Article

The promise of conjugate vaccines for Africa

Initiative for Vaccine Research, World Health Organization, Av Appia 20, 1211 Geneva 27, Switzerland.
Vaccine (Impact Factor: 3.62). 10/2007; 25 Suppl 1:A108-10. DOI: 10.1016/j.vaccine.2007.05.001
Source: PubMed
ABSTRACT
Capsular polysaccharide (PS) vaccines against Neisseria meningitidis and Streptococcus pneumoniae have proven safe and effective. Moreover, experience with N. meningitidis, Haemophilus influenzae type b (Hib) and S. pneumoniae conjugate vaccines has demonstrated that immunogenicity of PS vaccines can be greatly improved by chemical conjugation to a protein carrier. These vaccines have been shown to stimulate B cell- and T cell-dependent immune responses, to induce immunological memory and to confer herd immunity. Their introduction has had a dramatic impact on the incidence of the diseases caused by these bacterial pathogens, but questions remain on the optimal schedules for immunization. The current schedule recommended by the World Health Organization (6, 10 and 14 weeks) was developed in the early 1980s and does not take into consideration the crucial role of herd immunity in interrupting transmission. A review of the evidence in order to analyse how to optimize immunization schedules for conjugate vaccines is warranted.

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The promise of conjugate vaccines for Africa
Marie Paule Kieny
a,
, F. Marc LaForce
b
a
Initiative for Vaccine Research, World Health Organization, Av Appia 20, 1211 Geneva 27, Switzerland
b
Meningitis Vaccine Project (MVP), PATH, 01210 Ferney-Voltaire, France
Abstract
Capsular polysaccharide (PS) vaccines against Neisseria meningitidis and Streptococcus pneumoniae have proven safe and effective.
Moreover, experience with N. meningitidis, Haemophilus influenzae type b (Hib) and S. pneumoniae conjugate vaccines has demonstrated
that immunogenicity of PS vaccines can be greatly improved by chemical conjugation to a protein carrier. These vaccines have been shown to
stimulate B cell- and T cell-dependent immune responses, to induce immunological memory and to confer herd immunity. Their introduction
has had a dramatic impact on the incidence of the diseases caused by these bacterial pathogens, but questions remain on the optimal schedules
for immunization. The current schedule recommended by the World Health Organization (6, 10 and 14 weeks) was developed in the early
1980s and does not take into consideration the crucial role of herd immunity in interrupting transmission. A review of the evidence in order
to analyse how to optimize immunization schedules for conjugate vaccines is warranted.
© 2007 Elsevier Ltd. All rights reserved.
Keywords: Meningitis; Pneumonia; Vaccine strategy; Streptococcus pneumoniae; Haemophilus influenzae b; Neisseria meningitidis
1. Introduction
The first successful capsular polysaccharide (PS) vac-
cines against Neisseria meningitidis groups A and C were
developed 30 years ago. They proved safe and effective in
preventing group C disease in military recruits and in con-
trolling group A epidemics during mass campaigns in Africa.
Multivalent PS vaccines against groups A and C (bivalent),
A, C and W-135 (trivalent), or A, C, Y and W-135 (tetrava-
lent), are licensed and available worldwide, but only the bi-
and trivalent versions are affordable for developing countries.
During the epidemic season in the African meningitis belt,
PS vaccine from an international stockpile is made available
to countries through the International Coordinating Group on
Vaccine Provision for Epidemic Meningitis (ICG) set up in
1997 by the World Health Organization (WHO). However,
PS vaccines are poorly immunogenic in young infants and
children less than 2 years old, fail to induce immunological
Corresponding author. Tel.: +41 22 791 35 91; fax: +41 22 791 48 60.
E-mail address: kienym@who.int (M.P. Kieny).
memory and do not provide protection for more than 3–5
years.
Experience with Haemophilus influenzae type b (Hib)
conjugate vaccines has shown that the immunogenicity of PS
can be greatly improved by chemical conjugation to a protein
carrier. The resulting PS–protein conjugate vaccines are safe,
immunogenic in young infants and induce long-term immune
memory. Immunization also decreases nasopharyngeal car-
riage and transmission of the pathogen, resulting in what is
called herd immunity. Hib vaccine, initially licensed in 1987,
is now recommended for worldwide use, but the duration of
protective immunity afforded still needs to be fully studied.
2. Meningococcal conjugate vaccines
Meningococcal group C conjugate vaccines were intro-
duced into the UK through catch-up campaigns and are now
used in a routine three-dose infant immunization schedule
at 2, 3 and 4 months of age [1]. These new meningococ-
cal conjugate vaccines have been shown to stimulate both B
cell- and T cell-dependent immune responses and to induce
immunological memory. They also reduce nasopharyngeal
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carriage of N. meningitidis and confer herd immunity. The
vaccine had a dramatic impact on the incidence of the dis-
ease, resulting in a more than 90% decrease in the number of
cases and deaths [2]. Interestingly, the vaccine also decreased
by 70% the number of cases in unvaccinated individuals
through herd immunity. The duration of protective immu-
nity against invasive meningococcal C disease in children
who were immunized through mass-vaccination in early
childhood with a single dose vaccine immunization was eval-
uated 2 years after vaccination. Results showed that only
63% children still had serum bactericidal titres above pro-
tective level [3], suggesting that immunity with serogroup C
meningococcal glycoconjugate vaccines in infancy and early
childhood may be of relatively short duration, and that booster
vaccination might be warranted for the elimination of the
disease.
A different vaccination strategy was adopted in the Nether-
lands, where Men C conjugate vaccine was introduced
through a catch-up campaign in 1–18 year olds, coupled with
a single dose of conjugate vaccine at 14 months [4]. Like
in the UK and Spain [5], reduction of meningococcal C dis-
ease in the population was rapid and dramatic. Interestingly,
vaccine failures were not reported, contrary to the UK expe-
rience, which suggests that one dose of vaccine in the second
year of life might offer longer protection than three doses in
infancy.
These encouraging data clearly suggest that conjugate
meningococcal vaccines could have a major public health
impact in Africa where endemic rates of bacterial meningitis
are 50–100 times higher than that seen in Europe or the United
States. Furthermore, while epidemics of Group A N. menin-
gitidis are a thing of the past in indutrialized countries, such
epidemics are a constant threat in countries of the African
meningitis belt. A low-cost meningococcal group A conju-
gate vaccine is an essential product to eliminate epidemic
meningococcal disease in these countries. The lack of interest
among major industrialized country vaccine manufacturers to
develop such product led to the development of the Menin-
gitis Vaccine Project (MVP), a partnership between WHO
and the Programme for Appropriate Technology in Health
(PATH), with a mission to develop affordable meningococ-
cal conjugate vaccines for Africa [6]. Clinical development
of the Men A conjugate vaccine, which is manufactured by
the Serum Institute of India, started in 2005 in India [see
Chapter 19, this volume]. MVP is anticipating that the vac-
cine could be licensed for use in Africa as early as 2008. The
vaccine will be used as a single dose in mass vaccination
campaigns in 1–29 year olds and, depending on the results
of carriage studies, introduced in a one (12–18 months)
or 2-doses (14 weeks and 9 months) routine immunization
regimen.
Among other conjugate meningococcal vaccines are a
recently licensed tetravalent vaccine incorporating PS from
groups A, C, Y and W-135 and a heptavalent combination
(DTP-HepB-Hib-Conjugate Men A and C) that may become
available shortly.
3. Pneumococcal conjugate vaccines
Pneumococcal vaccines are similar to meningococcal vac-
cines in that polyvalent PS vaccines induce relatively good
antibody responses in most healthy adults following a sin-
gle intramuscular or subcutaneous immunization, but the
immune response is mediocre in children aged less than 2
years. Furthermore, pneumococcal PS vaccines do not induce
immunological memory. Over the past years, several vac-
cine manufacturers have developed pneumococcal conjugate
vaccines – one of which is licensed that elicit higher anti-
body levels and a more efficient immune response in infants,
young children and immunodeficient persons than the PS
vaccines,as well as providing immunological memory. More-
over, these vaccines induce herd immunity, i.e. they suppress
nasopharyngeal carriage of the pathogen and reduce bac-
terial transmission in the community. Introduction of the
conjugate vaccine in early 2000 in the USA resulted in dra-
matic decline in the rates of invasive pneumococcal disease,
with significant reductions also been seen in unvaccinated
individuals as a result of herd immunity [7]. The results
of the clinical trial of an experimental nine-valent pneu-
mococcal conjugate vaccine in The Gambia showed 77%
efficacy against vaccine-type invasive disease, 37% efficacy
against radiological pneumonia, as well as 16% reduction
in overall mortality in the vaccinated group [8], data that
clearly indicate the importance of such a vaccine for reduc-
ing child mortality in developing countries. However, unlike
the serogroup A meningococcal vaccine developed by MVP,
which is expected to be sold at less than 40 US cents/dose,
the only licensed conjugate pneumococcal vaccine is avail-
able at a price far beyond the financial capacity of developing
country programmes.
Optimization of immunization schedules to allow protec-
tion with fewer doses would be a great advantage. WHO is
supporting studies that will evaluate a two dose schedule of
pneumococcal conjugate vaccine, where the first dose is given
between 0 and 6 months and the second dose between 6 and
18 months. Going from three to two doses of pneumococcal
conjugate vaccine, while helpful, will still result in strategies
that are well beyond the financial realities of most African
Ministries of Health. There remains a major need for much
less expensive pneumococcal conjugate vaccines.
4. Conclusion
As described above, there is great interest in the expanded
use of conjugate vaccines to prevent meningitis. These
vaccines offer the potential for effective disease control
[9], but questions remain on the optimal schedules for
immunization, the duration of protection and the long-term
impact of vaccination on carriage. The current immuniza-
tion schedule for primary immunization recommended by
WHO was developed in the early 1980s [10], and more
than 20 years have passed since the “Expanded Programme
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on Immunization (EPI)” schedule of 6, 10 and 14 weeks
for diphtheria–tetanus–pertussis–polio (DTP-OPV) and 9
months for measles vaccines was introduced. We now have a
better understanding of immune responses and have identified
other interventions targeting preschool-aged children (e.g.
antihelminths, antimalarials, micronutrient administration)
that can provide opportunities to administer booster doses of
EPI vaccines. In addition, three additional vaccines have been
recommended for inclusion in routine immunization pro-
grammes (hepatitis B, Hib and yellow fever in endemic areas)
and several others are now licensed (rotavirus, pneumococ-
cal and meningococcal conjugate vaccines) or near licensure.
Among those, three (Hib, meningococcal and pneumococcal
vaccines) are conjugate vaccines. The crucial role of herd
immunity in interrupting transmission has been increasingly
recognized and it is important that vaccine schedules are har-
monized to allow for maximal impact from the vaccines that
will be used. A review of the evidence that underpins the
selection of optimal immunization schedules, in particular
for conjugate vaccines, is therefore timely as it is becoming
increasingly clear that the canonical 6, 10 and 14 week EPI
schedule may not be optimal for a number of antigens. The
World Health Organization is committed to re-examine this
issue, including the need for booster doses beyond infancy, in
collaboration with the global immunization community [11].
References
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  • Source
    • "A meningococcal A polysaccharide conjugated to tetanus toxoid, MenAfriVac ® vaccine (PsA-TT) was developed by the Serum Institute of India Ltd. (SIIL) and is currently undergoing country-phased introduction across the meningitis belt, already showing a major impact on case reduction and carriage of group A meningococci [10,21222324. Conjugate vaccines are known to be immunogenic in young chil- dren [6,16], induce immunological memory [6,16,25], prevent the acquisition of nasopharyngeal carriage [26] , and promote herd protection in the population [26]. The PsA-TT vaccine is immunogenic in children < 2 years of age [27]. "
    [Show abstract] [Hide abstract] ABSTRACT: Major epidemics of serogroup A meningococcal meningitis continue to affect the African meningitis belt. The development of an affordable conjugate vaccine against the disease became a priority for World Health Organization (WHO) in the late 1990s. Licensing of meningococcal vaccines has been based on serological correlates of protection alone, but such correlates might differ in different geographical regions. If high pre-vaccination antibody concentrations/titers impacts on the response to vaccination and possibly vaccine efficacy, is not clearly understood. We set out to define the pre-vaccination Meningococcal group A (Men A) antibody concentrations/titers in The Gambia and study their impact on the immunogenicity of Men A containing vaccines.
    Full-text · Article · May 2014 · Vaccine
  • Source
    • "This study defines districts where targeted surveillance and early action can have an important impact for reactive immunization campaigns. The new conjugate meningitis vaccine provides longer-term immunity , which may shift the focus of vaccination from reactive control to preventative coverage [41]. Identifying districts with high rates of meningococcal meningitis persistence and frequent reappearance will continue to be useful with the new management strategy monitoring circulating serogroups of N. meningitidis. "
    [Show abstract] [Hide abstract] ABSTRACT: Throughout the African meningitis belt, meningococcal meningitis outbreaks occur only during the dry season. Measles in Niger exhibits similar seasonality, where increased population density during the dry season probably escalates measles transmission. Because meningococcal meningitis and measles are both directly transmitted, we propose that host aggregation also impacts the transmission of meningococcal meningitis. Although climate affects broad meningococcal meningitis seasonality, we focus on the less examined role of human density at a finer spatial scale. By analysing spatial patterns of suspected cases of meningococcal meningitis, we show fewer absences of suspected cases in districts along primary roads, similar to measles fadeouts in the same Nigerien metapopulation. We further show that, following periods during no suspected cases, districts with high reappearance rates of meningococcal meningitis also have high measles reintroduction rates. Despite many biological and epidemiological differences, similar seasonal and spatial patterns emerge from the dynamics of both diseases. This analysis enhances our understanding of spatial patterns and disease transmission and suggests hotspots for infection and potential target areas for meningococcal meningitis surveillance and intervention.
    Full-text · Article · Oct 2011 · Epidemiology and Infection
  • Source
    • "Reactive mass vaccination of epidemic districts can prevent up to 70% of cases, if the vaccine administration happens on time [35]. If MenA conjugate vaccine can reproduce the effect of the MenC conjugate vaccine, which prompted a 90% decrease in cases and 70% reduction in rates of carriage in UK [6], then an even greater reduction in the number of cases can be expected in Africa. However, this will be determined by the ability to efficiently deliver the vaccine and obtain maximum coverage. "
    [Show abstract] [Hide abstract] ABSTRACT: Meningococcal meningitis is a major cause of disease worldwide, with frequent epidemics particularly affecting an area of sub-Saharan Africa known as the "meningitis belt". Neisseria meningitidis group A (MenA) is responsible for major epidemics in Africa. Recently W-135 has emerged as an important pathogen. Currently, the strategy for control of such outbreaks is emergency use of meningococcal (MC) polysaccharide vaccines, but these have a limited ability to induce herd immunity and elicit an adequate immune response in infant and young children. In recent times initiatives have been taken to introduce meningococcal conjugate vaccine in these African countries. Currently there are two different types of MC conjugate vaccines at late stages of development covering serogroup A and W-135: a multivalent MC conjugate vaccine against serogroup A,C,Y and W-135; and a monovalent conjugate vaccine against serogroup A. We aimed to perform a structured assessment of these emerging meningococcal vaccines as a means of reducing global meningococcal disease burden among children under 5 years of age. We used a modified CHNRI methodology for setting priorities in health research investments. This was done in two stages. In the first stage we systematically reviewed the literature related to emerging MC vaccines relevant to 12 criteria of interest. In Stage II, we conducted an expert opinion exercise by inviting 20 experts (leading basic scientists, international public health researchers, international policy makers and representatives of pharmaceutical companies). They answered questions from CHNRI framework and their "collective optimism" towards each criterion was documented on a scale from 0 to 100%. For MenA conjugate vaccine the experts showed very high level of optimism (~ 90% or more) for 7 out of the 12 criteria. The experts felt that the likelihood of efficacy on meningitis was very high (~ 90%). Deliverability, acceptability to health workers, end users and the effect on equity were all seen as highly likely (~ 90%). In terms of the maximum potential impact on meningitis disease burden, the median potential effectiveness of the vaccines in reduction of overall meningitis mortality was estimated to be 20%; (interquartile range 20-40% and min. 8%, max 50 %). For the multivalent meningococcal vaccines the experts had similar optimism for most of the 12 CHNRI criteria with slightly lower optimism in answerability and low development cost criteria. The main concern was expressed over the cost of product, its affordability and cost of implementation. With increasing recognition of the burden of meningococcal meningitis, especially during epidemics in Africa, it is vitally important that strategies are taken to reduce the morbidity and mortality attributable to this disease. Improved MC vaccines are a promising investment that could substantially contribute to reduction of child meningitis mortality world-wide.
    Full-text · Article · Apr 2011 · BMC Public Health
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