Optimising the use of conjugate vaccines to prevent disease caused by Haemophilus influenzae type b, Neisseria meningitidis and Streptococcus pneumoniae

Vaccine 26 (2008) 4434–4445

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Review

Optimising the use of conjugate vaccines to prevent disease caused byHaemophilus influenzae type b, Neisseria meningitidis and Streptococcuspneumoniae

Caroline L. Trottera,∗, Jodie McVernonb, Mary E. Ramsayc, Cynthia G. Whitneyd,E. Kim Mulhollande, David Goldblatt f, Joachim Hombachg, Marie-Paule Kienyg,

on behalf of the SAGE subgroup1

a Department of Social Medicine, University of Bristol, Canynge Hall, Whiteladies Road, Bristol, BS8 2PR, UKb Vaccine and Immunisation Research Group, Murdoch Children’s Research Institute & School of Population Health, University of Melbourne, Victoria, Australiac Immunisation Department, Health Protection Agency Centre for Infections, London, UKd Division of Bacterial and Mycotic Diseases, National Center for Infectious Diseases, Centers for Disease Control and Prevention, Atlanta, GA, USAe Infectious Disease Epidemiology Unit, London School of Hygiene & Tropical Medicine, London, UKf Immunobiology Unit, Institute of Child Health, University College London, London, UKg Initiative for Vaccine Research, World Health Organisation, Geneva, Switzerland

a r t i c l e i n f o

Article history:Received 9 November 2007Received in revised form 8 May 2008Accepted 25 May 2008Available online 17 June 2008

Keywords:

a b s t r a c t

Conjugate vaccines exist that offer protection against disease caused by Haemophilus influenzae type b(Hib), and selected serogroups/serotypes of Neisseria meningitidis and Streptococcus pneumoniae. Thesevaccines are not only able to prevent serious disease, but they also provide protection against asymp-tomatic carriage. The resulting herd immunity effects have been striking, and have played an importantrole in the public health success of conjugate vaccination programmes. The aim of this paper is to reviewthe state of the current evidence on conjugate vaccines and to identify important areas for further study,in order to inform the debate regarding the best use of these vaccines.

Haemophilus vaccinesMeningococcal vaccinesPneumococcal vaccines

Contents

1. Introduction. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .1.1. Epidemiology . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .1.2. Conjugate vaccines . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

2. Use of conjugate vaccines to date . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .2.1. Efficacy trials . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .2.2. Introduction of conjugate vaccines into national immunisation pr2.3. Vaccine effectiveness . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

2.3.1. Hib vaccines . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .2.3.2. Meningococcal vaccines . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .2.3.3. Pneumococcal vaccine . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

3. Factors influencing vaccine impact . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .3.1. Protection against carriage and herd immunity . . . . . . . . . . . . . . . . . . . .3.2. Catch-up campaigns . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .3.3. Comparison of vaccine schedules . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .3.4. Duration of protection . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

∗ Corresponding author. Tel.: +44 117 928 7220; fax: +44 117 928 7292.E-mail address: [email protected] (C.L. Trotter).

1 See Acknowledgements for SAGE subgroup members.

0264-410X/$ – see front matter © 2008 Elsevier Ltd. All rights reserved.doi:10.1016/j.vaccine.2008.05.073

© 2008 Elsevier Ltd. All rights reserved.

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3.5. Serotype/serogroup replacement . . . . . . . . . . . . . . . . . . . . . . . . . . . . .3.6. Differences between high-income and developing countries3.7. Interactions between vaccines given in combination/concom

4. Further research . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .4.1. Implications for future vaccine schedules . . . . . . . . . . . . . . . . . . . .

4.1.1. “2 + 1” routine immunisation schedule . . . . . . . . . . . . . .4.1.2. Campaigns with or without routine immunisation .

5. Conclusions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .Acknowledgements . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

1. Introduction

Haemophilus influenzae type b (Hib), Streptococcus pneumoniaeand Neisseria meningitidis are important causes of morbidity andmortality worldwide. Safe and effective conjugate vaccines havebeen developed to provide protection against infections causedby these organisms and offer excellent prospects for disease con-trol. Although the epidemiology of meningococcal, pneumococcaland Hib disease is very different, the bacteria and the conjugatevaccines designed to prevent them share some important prop-erties. In particular, the ability of conjugate vaccines to reduceasymptomatic pharyngeal carriage of vaccine-type strains is impor-tant because, for all three pathogens, disease is a rare outcome ofinfection and carriers are responsible for most transmission. Byreducing carriage, the vaccines can generate indirect protection(“herd immunity”), so that the risk of infection is lower in both vac-cinated and unvaccinated individuals. The population impact of thevaccine is thus much greater than the sum of the direct protectionafforded to immunised individuals. Maximising direct protectionis the traditional aim of vaccination programmes, and these herdimmunity effects have been seen as an additional, secondary bene-fit. However, a more holistic objective, which considers populationimpact (a combination of direct and indirect protection), may yieldgreater public health benefits. A further consideration must also beadded, in that positive population effects arising from herd immu-nity may be counterbalanced by negative population effects, suchas serotype replacement or reduced natural boosting.

In countries where conjugate vaccination programmes havebeen introduced the schedules and strategies have varied, althoughin general, routine infant immunisation has followed the sameschedule as diphtheria, tetanus and pertussis (DTP). Here, we
review the evidence on the immunogenicity, effectiveness and pub-lic health impact of different conjugate vaccine schedules. On thebasis of the knowledge and experience accumulated to date, wereflect whether alternative schedules and vaccine strategies areworthy of further consideration, particularly for use in develop-ing countries, where efforts to expand access to these vaccines areongoing through the Hib Initiative, PneumoADIP and the Menin-gitis Vaccine Project (MVP). Appropriate schedules must aim tomaximise public health impact while minimising costs, and alsobe programmatically feasible.
1.1. Epidemiology

Hib can cause a range of clinical manifestations, includingmeningitis, pneumonia, epiglottitis, cellulitis, bone and joint infec-tions. The World Health Organisation (WHO) estimates that Hibcauses around 3 million cases of serious illness and 386,000 deathseach year in children under 5 years of age [1]. Disease incidenceis highest in children aged 4–18 months and comparatively rare inolder children and adults. A substantial proportion of survivors ofHib meningitis (30–40%) may suffer from neurological sequelae [1].

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In unvaccinated populations asymptomatic carriage of Hib is notinfrequent in children under 5 years with several studies report-ing carriage prevalence around 5% (e.g. Uganda [2], Lombok Island,Indonesia [3], Brazil [4]), although higher population prevalences(up to 33%) have also been reported, e.g. in The Gambia [5,6]. Car-riage also varies by age [7]. Although data are sparse [7], carriagein older individuals may be important in maintaining transmissionin vaccinated populations [8].

The epidemiology of meningococcal disease varies throughoutthe world. In Africa, the ‘meningitis belt’ [9,10] stretches from Sene-gal to Ethiopia and is characterised by large epidemics which occurperiodically in the dry season [11]. During the last major epidemic in1996, around 200,000 cases and 20,000 deaths were reported andattack rates as high as 1 in 100 have been recorded [12]. Most epi-demics have been caused by serogroup A meningococci althoughserogroup C [11] and more recently serogroup W135 and serogroupX [13] outbreaks have been described. In the rest of the world,meningococcal disease is endemic, with incidence ranging typicallyfrom below 1 up to 10 per 100,000 population [14]. In industrialisedcountries serogroups B and C are responsible for most disease, withserogroup Y making an important contribution in some countries[12,15]. In Europe approximately 10% of the population are thoughtto be meningococcal carriers [16] and prevalence varies with age,peaking in teenagers and young adults [17,18]. In the African menin-gitis belt, the results of carriage studies have been highly variable,with overall carriage prevalence between 3% and 30% reported [19].

S. pneumoniae is a major cause of both mild and severe infec-tions worldwide. The primary clinical syndromes associated withpneumococcal infections are pneumonia, meningitis, bloodstreaminfections and acute otitis media. In 2005, WHO estimated that 1.6million people a year die from pneumococcal disease, includingup to 1 million children less than 5 years old [20], most of whomlive in developing countries. Major risk factors for pneumococ-
cal disease include young age (particularly <2 years), underlyingimmunodeficiency (such as HIV infection or AIDS), asplenia, sicklecell anaemia and certain other chronic illnesses. Disease burden isalso high in the elderly in high-income countries, although this ispoorly defined in the developing world [20]. Ninety-one distinctserotypes of S. pneumoniae have been identified based on struc-tural differences in the polysaccharide capsule, but approximately10 or 11 serotypes account for at least 70% of invasive paedi-atric infections in all regions of the world [21]. The distributionof serotypes causing disease varies by age, disease syndrome, dis-ease severity, geographic region, and over time [22]. Pneumococcithat are resistant to penicillin, erythromycin, co-trimoxazole ormultiple drugs are common in many regions [23]. Pharyngeal car-riage of S. pneumoniae is widespread, and prevalence is also highlyage specific with carriage being more common and prolongedamong children than among adults [24,25]. In developing countries,very high carriage rates, particularly in young children have beenreported [26–30], and colonisation may occur shortly after birth[31,32].

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1.2. Conjugate vaccines

Available vaccines offering protection against disease causedby Hib, N. meningitidis (with the exception of serogroup B) and S.pneumoniae are based on the polysaccharide capsule of the bac-teria. Although responses to different serotypes and serogroupsvary, in general, the early polysaccharide-only vaccines produceweak responses in infants and young children, and only offer short-term protection even in older age groups. Conjugate vaccines, inwhich the polysaccharide is attached to an immunogenic carrierprotein, are able to induce a T-cell dependent immune response,are immunogenic even in infants and have been shown to primefor immune memory (the ability of the immune system to elicita booster response on reencountering the antigen) [33]. Differentcarrier proteins have been used, including tetanus toxoid, mutateddiphtheria toxin CRM197 and outer membrane proteins of Neisse-ria meningitidis (OMP), which can lead to some variation in theproperties of the vaccines. In addition, interactions between otherantigens administered in combination or concurrently, can affectthe immunogenicity of these conjugate vaccines [34].

The first conjugate vaccines to be developed were againstHib disease. Four types of Hib conjugate vaccine have beenlicensed for use, each conjugated with a different carrier pro-tein: PRP-D (diphtheria), PRP-OMP (outer membrane protein ofNeisseria meningitidis), HbOC (CRM197) and PRP-T (tetanus). PRP-OMP induces higher antibody titres during priming than otherconjugates, evident after the second dose, but shows reducedimmunogenicity on boosting [35]. PRP-D was the least immuno-genic and least effective of these vaccines and has been withdrawnfrom the market [1].

Three monovalent serogroup C conjugate (MenC) vaccines arecurrently licensed and in use in several European countries, Canadaand Australia [36]. Both tetanus toxoid and CRM197 have been usedas conjugated proteins. A quadrivalent (serogroups A, C, W-135,Y) meningococcal vaccine is being used in the US, where it is cur-rently recommended for teenagers [37]. A combination Hib–MenCconjugate vaccine, administered at 12 months of age, was recentlyincorporated into the UK vaccine schedule in 2006 [38]. Monova-lent serogroup A conjugate (MenA) vaccines are being developedspecifically for use in the African meningitis belt by the Menin-gitis Vaccine Project [39] and other multivalent and combinationvaccines are also in trials. We should be cautious in extrapolatingthe results from MenC vaccines to other meningococcal conjugates(particularly MenA), given the differences in disease epidemiol-
ogy in countries where serogroup A disease is prevalent, and theobserved differences in responses to serogroup A versus serogroupC meningococcal polysaccharide vaccines [40].
A 7-valent pneumococcal conjugate vaccine (PCV7) is the onlyformulation that is currently licensed, although 10-valent (PCV10)and 13-valent (PCV13) vaccines are in late stage clinical develop-ment and expected to be licensed in the next few years. Additionalphase III trials have been performed using 9-valent (PCV9) and11-valent (PCV11) vaccines that are not expected to reach market.Approximately 20 other pneumococcal vaccines are in early stagesof development [20].

2. Use of conjugate vaccines to date

2.1. Efficacy trials

Phase III trials of PRP-D [41,42], HbOC [43] and PRP-T [44,45]showed 83–100% protection against invasive Hib infections inWestern children following three doses of conjugate vaccine ininfancy. Higher estimates of efficacy were obtained after a booster

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dose in the second year of life in the studies where initial protectionwas less than 100%. Consistent with the enhanced immunogenic-ity profile of conjugate vaccines, vaccine effect was independent ofage in these infant trials [46]. A phase III trial of PRP-OMP amongNavajo infants revealed 95% protection (95% CI 53% to 98%) overthe first 18 months of life after only two doses [47]. A large-scalefield trial of PRP-T in The Gambia, with doses scheduled at 2, 3, 4months of age demonstrated not only 95% (67–100%) protection oftwo or more doses against classical invasive Hib disease, but also a21% (4.6–34.9%) reduction in all cases of radiologically confirmedpneumonia [48].

Randomised controlled efficacy trials were not conducted formeningococcal serogroup C conjugate (MenC) vaccines, which werelicensed on the basis of safety and immunogenicity data [49]. Thequadrivalent A/C/W135/Y conjugate vaccine used in the US waslicensed on the basis of non-inferiority to the existing quadriva-lent polysaccharide vaccine. An effectiveness study in one of thecountries in the African meningitis belt is planned for the Menin-gitis Vaccine Project’s MenA vaccine, rather than a randomisedcontrolled trial [50].

The Northern California Kaiser Permanente trial of PCV7reported that the vaccine efficacy against episodes of pneumonia(confirmed using WHO radiograph protocols) was 25.5% (7–41%)in an intention to treat analysis, and 30% (11–46%) per protocol[51] in children less than 5 years of age. Efficacy against invasivedisease caused by vaccine serotypes was 97% (83–100%) [52]. Ina community randomised trial among Navajo and Apache chil-dren in the US, PCV7 was found to be effective against invasivedisease in children <2 years of age, reducing episodes caused byvaccine serotypes by 83% (21–96%) [53]. Efficacy studies in the US[52], Israel [54] and Europe [55] have also demonstrated modestprotection against otitis media. Two efficacy trials of PCV9 in chil-dren have been completed in developing countries; the first foundthat vaccination prevented invasive disease in both HIV-positiveand HIV-negative infants in South Africa, although point estimatesof efficacy were higher in HIV-negative children [56]. Vaccinationsignificantly reduced radiologically confirmed pneumonia in chil-dren who were HIV-negative. In The Gambia, PCV9 efficacy againsta first episode of radiologically confirmed pneumonia was 37%(27–45%), against invasive disease caused by vaccine serotypes was77% (51–90%), and against all invasive pneumococcal disease was50% (21–69%) [57]. The most striking findings in this second trialwere that vaccination significantly reduced hospital admissionsand deaths from any cause by 15% and 16%, respectively.

2.2. Introduction of conjugate vaccines into nationalimmunisation programmes

Most industrialised countries licensed Hib conjugate vaccines inthe late 1980s or early 1990s, with inclusion in routine infant immu-nisation schedules following shortly thereafter. More recently, Hibvaccines have been introduced for widespread use in many parts ofthe Americas [58], Eastern Mediterranean Region and Africa. WHOrecommends Hib vaccine introduction in all countries, even wheredisease burden is unclear [1] and the Hib Initiative seeks to facil-itate more widespread vaccine introduction (www.hibaction.org).Most industrialised countries currently use a 3-dose schedule inearly infancy with a further dose at 11–18 months. In Africa (whereimplemented) and the Americas, three dose infant-only schedulesare more common. The majority of Hib vaccines given worldwideare administered in combination with other antigens as part of theroutine infant immunisation schedule. In most instances, PRP-T iscombined with any or all of diphtheria and tetanus toxoids, pertus-sis (whole cell denoted as wP or acellular denoted as aP), inactivatedpolio (IPV) and hepatitis B (HepB) vaccines in a single injection.

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The UK was the first country to introduce MenC vaccines into itsnational immunisation programme in 1999; these vaccines havesubsequently been introduced in several other European coun-tries, Australia and Canada. Schedules initially chosen for routineinfant immunisation appear to be heavily influenced by the existingchildhood immunisation schedule in each country. Most countriescurrently give a dose in the second year of life, with or withouta primary infant series. Quadrivalent meningococcal vaccines arecurrently only used in a national programme in the US, where theyare recommended for teenagers. Monovalent MenA conjugate vac-cines and combination vaccines containing MenA are still in clinicaltrials.

The US incorporated PCV7 into the routine infant vaccine sched-ule (at 2, 4, 6 and 12–15 months) in 2000. Intermittent supplyproblems from 2001 through 2004 led to many children being par-tially immunised, and may have slowed introduction elsewhere,but these problems have been resolved and many (mainly indus-trialised) countries have moved or are moving to adopt PCV7. Mostcountries (with the exception of Australia) have implemented a 2-dose or 3-dose schedule in early infancy with an additional dosebetween the ages of 11 and 18 months. Australia uses a 3-doseschedule in infancy without a booster, except for the high-riskindigenous community, for whom a booster dose of 23-valentpneumococcal polysaccharide vaccine is given at 18 months.

2.3. Vaccine effectiveness

2.3.1. Hib vaccinesPost-licensure surveillance of Hib conjugate vaccines showed

near eradication of disease in the short term in the USA [59,60],Canada [61], the UK [62], the Netherlands [63], Israel [64] andScandinavia [65–67] regardless of the vaccine used or scheduleemployed. Hib meningitis has remained rare in Finland dur-ing 18 years of widespread Hib immunisation [68]. In high-risk,indigenous populations in the US and Australia [69], high short-term effectiveness was also demonstrated with PRP-OMP vaccines[70–72].

Following the success of a large efficacy trial, Hib vaccine wasintroduced into The Gambia’s routine immunisation schedule at 2,3 and 4 months of age in 1997. Five years later, the effectiveness of atleast two doses in preventing invasive disease was estimated at 93%using a case-control study [73]. South Africa introduced widespreadHib vaccination at 6,10 and 14 weeks in 1999, with a resultant rapiddecline in confirmed Hib meningitis in two sentinel hospitals [74],
and an estimated 65% minimum reduction in invasive Hib infec-tions during the first year of life by 2003–2004 [75]. A numberof other African nations introduced Hib conjugate vaccine accord-ing to the EPI schedule in 2001–2002 and clear benefit has beenobserved, even in countries with high HIV prevalence. For example,in Malawi, effectiveness of at least two doses against Hib menin-gitis was greater than 90% in a case-control study [76]. In Kilifi,Kenya, effectiveness of 88% was estimated from hospital labora-tory surveillance two years after vaccine introduction [77]. In bothKenya and South Africa however, HIV positive children were over-represented among vaccine failures [75]. In populations with a highprevalence of HIV, S. pneumoniae and non-capsular H. influenzae aremore important causes of invasive disease compared to populationswith low HIV prevalence; this might explain the lesser impact of Hibvaccine on other surrogate markers of bacterial meningitis in partsof Africa [74].
In Chile, around 50% of infants in metropolitan Santiago wereimmunised with Hib following a 2, 4, 6 months schedule in ademonstration project, resulting in reduction in the incidence ofinvasive infections from 8.6 to 0.85 per 100,000. This correspondedto 90% effectiveness (95% CI 75–100%, p < 0.0001) against inva-

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sive disease, and in addition 80% effectiveness (p = 0.039) againstbacteraemic pneumonia and empyema was observed [78]. Thisstudy provided the necessary evidence to support systematic useof Hib vaccine elsewhere in Latin America in the 1990s [58].Additional protection against radiologically confirmed pneumoniawas observed among Hib vaccinated Brazilian children, with thereported decline of 31% (95% CI −9% to 57%) [79]. In Brazil, fiveyears after Hib conjugate vaccine introduction with a 2, 4, 6 monthsschedule, the incidence of Hib meningitis declined from 2.39 to0.06 cases per 100,000. Argentina and Uruguay are examples ofcountries in the region that included a fourth dose in the secondyear of life, both experienced subsequent declines in Hib menin-gitis although a more rapid reduction was reported from Uruguay,where catch-up immunisation of children under 4 years accompa-nied implementation [74,80].

In a number of populations, resurgence of Hib disease has beenobserved several years after Hib vaccine introduction. Following theinitial success of PRP-OMP, an increase in Hib disease was observedamong Alaskan natives between 1996 and 1997 after a switch toHbOC vaccines [82]. It was concluded that the poorer immuno-genicity of HbOC after one or two doses had left infants vulnerableto acquiring Hib infection in the face of ongoing carriage and hightransmission pressure [70] and a switch back to PRP-OMP was rec-ommended for infant immunisation [70]. In the UK, the incidenceof Hib declined rapidly following Hib vaccine introduction in 1992,however from a nadir of 0.88 per 100,000 in 1998 the incidence ofHib subsequently increased to 4.16 per 100,000 in 2002, with mostcases occurring in fully immunised children [83]. Direct effective-ness of the infant schedule, calculated using the screening method[84], was only 61% in the first two years following vaccination, wan-ing to 27% thereafter [85]. The increase in cases was attributed toboth waning herd immunity in the population [85–87], and theuse of less immunogenic acellular pertussis containing (DTaP-Hib)combination vaccines [88]. To counter the increase in cases, a catch-up campaign was initiated and later, a fourth dose of Hib was addedto the routine immunisation schedule at 12 months of age. Expe-rience in the Republic of Ireland, where a 2, 4, 6 months schedule(i.e. 2-month interval between doses rather than 1-month inter-val) without a booster was used, mirrored that of the UK [89]. TheNetherlands reported an increase in invasive Hib infections in 2003,10 years after vaccine introduction [90]. In contrast to both the UKand Republic of Ireland, the Netherlands has consistently provideda booster dose of Hib at 11 months of age, following priming at 3, 4and 5 (1993–1998) or 2, 3 and 4 (1999-ongoing) months [90], and
acellular pertussis combinations were not used prior to 2005. InThe Gambia, a recent report suggests that the number of cases ofHib disease may be increasing 8 years after vaccine introduction,highlighting the need for continued surveillance [91].
2.3.2. Meningococcal vaccinesEffectiveness data are only currently available for MenC

vaccines. All countries that have introduced a national MenCvaccination programme have subsequently experienced substan-tial overall declines in serogroup C disease [36]. Formal vaccineeffectiveness estimates (measuring direct protection in vaccinatedindividuals) are currently available from England [92–94], Spain[95] and Canada [96]. Short-term vaccine effectiveness was high(87% or above) in all age groups in all settings. There was howeversignificant variation in effectiveness between age groups and overtime [94]. Of particular note is the rapid waning of effectivenessin children immunised in infancy. In England direct protection wasno longer significant just one year after completion of the primaryinfant series (2, 3, 4 months schedule) [94]. Nonetheless, infantswere at low risk of disease because of the strong indirect effectsresulting from the large catch-up campaign between the ages of

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1–18 years. In Spain the effectiveness of the 2, 4, 6 months infantschedule also declined over time; there was no significant differ-ence in the rate of the decline compared to the UK infant schedule[97], suggesting that infant-only schedules (regardless of whethera 1 month or 2 months interval is used) are not optimal. The UKchanged the MenC immunisation schedule in September 2006, sothat now two rather than three doses are recommended in infancy(at 3 and 4 months) and an additional dose is administered at 12months of age (in combination with Hib) in order to improve andextend direct protection into later childhood. In the Netherlands,MenC is routinely administered at 14 months of age; between 2002and 2004 no vaccine failures were reported among children immu-nised according to this schedule [98].

2.3.3. Pneumococcal vaccineRoutine use of PCV7 in the US has rapidly decreased rates of

invasive pneumococcal disease in children. The impact of the vac-cine was noted within 1 year of introduction. According to CDC’sActive Bacterial Core Surveillance (ABCs) the incidence of invasivepneumococcal disease among children <5 years dropped 75% from97 cases per 100,000 population during 1998 and 1999 to 24 casesper 100,000 population in 2005; disease caused by vaccine-typestrains fell 94% from 80 to 4.6 per 100,000 [99,100]. A multi-centrestudy of hospitalised patients found that 77% fewer cases in chil-dren <2 years were caused by vaccine serotypes in 2002 comparedto the average number of cases during 1994–2000 [101]. Publishedsurveillance data on vaccine impact from outside the US are cur-rently limited. Data from Calgary, Canada showed a 93% reductionin vaccine-type invasive disease in children <2 years of age [102]. InAustralia, the rate of vaccine-type invasive pneumococcal diseasedecreased by 78% between 2002 and 2006 in children aged under2 years [103].

Combined data from the US Pediatric Multicenter Pneumococ-cal Surveillance Group and the Massachusetts Department of PublicHealth were used to estimate the direct effectiveness of PCV7 usinga case-only method [104]. In children not at high risk for invasivedisease, the effectiveness of the vaccine against vaccine serotypeswas estimated to be 91% for the full 4-dose schedule [104]. Effective-ness was somewhat higher when measured in a large case-controlstudy that used cases of invasive disease identified through CDC’sABC multisite surveillance programme and age-matched controls.This study found that one or more doses of PCV7 was 96% effectiveagainst invasive disease in healthy children, 81% effective in chil-
dren with comorbid medical conditions and 76% effective overallagainst disease caused by strains resistant to penicillin [105]. Vac-cination was shown to be significantly protective against all sevenindividual vaccine serotypes and vaccine-related serotype 6A, butnot against vaccine-related serotype 19A. PCV7 use also appearsto be reducing non-invasive pneumococcal infections in the US,including otitis media and pneumonia [106–108].
3. Factors influencing vaccine impact

3.1. Protection against carriage and herd immunity

The ability of conjugate vaccines to provide some protectionagainst carriage, thereby reducing transmission and preventing dis-ease in unvaccinated individuals (herd immunity/indirect effects)has been an important component of the success of conjugate vac-cination programmes.

A sustained reduction in Hib colonisation prevalence has beendocumented following vaccine introduction in several countriesincluding Finland [109], the US [110], the UK [111] and The Gam-bia [73]. Hib carriage was 80% lower in vaccinated English infants

6 (2008) 4434–4445

studied in a family setting compared with their unvaccinated coun-terparts [112] and a similar degree of protection (81%) over the firstyear following vaccination was noted in toddlers attending nurs-ery in the US [113]. In addition to these observed reductions incarriage, disease rates declined in those outside the target age forvaccination in several countries [111], suggesting that a substan-tial component of the observed disease reduction is due to indirectprotection. In The Gambia, the reduction in Hib carriage follow-ing vaccine introduction – from 12% to 0.25% (p < 0.0001) – madea major contribution to disease control [73]. Vaccine delivery wasless than optimal – only half of the population at risk was effectivelyimmunised by the pre-vaccine median age at disease presentation– so direct protection alone could not explain the marked reductionin Hib meningitis. The duration of such herd effects is unclear at thepresent time.

There is compelling evidence that MenC vaccines offer someprotection against carriage of serogroup C meningococci, leading toherd immunity, but there is currently no evidence on the impact ofother meningococcal conjugate vaccines on carriage. Large carriagestudies were conducted in the UK in 1999, 2000 and 2001, before,1 and 2 years after the start of MenC vaccination to measure theprevalence of serogroup C carriage in teenagers. One year followingvaccination, serogroup C carriage was reduced by 66% (p = 0.004)[114]. Correspondingly, the attack rate in unvaccinated individualsin England was reduced by 67% (95% CI 52–77%) [115]. The numberof cases of serogroup C disease remained low in the UK, despiterapidly waning direct effectiveness following infant immunisation[94], because of herd immunity. In the Netherlands, routine MenCimmunisation was given at 14 months of age and a catch-up cam-paign targeted individuals up to the age of 19. Although infants werenot immunised, the number of cases in this age group declined from20 in 2001 to only 1 in 2004 [98]. It is not clear how long the indirecteffects of MenC vaccination will persist following the initial catch-up campaign. Given the low estimated basic reproduction number(R0) for serogroup C infection [116], it is expected that carriage rateswould be slow to recover to pre-vaccine levels, even if individualprotection against carriage is only sustained for a few years.

Clinical trials of pneumococcal conjugate vaccines demon-strated a reduction in nasopharyngeal carriage of vaccine serotypes[25,26,117–120]. Routine use of pneumococcal conjugate vaccine inthe US has also reduced carriage of vaccine serotypes among chil-dren, although the overall prevalence of pneumococcal carriage hasremained unchanged [121–126]. A fall in carriage of vaccine-typepneumococci in adults following routine childhood immunisation
has also been reported [125]. Evidence of herd immunity is alsoavailable from invasive disease rates outside of the ages targetedfor vaccination. In the US, invasive disease in adults ≥65 yearshas dropped by about one-third since introduction of pneumococ-cal conjugate vaccine for children, caused by an 80% reduction indisease caused by PCV7 serotypes between 1999 and 2005 (CDCunpublished data). A drop of similar magnitude was seen in hos-pitalisations for pneumococcal bacteremia in older adults [127]. Innewborns and infants too young to have been vaccinated, invasivedisease caused by PCV7 serotypes fell around 50% following PCV7introduction [128]. There is also some evidence that herd immunityresulting from PCV can reduce the incidence of pneumonia in addi-tion to invasive disease. In the USA, declines in rates of all-causeand pneumococcal pneumonia have been reported beyond the agegroups targeted for PCV7 [108]. Indirect protection against hospi-tal admission for pneumonia was not confirmed in a case-controlstudy in South Africa [129], but this study was done 3 years afterimmunisation, with low population coverage and in a setting withhigh prevalence of HIV and TB. Post-licensure surveillance fromother countries will help to clarify the indirect effects of PCV onpneumonia.

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3.2. Catch-up campaigns

Catch-up campaigns have been used in several countries to sup-plement routine vaccination with conjugate vaccines. In general,catch-up campaigns seem to have made a strong contribution todisease control, because a larger proportion of the population arevaccinated, within a short period of time, enhancing both direct andindirect effects. Indirect effects are particularly enhanced if the agegroups responsible for most transmission are targeted.

In the UK introduction of routine infant Hib vaccination wasaugmented by a catch-up campaign targeting all children ≤4 yearsold. Hib disease incidence fell rapidly in all age groups within 12months [111]. In contrast, the Netherlands did not employ catch-up immunisation and disease rates in the unvaccinated cohortsdeclined slowly over several years [63]. In the Veneto region of Italy,despite low reported uptake (26%) of the infant primary series, a90% reduction in Hib disease was observed in children aged lessthan 5 years within 2 years of vaccine introduction. This successwas attributed to catch-up vaccination in children aged 1–4 yearsin the region, even though uptake in the catch-up campaign wasrelatively modest (at most 53%) [130]. In the case of MenC vac-cination, herd immunity was much more limited in Spain, wherethe initial catch-up campaign only targeted children up to the ageof 6 years [95], compared to the UK and the Netherlands, whichtargeted teenagers up to age 18–19 years. By immunising the agegroup (15–19 year olds) in whom meningococcal carriage is mostcommon, the UK and the Netherlands had a much greater impacton overall prevalence and transmission of serogroup C meningo-cocci in the population. This result and explanation is supported bymathematical models [131]. The impact of catch-up campaigns onthe epidemiology of pneumococcal disease is not so clear, but datafrom the UK, where a catch-up campaign of children <2 years of ageis being conducted currently, will be enlightening.

3.3. Comparison of vaccine schedules

Several studies have indicated that two conjugate doses appearto provide similar direct protection to three doses during infancy.For Hib vaccines, the schedules used depend to some extent on thetype of vaccine, for example Hib–OMP vaccines produce substan-tial antibody rises after the first dose and are licensed in the USAfor a two-dose primary schedule [35]. In Finland, near eradicationof Hib disease continues where a 3, 5 and 11 months schedule hasbeen used since 1988 (with Hb-OC up to 1994 and PRP-T thereafter)
[68] even though the immunogenicity of a 2-dose priming sched-ule with these conjugates is relatively poor compared to a 3-doseschedule [35]. The 2-month interval between priming doses in thisreduced schedule may be important. In The Gambia, there was aclear difference between the effectiveness of one dose (VE = 38%,95% CI −58% to 75%) and two doses (VE = 94%, 95% CI 62–99%) butlittle added benefit of a third dose of Hib vaccine [73]. Again, tim-ing may be important; although The Gambia recommends a 2, 3,4 months schedule the median age at receipt of 2nd dose was 6.5months [73].
Although effectiveness data on reduced infant schedules arenot available for MenC, early immunogenicity studies of a 2, 3, 4months schedule showed that 98–100% of infants achieved protec-tive titres (defined as serum bactericidal antibody tire ≥8 usingrabbit complement) after the second dose and that there wasno incremental increase in antibody titres between the 2nd and3rd doses [132,133]. Further studies with MenC-tetanus toxoid(MenC-TT) vaccine administered concomitantly with DTwP-Hib-IPV showed that 98%, 100% and 99% of infants achieved an SBAtitre ≥8 after a 1, 2, and 3 dose schedule respectively [134], andwhen co-administered with acellular pertussis containing vac-

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cines, 92.2% achieved protective titres after one dose, compared to100% after two and three doses [135]. Priming for immunologicalmemory was also achieved with two or one dose infant sched-ules [134,135]. A range of infant immunisation schedules using abivalent serogroup A and C conjugate vaccine were tested in Niger[136]. There appeared to be little benefit either in terms of improvedimmunogenicity or memory response of additional doses at 6 and10 weeks, compared to a single dose at 14 weeks. The highest SBAlevels were achieved by immunising at 14 weeks and 9 months ofage. For serogroup A, immunological memory was induced with asingle dose at 14 weeks or 9 months.

For PCV, shortages of vaccine in the US provided evidence thatfewer than the recommended four doses (scheduled at 2, 4, 6 and12–15 months) are effective in preventing disease. Mahon et al.estimated that in children not at high risk for invasive disease, theeffectiveness against vaccine serotypes was 91% for the full 4-doseschedule, 77% for three doses given before 7 months of age, and71% for two doses given before 5 months of age, with no statisti-cally significant protection from a single dose given before 3 months[104]. A large case-control study from CDC’s Active Bacterial Coresurveillance programme found nearly all schedules provided someprotection compared to no vaccine, although a single dose at <7months was less protective than two or three doses received at<7 months of age [105]. In Italy, a single-blind cohort study ofvaccination at 3, 5, and 12 months showed less X-ray confirmedpneumonia, acute otitis media, and antibiotic use in children whohad received PCV7 compared to those that had not, but the effectswere not statistically significant after 12 months of age [137]. Animmunogenicity study from the UK demonstrated that the propor-tion of children achieving titres >0.35 �g/mL following two PCV9doses at 2, 4 months of age with a booster was comparable to theresponse following three doses at 2, 3, 4 months with a booster[138]. In developing countries, phase III trials of the 9-valent vac-cine in South Africa and The Gambia showed that a 3-dose primaryseries conferred substantial protection against disease [56,57], inthe absence of a later fourth dose. In the South African trial themean age at vaccination was 6.6, 11.2 and 15.9 weeks, and in theGambian trial the median age at 1st and 3rd dose was 11 weeks and24 weeks respectively. More immunogenicity data will be forth-coming on ‘reduced dose’ schedules (studies are being/have beenconducted in UK, Iceland, Israel and Fiji).

It is important to consider the role of a later dose given between9 and 18 months of age, even though developing countries havetended to trial and implement infant-only schedules for Hib and
PCV. The current EPI schedule does not include a visit in the 2ndyear of life, but potential exists to offer more antigens when measlesvaccine is given at 9 months. As reported above, the effectiveness ofinfant-only MenC and Hib schedules as used previously in the UKwaned rapidly and a dose at 12 months of age is now administeredto improve long-term protection. The relevance of the UK experi-ence for long-term disease control in developing countries usingan infant-only schedule is not yet clear, but ongoing surveillance isrequired in those countries (e.g. The Gambia) that introduced Hibvaccine earlier in order to address this issue. Further work may alsobe needed to address the immunogenicity of booster doses at dif-ferent ages in different settings: a UK study showed that the heightof the Hib antibody response and persistence after boosting wererelated to the age at administration, with better responses in thoseboosted after the first year of life [139]. In the US a direct comparisonof the effectiveness of three PCV doses before 7 months with andwithout a later dose at 12–15 months suggested that the boosterconferred additional protection (p = 0.03) [105]. Immunogenicitystudies from Finland and Italy demonstrated strong production ofantibodies following PCV vaccination with two doses <6 monthsof age with a booster doses at 11 or 12 months [140,141]. This later

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dose may also be important in preventing carriage (and may be par-ticularly important where reduced primary schedules are used).Even though correlates of protection against carriage have yet tobe defined it is generally thought that higher antibody titres arerequired to prevent carriage than to prevent disease [142,143]. Giv-ing the last dose of vaccine at an older age, where responses arehigher, may therefore have a more profound impact on carriage, andhence herd immunity. The impact of different schedules on carriageis not well understood at present, but is an important question toaddress, given the potential magnitude of herd effects.

3.4. Duration of protection

Knowledge of the precise duration of direct protection conferredby conjugate immunisation is limited because of the lack of corre-lates of long-term protection, difficulties in separating direct andindirect effects, and limited time of follow-up (at least for MenCand PCV). The ability of conjugate vaccines to induce persistingimmunological memory has been clearly established, but the abil-ity of that memory to protect from infection would appear to varydepending on the age at which the last dose is given. The experiencewith Hib and MenC vaccines suggests that the role of memory inproviding long-term protection when infants are immunised earlyin life with no boosters may have been overstated as direct protec-tion (and antibody levels) for such infants wanes quickly. Protectionpersists for those who receive a vaccine in the second year of life,and in this group antibody persistence is noted. The relationshipbetween memory and antibody persistence is not clear, but theability to maintain antibody titres may in itself be a manifestationof memory. Circulating antibody may also be maintained by natu-ral boosting following periods of asymptomatic carriage. A possiblenegative indirect consequence of conjugate vaccination is that byreducing carriage in the population, the opportunities for natu-ral boosting are also reduced. This may have played a role in theincrease in Hib infections in adults in England and Wales observedfrom the late 1990s [87].

3.5. Serotype/serogroup replacement

Conjugate vaccines are directed against a selected number ofcapsular serotypes/serogroups. One concern regarding the useof such selective vaccination is that it may lead to an increasein disease caused by other serotypes/serogroups, either throughserotype replacement (whereby other serotypes fill the ecological
niche vacated by vaccine-targeted strains) or capsular switching(whereby virulent vaccine-type isolates acquire a different capsulethrough genetic exchange thus gaining a fitness advantage) [144].These effects may attenuate the benefits of vaccination. While thereis no evidence that selective vaccination has led to a clinically sig-nificant increase in disease caused by non-vaccine types/groups forHib or MenC vaccines, serotype replacement is much more of aconcern with pneumococcal vaccines. In most but not all pneu-mococcal carriage studies, carriage of non-vaccine-type strainsincreased among children receiving conjugate vaccine such thatthe overall prevalence of pneumococcal carriage was not differentin vaccinated and unvaccinated children [25]. The implications ofthis replacement colonisation in terms of disease are not yet clearlyunderstood, although replacement disease is not anticipated toresult in higher levels of disease than observed pre-immunisation[20]. Replacement disease was not observed in the invasive diseaseefficacy trials, but in the Finnish otitis media trial, children in thepneumococcal vaccine group had 33% more episodes of otitis mediacaused by serotypes not in the vaccine or related to vaccine types[55]. Measurement of serotype replacement after vaccine introduc-tion is complicated by the natural variation in serotype distribution
6 (2008) 4434–4445

over time. In the US, sentinel data from CDC’s ABC surveillance from1998 to 2004 shows significant increases in the incidence of inva-sive disease due to serotypes 3, 15, 19A, 22F and 33F in childrenunder 5 years, with serotype 19A now the dominant cause of inva-sive disease in children. Further increases in non-vaccine serotypeswere also observed in the elderly, but the magnitude of replacementdisease is small compared to reductions in vaccine-type disease[145]. Surveillance in Utah (USA), where the overall reduction indisease was only 27%, showed that a decrease in vaccine-type dis-ease was accompanied by an increase in non-vaccine-type disease[146]. Of concern are recent data from Alaska showing an increase ininvasive disease caused by non-vaccine-type pneumococci amongAlaska native children, which has eroded the benefit from PCV7[147].

3.6. Differences between high-income and developing countries

In addition to the differences in the epidemiology of diseaseand carriage highlighted above there may also be differencesin responses to conjugate vaccines between high-income anddeveloping country settings. For example, an evaluation of PCV9immunogenicity in the UK found that antibody levels increasedfollowing either two or three infant doses but declined to nearpre-vaccine levels before the booster dose was given at 12 months[138]. In contrast, in South Africa, antibody levels remained higherin HIV-uninfected children than among controls for up to 5 years[148]. While direct comparisons between exact IgG GMC valuesfrom studies done at different times or in different laboratoriesshould be undertaken with caution, antibody levels 4 weeks afterthe 3rd infant dose in African studies [26,149] were generally higherthan that seen after the 3rd infant dose in the UK PCV9 study [138]or from PCV7 studies in the US [52,150]. The reasons for these differ-ences are poorly understood but may relate to the degree of naturalexposure to vaccine-type and cross-reactive organisms, differencesin co-administered vaccines (e.g., whole cell versus acellular per-tussis), and/or the maturation of immune responses. Caution isrequired in extrapolating results from high-income to develop-ing countries. Furthermore, even within high-income countries,important differences have been described between indigenousand non-indigenous populations [151].

3.7. Interactions between vaccines given incombination/concomitantly

Childhood vaccine schedules are becoming increasinglycrowded, and it is likely that conjugate vaccines will be admin-istered alongside or in combination with other antigens. Poorlyunderstood immunological interactions can arise when two ormore polysaccharide protein-conjugate vaccines are given incombination or concomitantly at different sites [34]. These inter-actions can enhance or reduce the immunological response tothe polysaccharide antigens and/or the protein epitopes, and themagnitude of the effect may vary depending on whether wholecell or acellular pertussis combination vaccines are administeredwith the conjugate vaccines. Other antigens (e.g. BCG) may alsohave an effect. Because of these (often unanticipated) interactions,it is important that the specific vaccine schedule being consideredis fully assessed using immunogenicity studies.

4. Further research

Conjugate vaccines are being actively researched. Ongoing stud-ies include randomised trials of new vaccines, demonstration orimplementation studies, immunogenicity and efficacy studies of

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alternative schedules, studies into maternal and neonatal immuni-sation and investigation of correlates of protection against carriage.The PneumoCarr project, which aims to develop novel analysesto measure vaccine efficacy against pneumococcal colonisationtogether with studying the transmission of the bacteria, is par-ticularly relevant [152]. In addition, WHO is conducting a reviewof how closely the EPI schedule is adhered to, which is importantfor schedule considerations. Mathematical modelling of alternativeschedules and strategies is also likely to be a useful approach (e.g.[131,153]). While these models may be complex, they can simulate awider range of options than is possible to evaluate in clinical trials.Although we have not explored the economic and programmaticfeasibility of different vaccine strategies in this review, this is alsoan important area of research.

4.1. Implications for future vaccine schedules

A focus on population impact rather than direct protection maybe beneficial, and there may be trade-offs between direct (indi-vidual level) protection and indirect protection (herd immunity)afforded by different schedules. Alternatives to the EPI schedule of6, 10 and 14 weeks for conjugate vaccines in developing countriesmust consider these trade-offs and be cost-effective and program-matically feasible. Two strategies in particular appear to be worthyof further investigation.

4.1.1. “2 + 1” routine immunisation scheduleThe incidence of Hib and pneumococcal disease is highest

in infants, and while risk of meningococcal disease is extendedinto adulthood, there is still a substantial burden of diseasein young children. Higher antibody levels are required to pro-tect against carriage than disease, and immunising at older ageswhere antibody responses are greater, may have a more pro-found impact on transmission. The optimal routine schedule istherefore likely to be a balance between the need to protectyoung infants who are at high risk of disease on one handand the desire to achieve higher and sustained antibody lev-els by vaccinating older infants and placing doses further apart.A schedule providing two doses in early infancy and a thirdtowards the end of the first year appears to offer a reasonablecompromise, with the two early doses providing protection asearly as possible and the third ensuring a strong herd effect andmore lasting protection. This approach has been used in high-income countries e.g. in Finland for Hib, in the UK for MenC and
PCV.
The timing of the 2 + 1 schedule is important. For the first dose,it seems sensible that this is administered between 4 and 8 weeksin keeping with current EPI practices, to initiate early protection.Neonatal vaccination is currently being investigated for pneumo-coccal (and pertussis) vaccines, but existing data and experiencewith Hib conjugate vaccines suggests that even if these studiesdemonstrate a beneficial effect, it is unlikely that a neonatal dosewill be the first dose in a “2 + 1” schedule as more than one sub-sequent dose would be required to ensure protection throughinfancy. Several studies have indicated that two doses may providesimilar direct protection to three conjugate doses during infancy.However, the interval between first and second dose, particu-larly for PCV, may be critical. This needs further study, especiallywith respect to the current EPI schedule, which has a short, 4-week interval between primary doses in infancy. The third dosecould follow at 9 or 12 months of age administered with measlesvaccine. This schedule can be expected to provide lasting pro-tection, while at the same time taking advantage of the herdeffect and limiting the number of doses required. Although care-ful evaluation is required, this schedule may also be suitable for

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diphtheria, pertussis, tetanus and hepatitis B (which is importantas most Hib vaccines are now delivered as combinations based onDTP).

4.1.2. Campaigns with or without routine immunisationAn alternative strategy is to concentrate resources for conjugate

vaccines in mass vaccination campaigns. This may be particularlyattractive to countries in which routine EPI coverage is poor andwhere the addition of new antigens into the EPI programme is notyet feasible. This ‘campaign’ strategy would take full advantage ofthe indirect effects of conjugate vaccines, focusing on carriage asthe vaccine target. The principal idea is that the campaigns wouldtarget age groups who are the most critical for transmission, thusmaximising the indirect effect against carriage. If children targetedin campaigns are aged 12 months or above, then one dose of vac-cine is likely to be sufficiently immunogenic. These campaignscould be followed by periodic follow-up campaigns to immunizecohorts too young to have been included in the initial catch-upcampaign (as is done for measles mortality reduction and elim-ination approaches), or by introduction of a routine dose in thesecond year of life – similar to the situation with MenC in theNetherlands.

This type of strategy is most obviously applicable to meningo-coccal vaccines, where the population at risk of disease coversa broad age range, and the age groups who are most importantfor transmission are also likely to be at risk of disease. Indeed,the Meningitis Vaccine Project is planning a demonstration studyof a MenA conjugate vaccine in Burkina Faso in 2009, where allindividuals aged between 1 and 29 years will be targeted in avaccine campaign. The 1–29 year old age group encompasses theages that are at most risk of disease, in whom one dose is likelyto be effective. From the experiences with MenC vaccine in theUK and the Netherlands, it is hoped that herd effects will be ofsufficient magnitude to protect unvaccinated infants, in whomdisease risk is high. In order to maintain a high level of immu-nity in the population as susceptible individuals not immunisedduring the campaign accumulate, two strategies are envisagedby the Meningitis Vaccine Project. The first builds on periodi-cal follow up campaigns, and the second envisages immunisationof birth cohorts (with two doses of vaccine given at 14 weeksconcurrently with DTP3 and at 9 months with measles vaccine;or with a single dose given with measles vaccine or at 12–14months).

This type of strategy may also be applicable to pneumococcaland Hib vaccines, although for Hib, more and more countries areintroducing routine immunisation with DTP combination vaccines,so this may not be so practicable. There may be an opportunityto test the hypothesis that PCV catch-up campaigns in older chil-dren (e.g. age 1–5 years) can provide indirect protection to thevery young by introducing PCV in conjunction with the MenA vac-cine.

The issues surrounding such a strategy, including the ethi-cal implications of not vaccinating infants who are at highestrisk of disease, with the underlying hypothesis that they willbe protected through herd-immunity, should be carefully con-sidered but this approach may have merit in certain settings.In developing countries where geographical constraints presentmajor problems of access for immunisation and other healthservices for identifiable sections of the population, it has beenargued that those who currently miss out on immunisation arethose at highest risk of diseases such as pneumonia. Campaign-like strategies may offer the best chance to reach these high-riskchildren, resulting in the most equitable use of the vaccines[154].

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5. Conclusions

To maximise the public health impact of immunisation pro-grammes with conjugate vaccines, consideration must be givento the role of indirect effects, alongside direct protection. A rangeof schedules and strategies are likely to be effective and furtherwork is needed to look at the cost-effectiveness and programmaticfeasibility of different options.

Acknowledgements

This work was carried out under the guidance of a WHOSAGE subgroup on optimising the use of conjugate vaccines.The subgroup comprised the following individuals, in additionto the authors of the paper: Hyam Bashour (Damascus Univer-sity, Syria), Mary Ann Lansang (University of the Philippines,Manila), Daniel Brasseur (Ministry of Public Heath, Belgium),Marc LaForce (PATH, France), Claire-Anne Siegrist (University ofGeneva, Switzerland), Robert Steinglass (JSI/IMMUNIZATIONbasics,USA), Thomas Cherian (WHO, Geneva), Ana-Maria Henao-Restrepo(WHO, Geneva), Marie-Pierre Preziosi (WHO, Geneva). We thankFelicity Cutts (formerly WHO, Geneva) for conceiving the projectand for her assistance in developing the conceptual framework.We also thank Liz Miller (Health Protection Agency, UK) for helpfulcomments.

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Optimising the use of conjugate vaccines to prevent disease caused by Haemophilus influenzae type b, Neisseria meningitidis and Streptococcus pneumoniae

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