A

Mtshf1t©

K

1

cdptMAlaDPtV1Pc

0d

Vaccine 25S (2007) A108–A110

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, Switzerlandb Meningitis Vaccine Project (MVP), PATH, 01210 Ferney-Voltaire, France

Available online 21 May 2007

bstract

Capsular polysaccharide (PS) vaccines against Neisseria meningitidis and Streptococcus pneumoniae have proven safe and effective.oreover, experience with N. meningitidis, Haemophilus influenzae type b (Hib) and S. pneumoniae conjugate vaccines has demonstrated

hat immunogenicity of PS vaccines can be greatly improved by chemical conjugation to a protein carrier. These vaccines have been shown totimulate B cell- and T cell-dependent immune responses, to induce immunological memory and to confer herd immunity. Their introductionas had a dramatic impact on the incidence of the diseases caused by these bacterial pathogens, but questions remain on the optimal schedules

or immunization. The current schedule recommended by the World Health Organization (6, 10 and 14 weeks) was developed in the early980s and does not take into consideration the crucial role of herd immunity in interrupting transmission. A review of the evidence in ordero analyse how to optimize immunization schedules for conjugate vaccines is warranted.

2007 World Health Organization. Published by Elsevier Ltd. All rights reserved.

oniae; H

my

cccimrcip

eywords: Meningitis; Pneumonia; Vaccine strategy; Streptococcus pneum

. Introduction

The first successful capsular polysaccharide (PS) vac-ines against Neisseria meningitidis groups A and C wereeveloped 30 years ago. They proved safe and effective inreventing group C disease in military recruits and in con-rolling group A epidemics during mass campaigns in Africa.

ultivalent PS vaccines against groups A and C (bivalent),, C and W-135 (trivalent), or A, C, Y and W-135 (tetrava-

ent), are licensed and available worldwide, but only the bi-nd trivalent versions are affordable for developing countries.uring the epidemic season in the African meningitis belt,S vaccine from an international stockpile is made available

o countries through the International Coordinating Group on

accine Provision for Epidemic Meningitis (ICG) set up in997 by the World Health Organization (WHO). However,S vaccines are poorly immunogenic in young infants andhildren 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).

2

duacci

264-410X/$ – see front matter © 2007 World Health Organization. Published by Eoi:10.1016/j.vaccine.2007.05.001

aemophilus influenzae b; Neisseria meningitidis

emory and do not provide protection for more than 3–5ears.

Experience with Haemophilus influenzae type b (Hib)onjugate vaccines has shown that the immunogenicity of PSan be greatly improved by chemical conjugation to a proteinarrier. The resulting PS–protein conjugate vaccines are safe,mmunogenic in young infants and induce long-term immune

emory. Immunization also decreases nasopharyngeal car-iage and transmission of the pathogen, resulting in what isalled herd immunity. Hib vaccine, initially licensed in 1987,s now recommended for worldwide use, but the duration ofrotective immunity afforded still needs to be fully studied.

. Meningococcal conjugate vaccines

Meningococcal group C conjugate vaccines were intro-uced into the UK through catch-up campaigns and are nowsed in a routine three-dose infant immunization schedule

t 2, 3 and 4 months of age [1]. These new meningococ-al conjugate vaccines have been shown to stimulate both Bell- and T cell-dependent immune responses and to inducemmunological memory. They also reduce nasopharyngeal

lsevier Ltd. All rights reserved.

/ Vaccin

cvecbtnwcu6tmcvd

ltaievryi

miaSgemgmadga(cotCcvcoor

rg(a

3

cagiyicvbyvontcmwiomeaicitwtac

tspb1ctMl

4

uv[i

M.P. Kieny, F.M. LaForce

arriage of N. meningitidis and confer herd immunity. Theaccine had a dramatic impact on the incidence of the dis-ase, resulting in a more than 90% decrease in the number ofases and deaths [2]. Interestingly, the vaccine also decreasedy 70% the number of cases in unvaccinated individualshrough herd immunity. The duration of protective immu-ity against invasive meningococcal C disease in childrenho were immunized through mass-vaccination in early

hildhood with a single dose vaccine immunization was eval-ated 2 years after vaccination. Results showed that only3% children still had serum bactericidal titres above pro-ective level [3], suggesting that immunity with serogroup Ceningococcal glycoconjugate vaccines in infancy and early

hildhood may be of relatively short duration, and that boosteraccination might be warranted for the elimination of theisease.

A different vaccination strategy was adopted in the Nether-ands, where Men C conjugate vaccine was introducedhrough a catch-up campaign in 1–18 year olds, coupled with

single dose of conjugate vaccine at 14 months [4]. Liken the UK and Spain [5], reduction of meningococcal C dis-ase in the population was rapid and dramatic. Interestingly,accine failures were not reported, contrary to the UK expe-ience, which suggests that one dose of vaccine in the secondear of life might offer longer protection than three doses innfancy.

These encouraging data clearly suggest that conjugateeningococcal vaccines could have a major public health

mpact in Africa where endemic rates of bacterial meningitisre 50–100 times higher than that seen in Europe or the Unitedtates. Furthermore, while epidemics of Group A N. menin-itidis are a thing of the past in indutrialized countries, suchpidemics are a constant threat in countries of the Africaneningitis belt. A low-cost meningococcal group A conju-

ate vaccine is an essential product to eliminate epidemiceningococcal disease in these countries. The lack of interest

mong major industrialized country vaccine manufacturers toevelop such product led to the development of the Menin-itis Vaccine Project (MVP), a partnership between WHOnd the Programme for Appropriate Technology in HealthPATH), with a mission to develop affordable meningococ-al conjugate vaccines for Africa [6]. Clinical developmentf the Men A conjugate vaccine, which is manufactured byhe Serum Institute of India, started in 2005 in India [seehapter 19, this volume]. MVP is anticipating that the vac-ine could be licensed for use in Africa as early as 2008. Theaccine will be used as a single dose in mass vaccinationampaigns in 1–29 year olds and, depending on the resultsf carriage studies, introduced in a one (12–18 months)r 2-doses (14 weeks and 9 months) routine immunizationegimen.

Among other conjugate meningococcal vaccines are a

ecently licensed tetravalent vaccine incorporating PS fromroups A, C, Y and W-135 and a heptavalent combinationDTP-HepB-Hib-Conjugate Men A and C) that may becomevailable shortly.

itWt

e 25S (2007) A108–A110 A109

. Pneumococcal conjugate vaccines

Pneumococcal vaccines are similar to meningococcal vac-ines in that polyvalent PS vaccines induce relatively goodntibody responses in most healthy adults following a sin-le intramuscular or subcutaneous immunization, but themmune response is mediocre in children aged less than 2ears. Furthermore, pneumococcal PS vaccines do not inducemmunological memory. Over the past years, several vac-ine manufacturers have developed pneumococcal conjugateaccines – one of which is licensed – that elicit higher anti-ody levels and a more efficient immune response in infants,oung children and immunodeficient persons than the PSaccines, as well as providing immunological memory. More-ver, these vaccines induce herd immunity, i.e. they suppressasopharyngeal carriage of the pathogen and reduce bac-erial transmission in the community. Introduction of theonjugate vaccine in early 2000 in the USA resulted in dra-atic decline in the rates of invasive pneumococcal disease,ith significant reductions also been seen in unvaccinated

ndividuals as a result of herd immunity [7]. The resultsf the clinical trial of an experimental nine-valent pneu-ococcal conjugate vaccine in The Gambia showed 77%

fficacy against vaccine-type invasive disease, 37% efficacygainst radiological pneumonia, as well as 16% reductionn overall mortality in the vaccinated group [8], data thatlearly indicate the importance of such a vaccine for reduc-ng child mortality in developing countries. However, unlikehe serogroup A meningococcal vaccine developed by MVP,hich is expected to be sold at less than 40 US cents/dose,

he only licensed conjugate pneumococcal vaccine is avail-ble at a price far beyond the financial capacity of developingountry programmes.

Optimization of immunization schedules to allow protec-ion with fewer doses would be a great advantage. WHO isupporting studies that will evaluate a two dose schedule ofneumococcal conjugate vaccine, where the first dose is givenetween 0 and 6 months and the second dose between 6 and8 months. Going from three to two doses of pneumococcalonjugate vaccine, while helpful, will still result in strategieshat are well beyond the financial realities of most African

inistries of Health. There remains a major need for muchess expensive pneumococcal conjugate vaccines.

. Conclusion

As described above, there is great interest in the expandedse of conjugate vaccines to prevent meningitis. Theseaccines offer the potential for effective disease control9], but questions remain on the optimal schedules formmunization, the duration of protection and the long-term

mpact of vaccination on carriage. The current immuniza-ion schedule for primary immunization recommended by

HO was developed in the early 1980s [10], and morehan 20 years have passed since the “Expanded Programme

A / Vaccin

ofmboatErgacAvirmwsfisWic

R[10] Henderson RH. The Expanded Programme on Immunization of

110 M.P. Kieny, F.M. LaForce

n Immunization (EPI)” schedule of 6, 10 and 14 weeksor diphtheria–tetanus–pertussis–polio (DTP-OPV) and 9onths for measles vaccines was introduced. We now have a

etter understanding of immune responses and have identifiedther interventions targeting preschool-aged children (e.g.ntihelminths, antimalarials, micronutrient administration)hat can provide opportunities to administer booster doses ofPI vaccines. In addition, three additional vaccines have been

ecommended for inclusion in routine immunization pro-rammes (hepatitis B, Hib and yellow fever in endemic areas)nd several others are now licensed (rotavirus, pneumococ-al and meningococcal conjugate vaccines) or near licensure.mong those, three (Hib, meningococcal and pneumococcalaccines) are conjugate vaccines. The crucial role of herdmmunity in interrupting transmission has been increasinglyecognized and it is important that vaccine schedules are har-onized to allow for maximal impact from the vaccines thatill be used. A review of the evidence that underpins the

election of optimal immunization schedules, in particularor conjugate vaccines, is therefore timely as it is becomingncreasingly clear that the canonical 6, 10 and 14 week EPIchedule may not be optimal for a number of antigens. Theorld Health Organization is committed to re-examine this

ssue, including the need for booster doses beyond infancy, inollaboration with the global immunization community [11].

eferences

[1] Pichichero ME. Meningococcal conjugate vaccines. Exp Opin BiolTher 2005;5:1475–89.

[

e 25S (2007) A108–A110

[2] Ramsay ME, Andrews NJ, Trotter CL, Kaczmarski EB, Miller E. Herdimmunity from meningococcal serogroup C conjugate vaccination inEngland: database analysis. BMJ 2003;326:365–6.

[3] Snape MD, Kelly DF, Green B, Moxon ER, Borrow R, Pol-lard AJ. Lack of serum bactericidal activity in preschool childrentwo years after a single dose of serogroup C meningococcalpolysaccharide–protein conjugate vaccine. Ped Inf Dis J 2005;24:128–31.

[4] de Greeff SC, de Melker HE, Spanjaard L, Schouls LM, van DerendeA. Protection from routine vaccination at the age of 14 months withmeningococcal serogroup C conjugate vaccine in the Netherlands. Pedi-atr Infect Dis J 2006;25:79–80.

[5] Larrauri A, Cano R, Garcia M, Mateo S. Impact and effectiveness ofmeningococcal C conjugate vaccine following its introduction in Spain.Vaccine 2005;23:4097–100.

[6] Jodar L, LaForce FM, Ceccarini C, Aguado T, Granoff DM.Meningococcal conjugate vaccine for Africa: a model for develop-ment of new vaccines for the poorest countries. Lancet 2003;361:1902–4.

[7] Whitney CG, Farley MM, Hadler J, Harrison LH, Bennett NM, LynfieldR, et al. Decline in invasive pneumococcal disease after the intro-duction of protein-polysaccharide conjugate vaccine. N Engl J Med2003;348:1737–46.

[8] Cutts FT, Zaman SM, Enwere G, Jaffar S, Levine OS, Okoko JB, etal. Efficacy of nine-valent pneumococcal conjugate vaccine againstpneumonia and invasive pneumococcal disease in The Gambia: ran-domised, double-blind, placebo-controlled trial. Lancet 2005;365:1139–46.

[9] Trotter CL, Gay NJ, Edmunds W. Dynamic models of meningococcalcarriage, disease, and the impact of serogroup C conjugate vaccination.Am J Epidemiol 2005;162:89–100.

the World Health Organization. Rev Infect Dis 1984;6(Suppl 2):S475–9.

11] Anonymous. Conclusions and recommendations from the Immuniza-tion Strategic Advisory Group. Wkly Epidemiol Rec 2006;81:2–11.