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Vaccine 29 (2011) 3149–3154

Contents lists available at ScienceDirect

Vaccine

journa l homepage: www.e lsev ier .com/ locate /vacc ine

ustaining GAVI-supported vaccine introductions in resource-poor countries

atrick L.F. Zubera,∗, Ibrahim El-Ziqb, Miloud Kaddara, Ann E. Ottosenb, Katinka Rosenbaumb,eredith Shireyb, Lidija Kamaraa, Philippe Duclosa

Department of Immunization, Vaccines and Biologicals, World Health Organization, 20 Av. Appia, 1211 Geneva, SwitzerlandSupply Division, UNICEF, UNICEF Plads, Freeport, 2100 Copenhagen, Denmark

r t i c l e i n f o

rticle history:eceived 16 January 2011eceived in revised form 8 February 2011ccepted 16 February 2011vailable online 24 February 2011

eywords:ew vaccines

a b s t r a c t

Since 2000, GAVI provided essential support for an unprecedented increase in the use of hepatitis B(HepB) and Haemophilus influenzae (Hib) containing vaccines in resource poor countries. This increasewas supported with significant funding from international donors, intended to be time-limited. To assessthe sustainability of this important expansion of the global access to vaccines, we reviewed supply chains,financial resources for procurement and decision-making in countries that introduced hepatitis B or Hibvaccines with GAVI support. During the period studied, the types of vaccine products supplied fluctuatedrapidly in relationship with the number of suppliers and availability of more combination products. The

upplyinancingecision-making

price of the cheaper vaccines decreased while that of pentavalent DTwP-HepB-Hib remained stable. Inaverage, vaccine introduction was associated with an increase of national programs budget, with newvaccines representing more than half of that increase, while the part of GAVI contributions to the budgetwent from 25% to 46%. Less than 20% of the vaccine introductions were decided by a national advisorybody. Strengthening supply chains, adjusting funding schemes and increasing national ownership willbe key to the sustained use of hepatitis B and Hib vaccines and the eventual addition of other important

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vaccines where they are t

. Background

The possibility of adding more antigens to the immunizationrograms of resource-poor countries has received great attentionrom many development partners [1]. The unprecedented increasen the number of countries with annual per capita incomes ofess than $1000 using hepatitis B and Haemophilus influenzae type

vaccines since 2000 resulted in great part from the financialpportunity presented by GAVI, a global health partnership formmunisation from both private and public sectors that has offeredupport for introduction of new and underused vaccines in over 70f the lowest income countries [2]. This remarkable success hasreated new expectations that other promising vaccines could beimilarly added to the national programs in those countries [3]. Thismbitious goal is justified as a desirable condition for meeting theourth Millennium Development Goal (MDG4) of child mortalityeduction by 2015 [4]. It is also highly desirable in terms of equity,

ince the public health burden of the diseases prevented by thoseaccines is much greater in the poorest countries than in the richerountries, where a larger number of vaccines are routinely offeredhrough national immunization programs.

∗ Corresponding author. Tel.: +41 22 791 1521.E-mail address: ZUBERP@WHO.INT (P.L.F. Zuber).

264-410X/$ – see front matter © 2011 Elsevier Ltd. All rights reserved.oi:10.1016/j.vaccine.2011.02.042

ost needed.© 2011 Elsevier Ltd. All rights reserved.

WHO “Vaccine Introduction Guidelines” [5] identify severalimportant policy and programmatic issues such as the public healthbenefits, economic impact, as well as vaccine product characteris-tics and operational dimensions. As the support offered by GAVIwill be limited in time, the ability of countries to sustain vaccinessupply in their national immunization programs beyond the GAVIsupport period remains a major challenge following those suc-cessful vaccine introductions. One of the expectations in the GAVImodel, as designed in 1999/2000, was that the price of the vac-cines would drop as global demand and supply had increased andthat, by the end of GAVI support, countries would be able to sus-tain these vaccines financially or would have identified alternativefunding options [6]. The initial five-year GAVI support had to berevised towards a longer timeframe. Simultaneously, GAVI empha-sized the importance of multi-year planning and early financialcommitment from the countries it supports [7]. Since 2007, coun-tries are requested to contribute financially, even at a very modestlevels, to the vaccine financing effort [8].

These new developments have highlighted three important ele-ments for decision-makers. Those include: the status of vaccine

specific supply markets, including projected trends in vaccine sup-ply and price over time; the impact of vaccine procurement costs onnational health budgets; and the national ownership of the diseasecontrol strategy. In this paper, we examine those three elementsthrough: trends in volumes and prices for three types of hepatitis

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- and Hib-containing vaccines; evolution of immunization costsnd financing in the countries that have introduced those vaccines;nd availability of national advisory bodies when the decision tontroduce those vaccines was made.

. Methods

.1. Countries studied and period covered

The study included 65 countries that introduced hepatitis B and8 countries that introduced Hib vaccine with support from GAVIetween 2000 and 2008. The World Health Organization (WHO),s the lead partner for the GAVI application process, maintains aatabase that records all GAVI applications. This data base trackshe submission and outcome of GAVI applications. It also includeshe date of the first vaccine introduction in each countries.

.2. Trends in volumes of vaccines offered and prices

UNICEF Supply Division is the main procurement agency forAVI-supported vaccines (supplying 63 GAVI-eligible countries in009). Through regular tender processes (typically 3-yearly), it haseveloped a supply base for hepatitis B- and Hib-containing vac-ines. For this analysis, we focus on three types of vaccine productshat represent the largest demand during the period studied: hep-titis B monovalent, DTwP-HepB (referred to as tetravalent) andTwP-HepB-Hib (referred to as pentavalent) vaccines (of note,o country used Hib monovalent vaccine). For each vaccine pre-entation we review the number of doses offered to UNICEF forAVI-eligible countries, the number of doses eventually procured,

he average price per dose and the number of manufacturers fromndustrialized and emerging economies supplying each year duringhe period studied.

.3. National immunization program budgets and financingources

The costing and financing information was extracted from datarovided in the national comprehensive multi-year plans (cMYP).hose data were estimated using the costing and financing tooleveloped by WHO and transferred into the immunization financ-

ng database [9,10]. The data from 50 countries were reviewed.he sample consisted of cMYPs that met quality indicators on theompleteness of the information and the quality of the financingnformation. Comparisons were made between the period pre-eding vaccine introduction and the period 2008–2010 when theaccines studied had been introduced. For the period precedingaccine introduction, costs were calibrated using 2006 as a yearf reference to make the figures comparable. Figures for the years008–2010 represent planned expenditures.

The indicators chosen in the costing and financing analysisre immunization expenditures and financing per infant using theumber of children under one year of age as the denominator foroth. Such indicators should be interpreted as based on infants inhe birth cohort, rather than infants fully immunized. The find-ngs are presented as overall averages and by stratifying countriesnto those that introduced hepatitis B and those that introducedoth hepatitis B and Hib vaccines into their national immunizationchedules.

.4. Availability of national advisory bodies

Currently GAVI requires that inter-agency coordination com-ittees (ICCs) [11] underwrite country applications. ICCs involve

he main external partners following while many countries doot rely on immunization technical advisory groups (NITAG). The

9 (2011) 3149–3154

information reported in this paper was collected through a ques-tionnaire survey conducted in March–April 2008 of all 193 WHOmember states [12,13]. Questionnaires were distributed throughthe network of WHO regional offices to each country for comple-tion by the immunization manager or a counterpart knowledgeablein the immunization development processes of the country such asthe national NITAG chairperson. Indication of existence of a NITAGreflects a positive reply documented in those questionnaires.

3. Results

From 2000 to 2008, 67 of 76 countries eligible during all partsof the period studied have introduced at least one of hepatitis B orHib vaccine with support from GAVI. As 11 countries had alreadyintroduced hepatitis B containing vaccines (with other fundingmechanism) and not all introduced Hib containing vaccines duringthe interval, 56 countries actually introduced hepatitis B containingvaccines and 38 introduced Hib containing vaccines with GAVI sup-port while 31 introduced both. UNICEF was the procurement agentfor all but 3 countries that used different procurement mechanisms(Guyana, China and Indonesia).

During the period studied, the number of doses offered to, andthose supplied by UNICEF of the three vaccine products differedsubstantially (Fig. 1A). Hepatitis B monovalent vaccine was avail-able in large quantities by 2000 already. The number of dosessupplied by UNICEF increased from just over 20 million doses in2000 to nearly 70 million in 2006, but subsequently decreased ascombination vaccines became available in larger quantities andreplaced the monovalent products. For the combination vaccines onthe other hand, supply remained constrained by a limited offer fromindustry for many years. Until 2005, tetravalent vaccine offeredto UNICEF for GAVI-eligible countries never exceeded 17 milliondoses. Similarly, before 2005 pentavalent vaccine offer did notexceed 25 million doses. The uptake of tetravalent vaccine, as mea-sured by the number of doses supplied by UNICEF remained veryclose to the number of doses offered to UNICEF during those years,reflecting a demand from countries that was higher than the supplyavailable. As the number of vaccine doses offered to UNICEF startedincreasing, the uptake of tetravalent vaccines increased rapidly toa maximum of more than 46 million doses in 2007. As the numberof pentavalent vaccine doses offered to UNICEF increased, uptakeraised modestly after 2004, but picked up more dramatically as of2007 following recommendations in 2006 from the WHO Strate-gic Advisory Group of Experts (SAGE) on the use of Hib vaccineand the availability of extended funding through GAVI [2,14]. By2008, shortly after pentavalent vaccine introduction accelerated,uptake of tetravalent vaccines dropped dramatically to fewer than10 million doses as a result of product substitution.

The evolution of vaccine prices was quite different for eachproduct as well (Fig. 1B). Hepatitis B vaccines were already lowerthan $0.50 per dose in 2001. As the number of suppliers with pre-qualified vaccines increased from 2 in 2001 to 6 in 2006, the pricedecreased below $0.25 per dose. WHO pre-qualified hepatitis B-containing tetravalent vaccines was priced slightly above $1 in2001 and supplied from a single source until 2006. Its price didnot decrease substantially until 2007. By 2008, with abundant offerfrom 3 manufacturers the weighted average price was $0.80 perdose. Pentavalent vaccines price did not change significantly until2008, fluctuating between $3.28 and $3.65. This type of productwas available from a single multinational manufacturer until 2006.

A second manufacturer, from an industrialized country, receivedWHO pre-qualification and started supply of pentavalent vaccinein late 2006. The first manufacturers from emerging economiesreceived WHO pre-qualification and started supply of pentavalentvaccines to UNICEF in 2008 only.

P.L.F. Zuber et al. / Vaccine 29 (2011) 3149–3154 3151

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Table 1Analysis of national program financing budgets (cost per infant), the year when the decision to introduce the vaccine was made and by 2010. Two groups of countriesaccording to type of vaccine introduced with GAVI support.

Vaccine introducedwith GAVI support

Budget component Expenditure per infantat baseline 2006

Projected expenditureper infant for2008–2010 (% of total)

Scale up (difference)

Hepatitis B Traditional vaccines $1.40 $2.20 $0.80New vaccines $1.10 $1.70 $0.60Injection supplies $0.60 $1.10 $0.50Systems costs $7.80 $10.70 $2.90Total $10.90 $15.70 $4.80

Hepatitis B and Hib Traditional vaccines $1.40 $1.60 $0.20New vaccines $3.60 $13.10 $9.50Injection supplies $0.60 $1.10 $0.50Systems costs $9.80 $14.50 $4.70Total $15.70 $30.30 $14.60

Overall average Traditional vaccines $1.40 $1.70 $0.30New vaccines $2.90 $10.10 $7.20Injection supplies $0.60 $1.10 $0.50Systems costs $9.30 $13.60 $4.30Total $14.20 $26.50 $12.30

3152 P.L.F. Zuber et al. / Vaccine 29 (2011) 3149–3154

Table 2Analysis of financing source (per infant), the year when the decision to introduce the vaccine was made and by 2010. Two groups of countries according to type of vaccineintroduced with GAVI support.

Vaccine introducedwith GAVI support

Budget component Financing per infant atbaseline 2006 (% oftotal)

Projected financing perinfant for 2008–2010(% of total)

Funding gaps(2008–2010)

Hepatitis B Government $6.7 (61%) $7.9 (64%)GAVI $1.4 (13%) $1.3 (10%)Multilateral $1.8 (17%) $1.1 (9%)Other $1.0 (9%) $2.1 (17%)Total $10.9 $12.4 $3.3

Hepatitis B and Hib Government $6.9 (44%) $8.5 (33%)GAVI $4.4 (28%) $13.3 (52%)Multilateral $2.9 (18%) $2.4 (9%)Other $1.6 (10%) $1.1 (4%)Total $15.7 $25.4 $4.9

Overall average Government $6.8 (49%) $8.4 (38%)))

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supply availability of vaccines considered for introduction (includ-ing number of manufacturers as an indication of the maturity ofthe global market and understanding of how price trends and pricelevels could compare with prices of traditional EPI vaccines) should

Table 3Number and proportion of countries with a NITAG at the time the decision to intro-duce GAVI-supported hepatitis B or Hib vaccine was taken, according to the antigenintroduced and by WHO region (number of countries with NITAG/number of coun-tries having introduced the vaccine).

WHO region Hepatitis B vaccine Hib vaccine

African 4/34 (12%) 4/25 (16%)American 0/1 (0%) 0/1 (0%)

GAVI $3.5 (25%Multilateral $2.6 (18%Other $1.3 (9%)Total $14.2

Prior to vaccine introduction, countries studied spent an average14.20 per infant for immunization (Table 1). Countries that intro-uced only hepatitis B (number of infants studied in 2006: 10.2illion) had a lower average immunization budget. Average bud-

et projections of countries that introduced new vaccines revealsubstantial projected cost increase for the period 2008–2010, in

verage $12.30 more per infant as compared to the period prior toaccine introduction, that almost doubles program costs. Overall,he largest contributor to cost increase is the new vaccines compo-ent that accounts in average for $7.20 or 58% of this increase. That

ncrease, however, was not as pronounced when countries intro-uced hepatitis B containing vaccines only. In that case, the totalverage increase was $4.80 per infant and the contribution of newaccines was rather small at an average of $0.60 (13% of the actualudget increase). In countries that introduced both hepatitis B andib containing vaccines (number of infants studied in 2006: 25.5illion), program costs almost doubled with an average increase of

14.60 (new vaccines cost contributed an average of $9.50 whichepresents 64% of that increase).

For those same countries, at baseline, national funding rep-esented overall 48% ($6.80 out of $14.20) of the averagemmunization budgets (Table 2). After introduction of hepatitis B orf hepatitis B and Hib vaccines, the average government financingas predicted to increase only modestly in absolute terms (from

6.80 to $8.40). As a result, it becomes a smaller proportion of theverall budget at 38%. GAVI represents the single external sourcef funding expected to contribute for most of the increase in pro-ramme financing. Overall, its contribution increases from 25% ataseline ($3.50 of $14.20) to 46% ($10.10 of $22.00). This increase

s even more pronounced for countries introducing both vaccines,here GAVI is expected to contribute 52% of the programme costs

$13.30 of $25.40). By contrast the overall contribution of multilat-ral and other donors is not expected to increase after new vaccinesntroduction. In addition, projected budgets reveal a substantialmbalance (funding gap or difference between projected expendi-ures and projected financing) already which in average amountso $4.50 per infant.

Few countries relied on a NITAG for the decision to introduceither vaccine product (Table 3). Only 10 (18%) of the 56 coun-ries had implemented such advisory body at the time they decided

o introduce hepatitis B vaccine. Among the 38 countries that hadntroduced Hib containing vaccines, the same proportion did so

ith a NITAG at the time of the decision. The proportion of coun-ries that did rely on a national advisory body was very small in all

HO regions.

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4. Discussion

This analysis of the experience with hepatitis B and Hib contain-ing vaccines introduction identifies risks and opportunities to bedealt with when considering introduction of new vaccines. Thosehave implications for the long-term sustainability of the strate-gies including future introduction of other important new vaccinesin resource-poor countries. The slowly evolving vaccine market,uncertainty related to GAVI support, unbalance of national immu-nization program budgets and limited national ownership of thedecisions are clearly identified here as major challenges. However,the analysis also identifies encouraging opportunities: 1/vaccineprices do tend to fall once there is market entry by multiple manu-facturers and in particular those from emerging economies, as GAVIsupport will continue until 2015 this may be long enough for pricesto decrease; 2/the budgetary process used with the cMYP pro-vides a rational means for financial planning in the broader healthsystem perspective; and 3/the inter-agency coordination commit-tees provide a platform that could possibly be used for greaternational ownership (building on ICCs to establish NITAGs). As thedemand and interest for other important new vaccines is increasingin resource-poor countries, it is urgent to address those issues inorder to ensure sufficient and affordable supply of those vaccines.The value of doing so is well recognized as the diseases that can beprevented incur a disproportionate burden in those countries whilethe potential impact and economic benefits are not questioned.

For national decision-makers, information about the overall

Eastern Mediterranean 0/3 (0%) 1/3 (33%)European 2/8 (25%) 0/4 (0%)South-east Asian 2/7 (29%) 1/1 (100%)Western Pacific 2/3 (67%) 1/4 (25%)

Total 10/56 (18%) 7/38 (18%)

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e an important element in deciding on vaccine introduction. Therice of vaccines tends to decrease with increased demand and reli-ble forecasting, when the number of manufacturers is increasing,lthough it will take longer than the period studied here for pen-avalent vaccines. Following the arrival of emerging manufacturerslarge drop in price per dose has been observed [15]. There is an

ndication that a similar trend will occur with pentavalent vaccine,hich had not decreased during the study period, as the averagerice for 2010 was below $3.00 for the first time.

Vaccine introduction results in substantial increase in the costsf national immunization programs that appear difficult to sustain.ib containing vaccines addition alone has been associated with aoubling increase in the program cost. In countries that introducedetravalent or pentavalent vaccines, vaccines are now the largestost component of national immunization expenditures. Financialupport for those budget items beyond the current GAVI commit-ent remains uncertain [8]. Government funding has been fairly

table (with some increase) but represents a decreasing proportionf the overall vaccines and immunization budget as new vaccinesre introduced. Among all donors, GAVI is expected to provide halff the resources projected by countries having introduced both newaccines. The recent communication of GAVI’s funding gap [16] isdramatic illustration of the countries vulnerability in the current

ituation. The new GAVI eligibility criteria that will lead countrieso a “graduation process” after they exceed a defined per capitancome level will also increase uncertainty [17].

In most countries studied, decision-making for vaccine intro-uction was essentially limited to partners forums (ICCs) to date. It

s likely that in several instances, decisions have been largely driveny funding availability and international immunization communityecommendations and support. NITAGs are a technical resourceupplying guidance to national policy makers and programmeanagers to enable them to make evidence-based immunization

elated policy and program decisions [18]. As such they providemechanism for policy making to reflect the long-term national

ommitment towards a new immunization strategy. Anchoredith local stakeholders, NITAGs provide a guarantee that policyecisions reflect the views of national experts who will likely bengaged with their program for the long term.

These findings have important implications for future newaccines introductions. Although traditional public health consid-rations (such as those described in the WHO vaccine introductionanual) remain important, national decision-makers must also

arefully examine actual evidence regarding the possibilities of sus-aining those new strategies over time. For technical partners anduppliers, there is a responsibility to provide national decision-akers with access to reasonable estimations about the prospects

or each vaccine market. This includes reliable timelines for suffi-ient supply, the mix of pre-qualified manufacturers and expectedrice trends. Equally important is a discussion of financing trends,

n other words an analysis of the mix of domestic and externalunding sources.

With respect to domestic funding, the value of immuniza-ion as an element that can reduce inequities towards health andtrengthen economic development should also be explored further19]. Better understanding of the value of vaccines as a povertyeduction tool could help develop higher expectations in communi-ies about immunization and enhance the priority given by decision

akers. Vaccine introductions should be supported by a broadase of national constituents to strengthen the local ownership ofhose decisions. In addition to NITAGs that represent one important

echanism to that effect, stronger national regulatory processesor ensuring the products quality and safety is another importantomponent for the local ownership of those strategies [20]. Suc-essful expansion of immunization programs to additional newaccines will require newer predictable and sustainable financing

9 (2011) 3149–3154 3153

mechanisms [21]. The evolving international development con-text, presenting contradictory and challenging trends such as globalfinancial crises, competing priorities, rich and expensive vaccinepipelines, new vaccine introduction and strengthening routine vac-cination is becoming and increasingly complex process.

As many more vaccine solutions than just hepatitis B and Hibcontaining products are now available [22], progress with con-trol of vaccine preventable diseases will require additional efforts.The current vaccine introduction model has shown its limitationsand risks. New approaches for promoting and financing vaccinesintroductions should be on the agenda of countries and partners.Possible ways forward will have to consider: 1/active effort toinvolve additional manufacturers into the markets by aggressivelyseeking ways to transfer technologies to developing country man-ufacturers; 2/extending GAVI support even longer than 2015 witha more substantial co-financing requirement; 3/helping countrieslook at adding new vaccines in the broader context of overall netcosts and the addition to national health spending, and 4/acceleratethe establishment of NITAGs.

Acknowledgements

The financial data in this manuscript were prepared by PatrickLydon. Authors are staff members of UNICEF and the World HealthOrganization. The authors alone are responsible for the viewsexpressed in this publication and they do not necessarily repre-sent the decisions, policy or views of UNICEF or the World HealthOrganization. Alan Hinman provided valuable editorial commentsand Marty Makinen provided significant advice for framing thediscussion with respects to risks, opportunities and ways forward.

All authors have completed the Unified Competing Interest format www.icmje.org/coi disclosure.pdf (available on request from thecorresponding author) and declare that (1) none have support fromindustry for the submitted work; (2) none have relationships withthat might have an interest in the submitted work in the previous 3years; (3) their spouses, partners, or children have no financial rela-tionships that may be relevant to the submitted work; and (4) nonehave non-financial interests that may be relevant to the submittedwork.

Role of the funding source: Authors are staff of WHO and UNICEF.They jointly designed and analyzed data available from their orga-nizations and agreed on interpretation and writing of the report.All authors had full access to the data and had final responsibilityfor the decision to submit for publication.

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