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The contribution of vaccination to global
health: past, present and future
Brian Greenwood
rstb.royalsocietypublishing.org
Review
Cite this article: Greenwood B. 2014 The
contribution of vaccination to global health:
past, present and future. Phil. Trans. R. Soc. B
369: 20130433.
http://dx.doi.org/10.1098/rstb.2013.0433
One contribution of 12 to a Theme Issue ‘After
2015: infectious diseases in a new era of
health and development’.
Subject Areas:
health and disease and epidemiology,
immunology, microbiology
Keywords:
vaccination, global health,
vaccine development
Author for correspondence:
Brian Greenwood
e-mail: [email protected]
Faculty of Infectious and Tropical Diseases, London School of Hygiene and Tropical Medicine,
London WC1E 7HT, UK
Vaccination has made an enormous contribution to global health. Two major
infections, smallpox and rinderpest, have been eradicated. Global coverage of
vaccination against many important infectious diseases of childhood has been
enhanced dramatically since the creation of WHO’s Expanded Programme of
Immunization in 1974 and of the Global Alliance for Vaccination and Immunization in 2000. Polio has almost been eradicated and success in controlling
measles makes this infection another potential target for eradication. Despite
these successes, approximately 6.6 million children still die each year and
about a half of these deaths are caused by infections, including pneumonia
and diarrhoea, which could be prevented by vaccination. Enhanced deployment of recently developed pneumococcal conjugate and rotavirus vaccines
should, therefore, result in a further decline in childhood mortality. Development of vaccines against more complex infections, such as malaria,
tuberculosis and HIV, has been challenging and achievements so far have
been modest. Final success against these infections may require combination
vaccinations, each component stimulating a different arm of the immune
system. In the longer term, vaccines are likely to be used to prevent or modulate the course of some non-infectious diseases. Progress has already been
made with therapeutic cancer vaccines and future potential targets include
addiction, diabetes, hypertension and Alzheimer’s disease.
1. Introduction
It is often stated that vaccination has made the greatest contribution to global
health of any human intervention apart from the introduction of clean water
and sanitation, but this is a claim that needs some qualification. Study of the
pattern of infectious diseases in industrialized countries from the end of the nineteenth century onwards shows that there was a large and progressive decline in
child mortality, owing largely to a reduction in mortality from infectious diseases,
prior to the development and deployment of vaccines. This was associated with
improvements in housing, nutrition and sanitation. Nevertheless, it is indisputable that vaccination has made an enormous contribution to human and animal
health, especially in the developing world. Mortality from smallpox and measles
was massive in the pre-vaccination period with up to a half of the population
dying from the former during epidemics and measles was only a little less
lethal in susceptible populations.
This review describes briefly some of the major past achievements of vaccination, the present situation in relation to the global use of vaccines and some of
the ways in which vaccination could contribute to global health in the future.
2. Past contribution of vaccination to global health
(a) Jenner and the eradication of smallpox
The development of vaccination as a public health tool is attributed to Edward
Jenner and his experiments with coxpox in 1796 (figure 1), although the practice
of variolation using ‘wild’ smallpox virus had been practiced in some countries
for much longer [1]. Variolation worked but carried a significant risk of severe disease or even death in the recipient. This risk was reduced dramatically by
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Figure 1. Edward Jenner by John Raphael Smith (Wellcome Library).
substituting smallpox material by fluid from a cowpox lesion.
The cowpox virus causes only mild infections in humans but
induces an immune response which provides cross-protection
against smallpox infection, the principle that has underpinned
the development of all subsequent vaccines based on an attenuated organism. Vaccination was adopted as a public health tool
relatively rapidly in Europe and the USA, although not without
fierce opposition from some sections of the community,
especially when vaccination was made compulsory as was
the case in the UK following the introduction of the Vaccination
Act in 1871 [2]. The anti-vaccination campaign, which continues
today in both industrialized and developing countries, had
some surprising supporters including Alfred Russel Wallace,
co-discoverer of evolution [3].
As smallpox vaccine was the first vaccine to be deployed
widely in man, it was appropriate that smallpox was the first
human infectious disease to be eradicated by vaccination, a
milestone achieved in 1979. The story of the eradication
of smallpox is described by Henderson, who played a key
role in the eradication campaign, in his book ‘Smallpox—
the eradication of a disease’, which sets out the challenges
that the eradication team faced and how these were met:
important lessons for today [4]. The key to the final stages
of the campaign was intensive surveillance for cases and a
focal response following detection of a case. Smallpox had
a number of advantages as a target for eradication. Firstly,
the disease has distinctive clinical features; secondly, it
was well recognized and much feared in the communities
where it was prevalent; and finally, and perhaps most importantly, sub-clinical infections were rare. Measles, another
potential candidate for eradication, has some of these features, and local transmission of measles virus has already
been interrupted in the Americas. However, polio virus,
unlike smallpox and measles viruses, usually causes a
hidden, asymptomatic infection, making eradication of this
infection especially challenging (see below).
The next human vaccine to be developed using the principle
of attenuation was rabies vaccine, developed by Pasteur and
first tested in man in 1885, nearly a century after Jenner’s
experiments [7]. This vaccine was based on material obtained
from infected rabbit brain attenuated by drying, an uncertain
process, and vaccines prepared in this way frequently caused
serious side effects. Most human rabies vaccines are now
based on inactivated virus grown in tissue culture [8]. Acquisition of the ability to grow viruses in tissue culture for an
extended period led to the development of attenuated vaccines
against measles and poliomyelitis in the 1950s and the 1960s
[9]. Subsequently, many other vaccines have been developed
using the principle of attenuation, including rubella, influenza,
rotavirus, tuberculosis and typhoid vaccines. Vaccines based
on attenuated organisms generally induce a strong and sustained immune response, induce more effective immunity at
mucosal surfaces than killed vaccines and are usually relatively
easy and cheap to make. Because the vaccine components are
alive, they can spread to non-vaccinated subjects, extending
the impact of vaccination to the community at large (table 1).
However, because these vaccines are alive, mutations may
occur in the attenuated vaccine strain with a reversion to virulence, as seen rarely with oral polio vaccine which causes
paralysis in about one in two million recipients, and they
may cause significant illness in subjects with impaired immunity, as has been seen with the anti-tuberculosis vaccine
bacille Calmette Guérin (BCG) when given to immunodeficient
patients, including those with human immunodeficiency virus
(HIV) infection [10].
An alternative way of making microorganisms safe for
use in a vaccine is to kill them, and at the beginning of the
twentieth century a number of vaccines based on killed
whole organisms, including the pneumococcus, meningococcus and typhoid bacillus, were developed and used.
These vaccines were usually poorly immunogenic and often
caused significant side effects (table 1), so that whole-cell vaccines have largely given way to subunit vaccines. However,
there has recently been a renewed interest in use of wholecell vaccines, which have the advantage of presenting
multiple antigens, and whole-cell, attenuated pneumococcal [11] and malaria [12,13] vaccines have recently been
developed and are being evaluated in clinical trials. The
Phil. Trans. R. Soc. B 369: 20130433
(b) The next generation of vaccines
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Smallpox is the only human infection to have been eradicated, although eradication of guineaworm infection is close.
Eradication of the rinderpest virus, formally recognized by
the World Health Organization in 2011, is less widely recognized than eradication of smallpox, but this represents
another major milestone in the control of infectious diseases
and has been a major contribution to global health [5,6].
Rinderpest, closely related to measles and distemper viruses,
can cause high mortality in cattle, impoverishing families in
developing countries dependent upon their cattle and making
them susceptible to malnutrition and many infectious diseases.
Recently, there has been closer interaction between research
groups developing human and veterinary vaccines through
organizations such as the Jenner Vaccine Institute (www.
jenner.ac.uk (accessed 8 November 2013)), a development to
be encouraged as common technologies can be applied in
each area and some vaccines, for example a tuberculosis
vaccine, could be used in man and his domestic animals.
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Table 1. Advantages and disadvantages of attenuated and killed vaccines.
3
killed vaccine
thermostability
usually low
usually high
reactogenicity
immunogenicity
usually low
usually long-lasting
frequently high
often short duration
mucosal immunity
safety
often strong
reversion to virulence may occur
variable
safety high
indirect herd protection
may cause serious infections in immunocompromised
may infect and protect non-vaccinated
can protect non-vaccinated by interrupting transmission
symptoms and signs of tetanus and diphtheria are caused
by soluble toxins produced by the causative bacteria, and
at the beginning of the twentieth century anti-toxins were
developed to treat and prevent these infections with some
success. However, the prevention provided by anti-toxins
was only short lived, and in the 1920s it was shown that
sustained protection against these infections could be
achieved by immunization with a modified toxin (toxoid);
these straightforward and safe vaccines are still being used
widely today. Tetanus toxoid, diphtheria toxoid and a
killed pertussis (whooping cough) vaccine (DPT) was
developed in 1931 and remains a key component of infant
immunization programmes across the world. In many
countries, the original whole-cell pertussis component of
DPT has been replaced with a less reactogenic, acellular
pertussis component, and DPT is now used widely in combination with hepatitis B and Haemophilus influenzae type b
(Hib) vaccines, a combination widely known as pentavalent
vaccine or ‘penta’.
By the late 1950s, the majority of children in developed
countries were receiving routine vaccination with DPT and
polio vaccines and, in some countries, vaccination against
tuberculosis. Consequently, the incidence of these infections
as important public health problems declined substantially,
although in the case of pertussis and measles, success has not
been complete as outbreaks of these infections still occur in
industrialized countries, including the UK, owing to periodic
declines in vaccine coverage. These declines in coverage are
often a consequence of the activities of an active anti-vaccination
lobby, as was the case in the UK following the spurious reports
of a link between autism and a combined measles, mumps and
rubella vaccine [14]. The measles virus has a high reproductive
potential, and a high, sustained level of vaccine coverage is
required to interrupt transmission.
(c) The expanded programme on immunization
By the 1960s, the vast majority of deaths and severe illnesses
attributable to the common infectious diseases of childhood
preventable by vaccination were occurring in children in the
developing world, where coverage with vaccines such as
measles was frequently less than 5% and restricted largely to
children of the small, wealthy section of the community, the
group at least risk of a serious outcome from an infection
such as measles. At this time, the early 1960s, about onethird of African children did not reach the age of 5 years and
infectious diseases, particularly measles, accounted for a
substantial proportion of these deaths. In the face of this
challenge, the World Health Organisation (WHO) established
the Expanded Programme on Vaccination (EPI) in 1974 to
increase the uptake of routine childhood vaccines across the
world. This programme has been very successful, with coverage rates of EPI vaccines climbing rapidly from less than 5%
to over 80% in many low and low middle-income countries
[15]. By the 1980s, coverage with EPI vaccines in many lowincome counties was similar to, or even better than, that
achieved in many parts of the industrialized world where the
infectious diseases of childhood were no longer seen as a significant threat.
The success of the EPI programme was achieved in part
because of sound leadership in WHO and in many developing countries, and in part through financial support from the
international community. Because EPI vaccines are relatively
cheap when mass produced, full immunization of a child cost
around $15 in the 1990s. Introduction of effective national EPI
programmes in most developing countries has led to major
reductions in deaths and hospital admissions from measles
and neonatal tetanus. It has been estimated that in 2012
there were about 157 000 deaths from measles (www.who.
int/topics/measles (accessed 8 November 2013)), a dramatic
decrease from the situation 20 years ago (figure 2) but still an
unacceptable burden from a preventable infection. There has
also been a dramatic reduction in the number of deaths from
neonatal tetanus (over 90% since the 1980s), achieved through
routine immunization of mothers attending antenatal clinics
with tetanus toxoid, but it is estimated that there were
still about 60 000 preventable deaths from this infection in
2012 (www.who.int/topics/tetanus (accessed 8 November
2013)). The impact of vaccination has not been limited to
the developing world, and a recent review from the USA
[16] estimated that 103 million cases of selected infectious
diseases had been prevented by vaccination since 1924.
Work conducted largely in Guinea Bissau, but supported
by some studies conducted elsewhere, has shown sex differences in the response to routine EPI vaccines and also
suggested that in developing country situations, EPI vaccines
have non-specific effects on child mortality independent of
their impact on the disease at which they are directed [17].
Much of the information supporting these ideas has come
from observational studies because of the difficulty in conducting placebo controlled trials with established vaccines,
but a recent randomized trial of BCG given to low birth
weight babies showed a significant reduction in neonatal
but not in infant mortality [18]. Acceptance of the results of
these studies has, until recently, been met with some scepticism because of the lack of an apparent mechanism through
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attenuated vaccine
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characteristic
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4
4 500 000
90
4 000 000
80
3 500 000
70
3 000 000
60
2 500 000
50
2 000 000
40
1 500 000
30
1 000 000
20
500 000
10
immunization coverage (%)
no. cases
100
0
1980
1981
1982
1983
1984
1985
1986
1987
1988
1989
1990
1991
1992
1993
1994
1995
1996
1997
1998
1999
2000
2001
2002
2003
2004
2005
2006
2007
2008
2009
2010
2011
2012
0
no. cases
official coverage
Source: WHO/IVB database, 2013
194 WHO Member States.
Data as of July 2013
WHO/UNICEF estimates
Data of slide: 12 July 2013
Figure 2. Uptake of measles vaccination and associated decline in the incidence of measles (WHO immunization database). (Online version in colour.)
which these effects could be achieved. However, recent
animal studies which have shown a sustained epigenetic
effect of BCG immunization on monocyte function provide a potential mechanism by which BCG could have an
indirect effect against infections other than tuberculosis [19].
Further carefully controlled trials are needed to establish
the clinical importance of non-specific vaccine effects, but
there are constraints on how these can be conducted ethically.
A WHO committee is currently reviewing the topic of nonspecific vaccine effects and it is expected that this committee
will make some recommendations on how to carry this
controversial issue forward.
3. Current challenges for global immunization
Current challenges in ensuring that currently available vaccines achieve their maximum impact on global health include
enhancing the uptake of the old ‘EPI’ vaccines even further
than achieved so far, eradication of polio and introduction of
recently developed vaccines into the routine immunization of
low- and middle-income countries, where they are likely to
achieve their maximum impact.
(a) Enhancing uptake of current vaccines
Although coverage with the initial package of routine infant
vaccines (BCG, DPT, measles and polio) is now as high in
many low- and middle-income countries as it is in the industrialized world (table 2), pockets remain where this is not the
case, often among the poorest and most vulnerable sections
of the community. Many further lives could be saved by
reaching these populations with routine EPI vaccines such
as measles. Finding better ways of reaching these groups,
who account for an increasing proportion of child morbidity
and mortality in many developing countries, with appropriate health interventions is likely to be a key target of the
post-2015 development goals. Methods being explored
include gaining a better understanding of why these communities or individuals are resistant to vaccination, making
vaccination more accessible through home visits and using
mobile phone technologies for reminders and data collection.
However, more operational research is needed on how to
help these vulnerable groups [20].
Handling sensitively the issue of vaccine safety is a key
factor in ensuring high vaccine uptake. All vaccines have side
effects in a small proportion of vaccine recipients and that
needs to be acknowledged while at the same time stressing
the benefits that accrue from vaccination. Recently developed
rotavirus vaccines provide a good example of this principle.
Both widely used rotavirus vaccines cause the serious condition
of intussusception in a small proportion of vaccine recipients,
perhaps one to five additional episodes per 100 000 vaccines,
an acceptable risk considering the major reduction in hospital
admissions and deaths achieved with these vaccines [21].
The issue of true vaccine side effects needs to be separated
from incorrect claims such as the reported association between MMR vaccine and autism [14], and such false claims
vigorously rebutted.
(b) Eradication of poliomyelitis
In 1988, the World Health Assembly made a decision to support
the eradication of poliomyelitis with an initial target date of
2000. However, eradication of polio has proved to be a more
challenging task than had been envisaged originally; the
target date for eradication has had to be extended on several
occasions and this is now 2014/2015 (www.polioeradication.
org (accessed 15 February 2014)). One of the three serotypes
of polio virus (type 2) has been eradicated, and this is probably
also the case for serotype 3, but serotype 1 has proved more
stubborn and this virus continues to circulate in three countries
(Nigeria, Pakistan and Afghanistan) with periodic spread to
other countries including Chad, Somalia and recently Syria
(figure 3) [22]. Nevertheless, there has been a 99.9% drop in
the number of polio cases since the start of the eradication programme and in 2013 only 400 cases were reported. Reaching the
final goal of eradication of the last polio virus faces a number of
challenges—technical, financial and social. Routinely used oral
polio vaccines contain viruses belonging to each of the three serotypes and this can lead to an unbalanced immune response
directed predominantly at one or two of the serotypes. This problem has been overcome by the development and deployment
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5 000 000
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measles global annual reported cases and
MCV coverage, 1980–2012
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wild poliovirus – 2013
1 January – 5 November
5
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Phil. Trans. R. Soc. B 369: 20130433
wild polio virus type 1
endemic country
importation countries
excludes vaccine-derived polioviruses and viruses
detected from environmental surveillance.
data in WHO HQ as of 5 November 2013
Figure 3. Cases of paralytic poliomyelitis in 2013 (www.polioeradication.org (accessed 15 February 2014)). (Online version in colour.)
Table 2. Vaccine coverage (percentage) by WHO region, 2012 (data from [15]). BCG, bacille Calmette Guérin vaccine; DTP3, three doses of diphtheria, tetanus,
pertusssis vaccine; MCV1, at least one dose of measles vaccine; HepB3, three doses of hepatitis B vaccine; Hib3, three doses of Haemophilus influenzae type b
vaccine; rotavirus, received the last dose of the recommended rotavirus series of immunizations; PCV3, three doses of a pneumococcal conjugate vaccine.
WHO region
BCG
DTP3
Polio3
MCV1
HepB3
Hib3
Africa
82
72
77
73
72
65
5
21
Americas
Mediterranean
96
83
93
83
93
82
94
83
91
81
91
58
69
14
77
13
Europe
93
95
96
94
79
83
2
39
Southeast Asia
Western Pacific
88
97
75
97
74
97
78
97
72
91
11
14
—
1
0
1
Global
89
83
84
84
79
45
11
19
of bivalent and monovalent serotype 1 vaccines. The polio eradication programme has been expensive, both financially and in
the use of scarce human resources. Currently, the campaign costs
about $1 billion a year, provided largely by international donors
and foundations, including the Bill & Melinda Gates Foundation
and the Rotary Club which have both made major contributions
to the campaign. Currently, there are no signs of a lack of intent
among the international donors to pursue the campaign through
to a successful conclusion but expenditure on a single infection at
this level could not be sustained indefinitely. Finally, there is
the challenge of resistance to vaccination in some countries,
especially Nigeria and Pakistan, where this has been sufficiently
extreme to lead to the murder of health workers. It would be a
tragedy if the polio eradication campaign failed at this point,
not only because of the resurgence in cases that would inevitably
rotavirus
PCV3
follow, but also because of the negative effect that this might
have on international support for global health issues overall.
Recent success in eliminating all wild polio viruses from India
provides grounds for optimism. If the wild virus is eradicated
successfully in 2014 or 2015, then a decision will be needed on
when to stop immunization with oral polio vaccine virus
which can, very rarely, mutate to a more virulent virus causing
paralysis. Some countries may decide to use the more expensive
killed polio vaccine for a few years until all vaccine type polio
viruses have disappeared [23].
(c) Introduction of newer vaccines
Since the establishment of the global EPI programme in 1974, a
number of new vaccines has been introduced into routine use
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pneumonia
other
malaria
measles
sepsis
tetanus
Figure 4. Infectious and potentially preventable causes of child mortality in
2012 [24]. (Online version in colour.)
in industrialized countries including hepatitis B, Haemophilus
influenzae serotype b (Hib), pneumococcal and meningococcal
polysaccharide/protein conjugate, rotavirus and human papilloma virus (HPV) vaccines. Uptake of these vaccines in the
developing world has generally been slow despite their
proven efficacy and a high burden from many of the diseases
that they could prevent. Uptake of hepatitis B vaccine into
the routine EPI of developing countries in Africa and Asia
took over 20 years, despite the fact that the hepatitis B virus
is a major cause of liver cancer in many parts of sub-Saharan
Africa and parts of Southeast Asia. This delay was due in
part to the initial high cost of the vaccine but also to difficulty
in persuading health officials and communities to accept vaccination of a child for a potential benefit that would not become
apparent for 30 or 40 years. Coverage with hepatitis B vaccine
now approaches 80% at the global level and its uptake has
been facilitated by a fall in cost and its incorporation into the
pentavalent vaccine described above.
Pneumonia and diarrhoea still account for a high proportion of deaths and severe disease in children in the
developing world (figure 4) [24]. The most frequent cause
of severe pneumonia in children is Streptococcus pneumoniae
(the pneumococcus), followed by Hib, while rotavirus is the
most frequent cause of severe diarrhoea. Thus, the development of effective vaccines against the pneumococcus and
rotavirus [25,26] and their incorporation into the EPI programmes of countries with a high child mortality should
result in a further major reduction in childhood deaths.
Whether pneumococcal conjugate and rotavirus vaccines in
developing countries will have the dramatic effect on nonvaccinated subjects observed in industrialized countries,
through the induction of herd immunity, remains to be
seen. Incorporation of these vaccines in the routine immunization programmes of the developing world countries, where
they could have their greatest impact, has faced a number of
challenges. Firstly, these vaccines are more difficult to make
than the first generation of paediatric vaccine (pneumococcal
conjugate vaccines contain 10 or 13 different components) and
they are consequently more expensive to produce. Secondly,
much less was known by the target populations about the
infections that these vaccines prevent than had been the case
for measles or poliomyelitis. To address the first issue, the
Global Alliance for Vaccines and Immunization (GAVI) (www.
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AIDS
meningitis
6
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diarrhoea
gavialliance.org (accessed 8 November 2013)), established in
2000, has obtained substantial support from international
donors, currently over $1 billion per year, enabling the organization to subsidize the costs of these new vaccines for countries
with a GDP of less than $1550 and to provide support for
improvements in vaccine delivery programmes. Introduction
of pneumococcal conjugate vaccines has also benefitted from
another novel funding process, the Advanced Market Commitment, which has attracted substantial funds from a number of
major donors.
To assist potential recipient countries in an appreciation
of the value to their communities of introducing these new
vaccines, GAVI established three special interest groups, the
pneumococcal and rotavirus Accelerated Development and
Introduction Plans (ADIPs) and the Hib Initiative. These
groups, based in academic institutions but working closely
with Ministries of Health and Finance, non-governmental
agencies and the pharmaceutical industry, helped to generate
local information on the burden of disease by providing education to all sectors of the community on the importance of the
infection in question and, in some cases, undertaking detailed
epidemiological studies and even vaccine trials [27]. They
also assisted in negotiations with the pharmaceutical industry
over pricing arrangements. As a result of the activities of
these groups and others, Hib and pneumococcal conjugate
vaccines have been introduced more rapidly into countries
with a high child mortality than was the case for hepatitis B vaccine (figure 5). Currently, 30 and 15 of the 56 GAVI eligible
countries have introduced pneumococcal conjugate and rotavirus vaccines, respectively (www.gavialliance.org (accessed
8 November 2013)). A number of GAVI eligible countries are
making good economic progress and will soon move above
the GDP level that makes them eligible for GAVI support. Finding ways of supporting routine immunization in these countries
as they become lower middle-income countries will be a challenge—use of a tiered pricing system and mass purchasing are
two of the options that are being explored.
The vaccination schedule currently used in the majority of
developing countries was developed, largely empirically,
when there was only a limited number of vaccines in the routine immunization schedule and when it was considered that
vaccines should all be given in the first year of life when clinic
attendance is highest. However, as more and more vaccines
are added to the immunization schedule, this approach
has had to be reviewed because of the potential for immunological interference between vaccines when given together
and because the immunization schedule developed for the
original EPI vaccine may not be the one that will give
the best immune response for a number of the recently
developed vaccines. Thus, it is likely that more frequent
attendances at a vaccination clinic will be needed and that
vaccination of children will need to extend into the second
year of life, as is already the case in many industrialized
countries. Because vaccination responses, as well as the
epidemiology of many infectious diseases, can vary significantly between populations, immunization schedules need
to be designed to meet local needs and a ‘one-size fits all’
approach is no longer appropriate.
Vaccination programmes in the developing world focused initially on prevention of potentially lethal infections in
young children because of the high burden of mortality
in this age group. However, there is increasing recognition
that the public health benefits provided by vaccination are
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80
60
40
20
0
1
3
5
7
9
11
13
15
years from first-country introduction
high-income countries (Hib)
low-income countries (Hib)
17
19
21
high-income countries (PCV)
low-income countries (PCV)
low-income countries (PCV)
(projected)
Figure 5. Uptake of Haemophilus influenzae type b (Hib) and pneumococcal conjugate vaccines (PCV) [27]. (Online version in colour.)
not restricted to the first year of life but are much broader, for
example the prevention of cancer in adults through the
immunization of older children with HPV vaccine [28] and
immunization of older children and young adults against
meningococcal disease in the African meningitis belt through
mass campaigns [29].
4. The next generation of vaccines
(a) Developing the new vaccines
Developing the next generation of vaccines will be increasingly challenging as many of the organisms at which they
are targeted have complex structures and life cycles, for
example the malaria parasite, or are very effective at outwitting the human immune response through antigenic
diversity, such as HIV and influenza viruses. Development
of new vaccines against other important infectious disease
targets such as dengue or novel corona viruses should be
easier using established technologies but the modest efficacy
of a recently tested dengue vaccine [30] emphasizes that challenges remain even in the development of more conventional
vaccines. The limited success obtained with the most promising malaria vaccine RTS,S/AS01 [31,32] and with a prime
boost HIV vaccine regimen [33] and the failure of a new
tuberculosis vaccine [34] illustrate how challenging developing effective vaccines against these important infections will
be. However, many novel approaches to the development
of new vaccines are being explored [35 –37], for example
use of attenuated whole organisms (as described earlier),
reverse vaccinology, which identifies potential candidate
antigens through interrogation of the genome, and detailed
structural studies, which are helping to define the antigenic
determinants that might be able to induce an immune response that would be effective across strains of highly variable
organisms such as influenza and HIV viruses. Additional
approaches that are being explored are production of novel
particles, and the use of RNA instead of DNA to induce
an immune response. Nevertheless, it seems likely that for
complex infectious agents, such as malaria, a combination of
different antigens and/or vaccine formulations will be needed
to provide a high level of protection, for example combination
of a component that induces a strong antibody response with
one that induces a strong CD4 or CD8T cell response. New
adjuvants directed at improving the immune response are
being tried and the success of the RTS,S vaccine [31,32] is
due in large part to the use of the powerful adjuvant AS01.
Better methods of preserving vaccines at ambient temperature
are being developed [38] and alternative delivery systems
including needle-less devices are being explored [39], both of
which could facilitate uptake of vaccines in hard to reach areas.
(b) Financing the development of new vaccines
Table 3 indicates some of the organisms that are currently the
target of vaccine research; recent and continuing technical
advances should make it technically possible to develop
effective vaccines against most of these pathogens. However,
whether all these vaccines will prove cost effective or be used
widely enough to provide a sufficient financial return to the
manufacturer is uncertain, as illustrated by the recent case of
a serogroup B meningococcal vaccine developed using an innovative technical approach but whose deployment in the UK is
being queried on the grounds of cost effectiveness [40].
It has, until recently, been the usual practice to have a
standard national vaccination policy implemented countrywide. However, as vaccination programmes include an
increasing number of vaccines and more complex schedules,
targeted vaccination programmes based on a sound local
knowledge may become an important way of improving efficiency and reducing costs. For example, in Nigeria, with its
large population, the new serogroup A meningococcal conjugate is being deployed only in the states that are known to be
at risk of epidemics.
Developing a new vaccine to the high standards required
is expensive and new vaccines are bound to be costly until
these recovery costs have been paid off. However, once
Phil. Trans. R. Soc. B 369: 20130433
birth cohort with access to vaccine (%)
7
100
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Table 3. Some of the infectious diseases currently the target of research to develop new or improved vaccines. HIV, human immunodeficiency virus;
RSV, respiratory syncytial virus; NTS, non-typhoidal salmonella bacteria.
protozoa
bacteria
viruses
hookworm
schistosomiasis
Cryptosporidium
lesihmaniasis
enteric bacteria
cholera
cytomegalovirus
dengue
NTS
Shigella
HIV
influenza
typhoid
Japanese B
norovirus
RSV
meningococcus
pneumococcal
West Nile
protein
Staphylococcus
tuberculosis
research and development costs have been recouped through
the sale of the vaccine at an appropriate price in industrialized countries and sale volume has been increased through
adoption of the vaccine in developing countries with their
large populations, experience has shown that the costs of a
vaccine fall, a fall sometimes aided by vaccine manufacture
in a developing country.
5. The long-term future of vaccination
It is probable that effective vaccines will be developed against
the major infections such as HIV, TB and malaria, although it is
difficult to predict how long this will take, and that eventually
these infections will cease to be a major public health priority even if they cannot be eradicated completely. Ensuring
the maximum benefit that vaccination can provide against
infectious diseases will be achieved only if there is global,
high-level surveillance to detect the emergence of new potentially dangerous infections and also to detect the emergence
of strains resistant to the vaccines in routine use as quickly as
possible so that countermeasures can be put into place.
As the incidence of infectious diseases declines and living
standards improve across the developing world, many developing countries are entering a transition phase in which they have
a residual challenge from infectious diseases, such as HIV
and tuberculosis, while at the same time experiencing major
challenges from emerging non-infectious diseases such as diabetes, cardiovascular disease and cancer. Could vaccination
have a role to play in ameliorating this increasing global
burden of non-infectious diseases? Prevention of a substantial
proportion of liver and cervical cancers should be achievable
by ensuring universal hepatitis B and HPV vaccination, and prevention of some stomach and nasopharyngeal cancers might be
possible in communities where there is a high risk of these
cancers by vaccination against Helicobacter pylori and Epstein
Barr virus infections, respectively. Vaccination to prolong
survival from other cancers, as recently demonstrated for prostate cancer, may become practicable, but highly personalized
cancer immunotherapy is likely to be too expensive for universal
use in even middle-income countries [41].
Management of chronic conditions such as diabetes and
hypertension is difficult in communities with limited access
to healthcare and it is possible that vaccination against
these conditions could help by reducing the need for frequent
contacts with the health system, although there is much work
to be done before this approach could become a practical reality. Some progress is being made in developing vaccines
which modulate the course of diabetes and hypertension
[42]. Vaccination against addiction, including smoking, is
also feasible, although very high antibody concentrations
are required to achieve an effect [43], and there are early
results suggesting that vaccination against Alzheimer’s disease might slow the progress of this condition [44]. In the
coming decades, vaccination is likely to expand its scope
beyond prevention of the common infections of childhood
which has been its main success so far.
6. Conclusion
Vaccination has achieved much since the original work of
Jenner 200 years ago, and many new vaccines are likely to be
developed within the next decade, including some directed
at non-infectious diseases. Which of these new vaccines are
cost effective and affordable is likely to generate much
debate. New vaccines will be more expensive than the vaccines
whose developmental costs have been met, and this is likely to
pose a major challenge to developing countries where many of
these vaccines could be of most use. Currently, it is envisaged
that the enhanced costs of an expanded national programme
of immunization will be met through international aid, primarily through GAVI, but a number of developing countries,
including some in sub-Saharan Africa, are making substantial
economic progress so that they are, or shortly will be, no longer
eligible for GAVI support. Although methods are being developed to facilitate this transition, existing and new lower
middle-income countries are likely to be required to make a
greater contribution to the costs of their national vaccination
programme than is currently the case. There is no better way
in which national revenue could be spent.
Phil. Trans. R. Soc. B 369: 20130433
group A Streptococcus
group B Streptococcus
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helminths
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