THE LANCET

Vaccine series

Future vaccines and a global perspective

Samuel L Katz

Advances in medical biotechnology mean that vaccines to prevent more than 75 infectious diseases are being or have
been developed. Vaccination is unfortunately not reliant purely on biotechnology but also on politics and resources.
Countries with the greatest demand for vaccines have the least ability to pay for or produce them. Health-care
infrastructure and diagnostic facilities also hamper immunisation projects in developing countries. Charitable
organisations are relied on heavily to support such projects but the challenge to ensure all infants are immunised
against the most common infections of childhood is still enormous. Difficulties that present themselves now should
not prevent us looking into future possibilities such as immunisation during pregnancy and targeting of children for
immunisation against sexually transmitted diseases. Other avenues for research are in administration of vaccines. A
move to mucosal immunisation rather than use of the syringe and needle would be positive both economically and
from the point of view of risk of needle contamination. Plant science may also provide a new vehicle for vaccines by
engineering plants such as the banana tree to be naturally bioencapsulated vaccines. Prospects for control and
eradication of infectious disease in the next century are certainly good.

The interaction of several factors are critical to the
development of new vaccines as well as to the
improvement of older vaccines. The scientific and
biomedical technology encompassing both microbiology
and immunology continue to advance rapidly and
provide the fundamental concepts and materials with
which to work. The economic support for expanded
research, development, and implementation must come
from a number of sources: government (taxes), the
pharmaceutical industry, non-governmental foundations,
and community organisations. Essential to all of these
are the political and social commitment of society.
Commitment will vary depending on disease prevalence
in different regions of the world.
There are vaccines to prevent more than 75 different
infectious diseases of man in varying stages of research
and development (panel 1). Thanks to modern
biotechnology there is optimism that most human
pathogens of major significance will eventually have an
effective vaccine. Only HIV-1, malaria, and
Mycobacterium tuberculosis continue to defy efforts to
prevent infection with new vaccines (HIV and malaria)1–3
or to improve a less than optimal vaccine (BCG for
tuberculosis).4
Resources and health-care infrastructure
Most of the infrastructure and capital for the
development of new products is in developed countries.
Although much of the financial support for basic
research and some clinical investigations is derived from
government groups and from non-government
foundations, the major funding for subsequent product
research and development as well as clinical trials most
often emanates from private industry. As a result,
priorities often lie with vaccines that will prevent diseases
most prevalent in developed countries and in where a
Lancet 1997; 350: 1767–70
Division of Pediatric Infectious Diseases, Duke University School of
Medicine, Durham, NC 27710, USA (S L Katz MD)
financial market exists. An example is the rapid
development of a vaccine for Lyme borreliosis disease5 in
the USA where it has been a recognised entity for less
than 20 years. In contrast, a number of illnesses
producing the greatest global morbidity and mortality
more often occur in developing countries with minimal
economies, unsophisticated manufacturing capabilities,
and scant markets for products produced by companies
in the developed countries.6 Although organisations such
as the WHO Expanded Programme on Immunization
(EPI), United Nations Children’s Fund (UNICEF),
United Nations Development Programme, World Bank,
Rockefeller Foundation, and Rotary International may
invest heavily in specific programmes, such as the global
eradication of poliomyelitis, their resources are limited
but the challenges are enormous.
In some instances the lack of public-health
infrastructure precludes the surveillance and collection of
data to find out which infections are most prevalent and
result in the greatest morbidity and mortality. In the case
of a disease such as paralytic poliomyelitis, it is relatively
easy to do lameness surveys as a rough indicator of
poliomyelitis by finding out the rates of flaccid unilateral
lower-limb paralysis among children starting school,
since few other disorders result in this disability. In
contrast, the specific viruses and bacteria responsible for
common syndromes such as lower-respiratory-tract
disease, gastroenteritis, dysentery, and meningitis may
not be prioritised because of lack of diagnostic facilities
with which to identify aetiological agents. To exercise
rational judgment regarding which vaccines might be
most helpful it is essential to collect these data. One
cannot assume that because serotypes 6, 14, 19, and 23
are responsible for invasive pneumococcal disease in the
USA and Europe that the same serotypes will prevail in
Rwanda or Bangladesh. To provide appropriate vaccines
for such countries it will be essential first to identify the
specific pathogens responsible for disease syndromes.
The clinical, epidemiological, and laboratory surveillance
to achieve these goals are costly in personnel, facilities,
and funds.7

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Panel 1: Some vaccines at varying stages of research and development
Viruses Bacteria
Rotaviruses 1-4 Borrelia burgdorferi
Dengue 1-4 Pneumococcal conjugates
Herpes 2 and 1 Meningococcal conjugates
Hepatitis C,E Vibrio cholera
Papilloma (16,18,31,45) Helicobacter pylori
Cytomegalovirus Groups A & B streptococci
Epstein Barr Chlaymdia trachomatis
HIV-1 Escherichia coli
Parainfluenza 1,3 enteropathogenic
Respiratory syncytial enterotoxigenic
Encephalitis Shigella sonnei
Venezuelan equine Shigella flexneri
Western equine Mycoplasma pneumoniae
Eastern equine Non-typeable haemophilus
Japanese Mycobacterium leprae
Neisseria gonorrhoea
Campylobacter jejuni
Rickettsia rickettsii
Treponema pallidum
Legionella pneumophila
Targeting vaccine programmes
The most extensive and successful global immunisation
programmes to date have been those of EPI, targeting
infants in the first 9 months of life (panel 2). As newer
immunogens have become available, they are under
consideration for addition to the EPI, currently hepatitis
B and Haemophilus influenzae type b (Hib) conjugate.
The one exception to targeting infants aged up to 9
months has been the attempt to prevent neonatal tetanus
by administration of tetanus toxoid (one or two doses) to
women in the later months of pregnancy. Active transport
of IgG across the placenta in later gestation provides the
newborn with high titres of tetanus antitoxin effective in
the prevention of neonatal disease. This same strategy has
been proposed for other infections which threaten the
newborn or young infant, before successful vaccination
can be administered and before maturation of the needed
components of the newborn’s immune system.8 This
approach has been considered for respiratory-syncytial
virus infection and for group B streptococcal perinatal
infections. Paradoxically, in developed countries where
research on such products is highly promising, there is a
significant reluctance to use them because of concern
regarding liability for unfavourable pregnancy outcomes
that might mistakenly be attributed to vaccine
administration.
Although infants have been the focus of most
immunisation programmes, the advances in development
of vaccines for sexually transmitted diseases (panel 3)
raise the issue of a new focus on young people before the
onset of high-risk behaviours. Ideally this might
concentrate on school-aged children perhaps of 10–11
years. In contrast to their infant siblings, these young
people rarely come to the attention of health supervisors
and visit physicians or health facilities only sporadically
when injury or illness occurs. Innovative approaches will
be required to reach such age groups if or when vaccines
for sexually transmitted diseases are licensed.
A site for such programmes might be through school
health systems, if those responsible for educational
facilities would be willing to accept the superimposition of
immunisation programmes in the school curriculum.
Several such experiments have been fairly successful and
have achieved high rates of acceptance of the three-dose
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Fungi and parasites
Histoplasma capsulatum
Coccidioides immitis
Cryptococcus neoformans
Blastomyces dermatidis
Plasmodium falciparum
Entamoeba histolytica
Leishmania
Schistosoma mansoni
Toxoplasma gondii
schedule for hepatitis B among school-attending
youngsters.9
Another age group for whom immunisations would be
of major benefit are the aged. Of current vaccines both
influenza virus and pneumococcal vaccines have been
shown to be effective in the reduction of the rates of
pneumonia and excess mortality that occur with
influenza-virus cycles and with invasive pneumococcal
infections.10 Improvement in these vaccines, use of protein
conjugation of the pneumococcal polysaccharides, and
possible alternative routes of administration of influenza
virus vaccines may increase their use.
Route of administration
With few exceptions, vaccines currently being used are
administered by needle and syringe, subcutaneously or
intramuscularly. Only oral poliomyelitis virus vaccine, one
of the typhoid vaccines (Ty21a), and a cholera vaccine
(CVD103-HgR) are given orally. For many reasons,
future generations of vaccines should focus more heavily
on mucosal immunisation. The logistical and economic
assets are clear: avoidance of needles and syringes, less
likelihood of contamination, avoidance of transmission of
blood-borne infections (HIV, hepatitis B, hepatitis C),
lack of necessity for direct involvement of nurses and
physicians, and in general lower price of production.
Beyond these pragmatic advantages is the desirability to
exploit the mucosal immune system. Mimicry of the
natural route of infection (oral, respiratory, genital)
assures the exposure of large surface areas to vaccines, the
development of a first-line defence mediated by secretory
immunoglobulin A, recruitment of a humoral antibody
response via lymphocyte trafficking from mucosal
lymphoid tissues, and involvement of glandular
epithelium linked to the mucosal system. Among those
vaccines nearing availability that are potentially given by
this route are the rotaviruses, improved influenza virus
vaccines, respiratory syncytial virus, and Helicobacter pylori
vaccine. When these vaccines are appropriate for use in
developing countries they offer enormous advantages in
population coverage, best exemplified by the success of
oral poliomyelitis vaccine under the global poliomyelitis
eradication programme.
With injectable vaccines, several approaches have
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Panel 2: EPI schedule
At birth BCG and oral poliomyelitis virus vaccine
6 weeks DTP and oral poliomyelitis virus vaccine
10 weeks DTP and oral poliomyelitis virus vaccine
14 weeks DTP and oral poliomyelitis virus vaccine
9 months Measles
DTP=diphtheria, tetanus, pertussis vaccine.
proven successful in reduction of the numbers of
injections as well as the numbers of visits to or by a health
worker. Although we have long been accustomed to a
combination of diphtheria and tetanus toxoids with
Bordetella pertussis, newer vaccines incorporate
components of pertussis (pertussis toxoid, filamentous
haemagglutinin, outer membrane protein, agglutinogens).
Even more recent products add Hib conjugate,
inactivated poliomyelitis virus vaccine and/or hepatitis B
to such mixtures. With live attenuated replicating agents,
measles, mumps, and rubella have long been used (since
1971) as a trivalent product and varicella-zoster virus will
soon be added making this a quadrivalent product. Many
of the inactivated or subunit vaccines require multiple
injections to initiate a satisfactory, protective immune
response. Incorporation of such antigens in biodegradable
microspheres or particles has enabled a single injection to
suffice with eventual antibody responses from timed
release of antigen to produce titres equivalent to those
achieved with multiple injections.11 With the newer, more
purified subunit vaccines, the need for adjuvants to
stimulate host immune cells has been apparent and much
investigation has been devoted to the development of
newer adjuvants, to supplement or replace the standard
mixture of aluminum salts.12 Adjuvants being studied are
all oil-based emulsions containing biodegradable
materials, liposomes, and immunostimulatory complexes
in which antigens are mixed with a biocompatible
detergent and Quil A (an active extract of saponin from
the bark of the Quillaja saponania tree).13 Various
cytokines have also been administered with vaccines to
increase the magnitude of response and evolve a T helper
1 type predominance. Interleukin 12 (IL-12) has
augmented immune responses to both leishmania and
schistosomes. Failure of infants to mobilise a T-cell
dependent memory response to carbohydrate
(polysaccharide) antigens has been overcome by the
protein conjugation technique—eg, Hib conjugate
vaccine.14,15 Similar technology is now being applied to
meningococcal and pneumococcal antigens. With the
latter, as mentioned above, it will be necessary to select
from the more than 80 those serotypes to be included in
order to provide immunity against the commonly
circulating strains. An unanticipated advantage of the Hib
conjugate vaccine has been sufficiently augmented
immunity to abort nasopharyngeal carriage of the
organism and thereby to reduce transmission to
unimmunised susceptible contacts. Similar success with
pneumococcal and meningococcal conjugates would
greatly enhance their potential for disease control.
An entire new field in vaccinology has been generated
by the use of recombinant DNA vectors encoding
Panel 3: Candidate vaccines for sexually transmitted
diseases
Neisseria gonorrhoea Human papilloma viruses
Chlamydia trachomatis Treponema pallidum
Herpes simplex type 2
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antigens.16 DNA vaccines have generated great
excitement, enthusiasm, and new investigations as studies
in animals have proven successful and permitted the
initiation of human investigation. Although initially
delivered intramuscularly by a gene gun via DNA-coated
gold particles, it now appears that a variety of routes may
be exploited with similar success. The antigens coded by
the injected materials are expressed in the cytosol of cells
and result in endogenous protein expression with
subsequent induction of both specific antibodies and cell-
mediated immunity via T-cell pathways. In initial studies,
mice immunised with haemagglutinin and nucleoprotein
of influenza viruses were used. Subsequent successful
studies have included hepatitis B, HIV-1, Salmonella
typhi, rabies, and plasmodia. Concerns have been raised
that plasmid DNA might be integrated into the host cell
genome leading to insertional mutagenesis or
carcinogenesis. The induction of an autoimmune or
tolerance response has also been of concern but to date
has not been found. Because the encoded antigens are
produced by the host cell, they enter the MHC class 1
pathway and thereby reach the cell surface and stimulate
a T-cell response. The avoidance of whole viral vectors
such as those used in other recombinant technology
(vaccinia, adenovirus, canarypox) offers the advantage of
no immune response against the delivery vector and no
concern regarding its possible adverse effects such as
those seen in the past with vaccinia.17,18
Plant science
The most exciting development in vaccine research has
been the recruitment of plant science to the field. The
Children’s Vaccine Initiative19 was launched at the World
Summit for Children in September, 1990. At this summit
the initiative group expressed their goal of producing an
omnivalent neonatal vaccine that can be given orally.
Several groups of plant biologists have taken up this
challenge by looking into the potential of producing
recombinant proteins from transgenic plants so that the
food product can be used as a consumable vaccine. Two
strategies have been used. One involves the integration
into the host plant’s chromosome of a microbial gene
encoding an antigenic protein. A second approach
exploits expression of a desired foreign gene that has been
incorporated into the genome of a common plant virus.
There are several advantages to these systems which hold
great promise for practical application. Plant virions have
great structural stability and accumulate to high titres in
their natural hosts. Such viruses can be exploited as
vectors to express encoded genes for antigenic epitopes
as desired. If appropriate systems can be developed from
edible plants expressing antigens in their tissues, these
naturally bioencapsulated vaccines could be ingested with
subsequent release of antigen as foods were degraded in
the human gastrointestinal tract. Contact of the
bioencapsulated vaccine with the extensive
gastrointestinal-associated lymphoid tissue could induce
mucosal immunity followed soon after by humoral
immunity secondary to the trafficking of lymphoid cells.
Successful experiments have been done with potatoes20 as
a source, but since these are an unlikely food for young
infants, current studies focus on bananas.21 Bananas offer
multiple advantages including their availability in tropical
and subtropical countries where so much of future
control of vaccine-preventable diseases will be focused,
their palatability and digestibility by infants and because
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they do not need cooking (which can destroy antigens).
The major disadvantage of the banana plant is the time
that must elapse from first introduction of new genes to
harvest of the fruit, estimated to be 2 or 3 years.
However, enthusiastic plant biologists have already
calculated the numbers of tons of bananas that would be
necessary to provide global immunisation, a target well
within agricultural capability.
Vaccines for non-infectious diseases
The eight papers in this vaccine series have focused on
vaccines to prevent infectious diseases, but several other
diseases are the targets of current research. Virus vaccines
to prevent hepatitis B infection, Epstein Barr virus
infections, and human papilloma virus22 infection may
well be categorised as cancer vaccines since they may
prevent hepatocellular carcinoma, nasopharyngeal
carcinoma, and carcinoma of the uterine cervix,
respectively. Additionally, however, studies of cancer
vaccines that use alternative immunisation strategies are
an active area of investigation for varied cancers with no
known viral aetiology.23 Similarly, exploration of vaccines
that use T-cell subsets to prevent autoimmune disease
(diabetes mellitus, rheumatoid arthritis, and central
nervous system demyelinating disorders) is promising and
progressing slowly.24 Some of these approaches may lead
to preventive immunogens or others to therapeutic ones.
181 years elapsed between Jenner’s studies of vaccinia
and the eradication of smallpox. Perhaps only 51 years
may pass between Enders’ cultivation of poliomyelitis
viruses in cell culture and the global eradication of
poliomyelitis. Prospects for control, if not elimination, of
many infectious diseases of infants, children and adults lie
excitingly in the twenty-first century. Now the obstacles
to achievement will not be the scientific ones; they will be
the challenges to all of us for globalisation of economic
and political commitment to the humane goal of better
health and longer life for all.
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