Hepatitis B Varicella Diphtheria Diphtheria Tetanus Gas gangrene Botulism Rabies

These are materials prepared in animals or non human sources such as horses.

Passive immunity is acquired (i) by the newborn from the mother; (ii) by administering preformed immunoglobulins to an individual. Maternal transfer of antibodies: The neonate has a relatively immature lymphoid system. In early life, the newborn is thus protected by maternally derived antibodies (IgG) transferred passively via the placenta. Colostrum and breast milk also afford significant protection to the neonate.

The major immunoglobulin in milk is the secretory IgA, which remains in the gut of the newborn, protecting the intestinal mucosal surfaces from enteric pathogens. It is presumed that IgA producing cells responding to gut antigens migrate from the gut mucosa to colonize breast tissue, now considered to be a part of the mucosal associated lymphoid tissue (MALT).

Here the IgA producing cells secrete specific antibodies which appear in milk. This circuit has also been termed the enteromammary axis.

Antibody, either as whole serum or concentrated gamma globulins (immune globulin), is obtained from human volunteers who have recovered from a specific infectious disease or have received immunization. The globulin consists predominantly of IgG. Administration of such human immune globulin (HIG) offers immediate protection to individuals who are at risk, particularly where active immunization may take 7-10 days for effective antibody production.

Passive immunization is also useful to those individuals who are unable to produce antibody for themselves. Antibodies may also be available from animal sera. However, such immunoglobulins are less desirable, as non human proteins are cleared away by the host immune response against them. In addition, hazardous immune reactions against animal proteins may lead to the development of anaphylaxis or serum sickness.

Neither human nor animal immune globulin should be administered intravenously for fear of anaphylactic reactions. Hazards associated with administering human immune globulin (as pooled serum) include transmission of blood borne viruses - hepatitis B or C viruses and the human immuno deficiency virus (HIV). Purified IgG preparations are, however, free of these virus particles.

Antibodies (equine) for non infectious conditions is also available: antivenin against black widow spider and snake venoms. Human immune globulin to the Rh blood group is widely used to prevent haemolytic disease of the newborn. Tetanus antitoxin, now a human immune globulin, is given both prophylactically and therapeutically in appropriate cases.

Besides suffering the disease (and surviving it!), vaccination is the only other way of acquiring active immunity against an infectious agent. The advantages of active over passive immunization are due to the fact that the individuals immune system is stimulated to produce an immune response against a given antigen.

Host participation ensures that both the humoral and cellular components of the immune system are activated. Consequently, T cell help is recruited and immunologic memory is available to boost the response after subsequent exposure to the antigen. Antibodies so formed are longer lasting as compared to passively acquired immunoglobulin.

Live vaccines Attenuated live vaccines Inactivated (killed vaccines) Toxoids Polysaccharide and polypeptide (cellular fraction) vaccines Surface antigen (recombinant) vaccines.

Live vaccines are made from live infectious agents without any amendment. The only live vaccine is Variola small pox vaccine, made of live vaccinia cow-pox virus (not variola virus) which is not pathogenic but antigenic, giving cross immunity for variola.

Live vaccines Small pox variola vaccine

Live Killed Attenuated Inactivated vaccines vaccines BCG Typhoid oral Plague Oral polio Yellow fever Measles Mumps Rubella Intranasal Influenza Typhus Typhoid Cholera Pertussis Plague Rabies Salk polio Intramuscular influenza Japanise encephalitis

Toxoids

Cellular fraction vaccines Meningococcal polysaccharide vaccine Pneumococcal polysaccharide vaccine Hepatitis B polypeptide vaccine

Recombinant vaccines Hepatitis B vaccine

Diphtheria Tetanus

Active immunization may be performed with either killed or live attenuated vaccines and toxoids. The commonly used killed vaccines are: bacterial vaccines for typhoid cholera pertussis Plague viral vaccines for rabies poliomyelitis (the Salk vaccine) hepatitis B influenza

Live Attenuated Vaccines Include bacterial BCG a live attenuated Mycobacterium bovis for tuberculosis. Ty21a live oral attenuated mutant typhoid bacillus viral: live vaccinia virus for small pox rubella measles mumps polio (the Sabin vaccine) yellow fever virus

Polysaccharide vaccines for Haemophilus influenzae type B (Polyribosyl-ribitolphosphate, conjugated to tetanus protein) Neisseria meningitidis (a combination vaccine against groups A,C,Y,W135 and the new Meningitis C vaccine) Streptococcus pneumoniae (a polyvalent 23 valent polysaccharide vaccine and the new 7valent vaccine)

They are prepared from extracted cellular fractions e.g. meningococcal vaccine from the polysaccharide antigen of the cell wall, the pneumococcal vaccine from the polysaccharide contained in the capsule of the organism, and hepatitis B polypeptide vaccine.

Their efficacy and safety appear to be high.

Besides these, there are toxoid vaccines for: diphtheria tetanus. They are prepared by detoxifying the exotoxins of some bacteria rendering them antigenic but not pathogenic. Adjuvant (e.g. alum precipitation) is used to increase the potency of vaccine. The antibodies produces in the body as a consequence of toxoid administration neutralize the toxic moiety produced during infection rather than act upon the organism itself. In general toxoids are highly efficacious and safe immunizing agents.

The simplest way to destroy the ability of microbes to cause disease yet maintain their antigenicity is to prevent their replication by killing in an appropriate manner, such as with formaldehyde treatment. Inactivated microorganisms have generally provided safe antigens for immunization. Examples are typhoid, cholera and killed poliomyelitis (Salk) vaccines. Care has to be taken to ensure that important protective antigens are not destroyed in the inactivation process.

Live attenuated vaccines have many advantages. Attenuation mimics the natural behaviour of the organism without causing disease. The immunity conferred with live attenuated vaccines is superior because actively multiplying organisms provide a sustained antigen supply. The immune response takes place largely at the site of natural infection as in the case of the live polio vaccine and the oral typhoid vaccine producing an obviously advantageous local secretory IgA response.

A very small number of individuals develop encephalitis following measles vaccine. The danger of developing encephalitis from natural infection is far greater. There is the possibility of the attenuated virus reverting to its virulent form; chances of this decrease if the attenuation incorporates several gene mutations instead of just one.

Live attenuated vaccines are not advised in patients with an immunodeficiency disease, in patients on steroid and other immunosuppressive treatment and for those undergoing radiotherapy. Malignancies such as lymphomas and leukaemias and pregnancy are all contraindications to the administration of live attenuated vaccines.

Since the process of attenuation is cumbersome and time consuming, several newer approaches to vaccine development are being researched. (a) Sub unit vaccines Sub unit vaccines are being designed, which use only the relevant immunogenic portions of the organism. If the low immunogenicity of these sub units can be overcome, such vaccines are stable, free from extraneous proteins and nucleic acids and precise in their composition.

(b) Biosynthesis of immunogenic proteins Specific immunogenic surface proteins need to be available in large quantities for vaccine preparation. The problem of isolating and characterizing antigenic protein moieties has been overcome by cloning the genes that code for these proteins in bacterial or eukaryotic (yeast) cells or in the vaccinia virus. In 1986, the first recombinant (cloned) viral vaccine was licensed for use.

The Hepatitis B surface antigen (HBsAg) is the immunogen that stimulates protective immunity. It is prepared by cloning HBsAg gene in yeast cells where it is expressed. HBsAg produced is then used for vaccine preparations. Their efficacy and safety also appear to be high.

(c) Synthetic peptide vaccines A limited number of sites on an organism are involved in evoking an immune response. If these sites, consisting mainly of peptide fragments, can be synthesized they provide a possible means of obtaining chemical polypeptides as vaccines.

Live vaccines Small pox variola vaccine

Live Killed Attenuated Inactivated vaccines vaccines BCG Typhoid oral Plague Oral polio Yellow fever Measles Mumps Rubella Intranasal Influenza Typhus Typhoid Cholera Pertussis Plague Rabies Salk polio Intramuscular influenza Japanise encephalitis

Toxoids

Cellular fraction vaccines

Recombinant vaccines

Diphtheria Tetanus

Meningococcal polysaccharide vaccine Pneumococcal polysaccharide vaccine Hepatitis B polypeptide vaccine

Hepatitis B vaccine

Deep subcutaneous or intramuscular route (most vaccines) Oral route (sabine vaccine, oral BCG vaccine) Intradermal route (BCG vaccine) Scarification (small pox vaccine) Intranasal route (live attenuated influenza vaccine)

Absolutely protective(100%): yellow fever vaccine Almost absolutely protective (99%): Variola, measles, mumps, rubella vaccines, and diphtheria and tetanus toxoids. Highly protective (80-95%): polio, BCG, Hepatitis B, and pertussis vaccines. Moderately protective (40-60%) TAB, cholera vaccine, and influenza killed vaccine.

1. Reactions inherent to inoculation:

These may be local general reactions. The local reactions may be pain, swelling, redness, tenderness and development of a small nodule or sterile abscess at the site of injection. The general reactions may be fever, malaise, headache and other constitutional symptoms. Most killed bacterial vaccines (e.g., typhoid) cause some local and general reactions. Diphtheria and tetanus toxoids and live polio vaccine cause little reaction.

Faulty techniques may relate to faulty production of vaccine (e.g. inadequate inactivation of the microbe, inadequate detoxication), too much vaccine given in one dose, improper immunization site or route, vaccine reconstituted with incorrect diluents, wrong amount of diluent used, drug substituted for vaccine or diluent, vaccine prepared incorrectly for use (e.g., an adsorbed vaccine not shaken properly before use), vaccine or dliluent contaminated, vaccine stored incorrectly, contraindications ignored (e.g. a child who experienced a severe reaction after a previous dose of DPT vaccine is immunized with the same vaccine), reconstituted vaccine of one session of immunization used again at the subsequent session.

Use of improperly sterilized syringes and needles carry the hazard of hepatitis B virus, and staphyloccocus and streptococcal infection

Administration of antisera (e.g., ATS) may occasionally give rise to anaphylactic shock and serum sickness. Many viral vaccines contain traces of various antibiotics used in their preparation and some individuals may be sensitive to the antibiotic which it contains. Anaphylactic shock is a rare but dangerous complication of injection of antiserum. There is bronchospasm, dyspnoea, pallor, hypotension and collapse. The symptoms may appear within a few minutes of injection or may be delayed up to 2 hours. Some viral vaccines prepared from embryonated eggs (e.g., influenza) may bring about generalized anaphylactic reactions. Serum sickness is characterized by symptoms such as fever, rash, oedema and joint pains occurring 7 -12 days of injection of antiserum.

Neuritic manifestations may be seen after the administration of serum or vaccine. The well-known examples are the postvaccinial encephalitis and encephalopathy following administration of anti -rabies and smallpox vaccines. GuillainBarre syndrome in association with the swine influenza vaccine is another example.

Occasionally following immunization there may occur a disease totally unconnected with the immunizing agent (e.g., provocative polio after DPT or DT administration against diphtheria). The mechanism seems to be that the individual is harboring the infectious agent and the administration of the vaccine shortens the incubation period and produces the disease or what may have been otherwise only a latent infection is converted into a clinical attack.

These may comprise damage to the fetus (e.g., with rubella vaccination).

Infants and children expanded immunization program (schedule) Active immunization for adult females Vaccination for special occupations Vaccination for special life styles Vaccination for special environmental situations Vaccinations for special health status persons Vaccinations in travel Vaccines against bioterrorism