Making new vaccines affordable: a comparison of financing processes used to develop and deploy new meningococcal and pneumococcal conjugate vaccines

Transcription

1 Making new vaccines affordable: a comparison of financing processes used to develop and deploy new meningococcal and pneumococcal conjugate vaccines James R Hargreaves, Brian Greenwood, Charles Clift, Akshay Goel, Anne Roemer-Mahler, Richard Smith, David L Heymann Mechanisms to increase access to health products are varied and controversial. Two innovative mechanisms have been used to accelerate the development of low-price supply lines for conjugate vaccines. The Meningitis Vaccine Project is a so-called push mechanism that facilitated technology transfer to an Indian company to establish capacity to manufacture a vaccine. The Advanced Market Commitment for pneumococcal vaccines is a so-called pull mechanism that guarantees companies a supplement paid in addition to the purchase price for vaccines for a specific period. We compare these approaches, identifying key dimensions of each and considering their potential for replication. We also discuss issues that the Global Alliance for Vaccines and Immunisation (GAVI) face now that these new vaccines are available. Progress towards GAVI s strategic aims is needed and funding is crucial. Approaches that decrease the financial pressure on GAVI and greatly increase political and financial engagement by low-income countries should also be considered. Introduction Bill and Melinda Gates have committed US$10 billion to research, develop, and deliver vaccines for the world s poorest countries during the next decade. 1 However, as Margaret Chan, Director-General of WHO, commented in January, 2010, it is also absolutely crucial that both governments and the private sector step up efforts to provide life-saving vaccines to children who need them most. 1 Global health partnerships can help to bridge the public, private, and philanthropic sectors. But what strategies should these partnerships pursue? Whereas major scientific advances are sometimes needed to develop vaccines, such as for HIV and malaria, this is not always the case. Conjugate vaccines against Neisseria meningitidis and Streptococcus pneumoniae have been available since the 1990s, but affordable vaccines covering the strains of these bacteria that cause the greatest public health burden in low-income countries have not been available until recently (panel). Two global health partnerships the Meningitis Vaccine Project (MVP) and the Advanced Market Commitment for pneumococcal vaccines (AMC) sought to fill these gaps. Since these initiatives had sufficiently similar objectives, but took different approaches, we compare the key aspects of both and identify aspects of each that might be suitable for replication. We discuss issues facing the Global Alliance for Vaccines and Immunisation (GAVI) now that new vaccines are available. Neisseria meningitidis and Streptococcus pneumoniae in low-income countries S pneumoniae, the pneumococcus, is a leading cause of bacterial pneumonia and meningitis worldwide, causing about to 1 million deaths in children every year (figure 1). Although pneumococcal disease occurs in most countries, ten countries in Africa and Asia account for 61% of cases. 11 A variety of strains of the bacterium circulate, with the most important serotypes causing disease differing between countries. This is also the case for N meningitidis, the meningococcus. Outbreaks of meningitis that occur during the dry season nearly every year in one or more of the countries of the African meningitis belt, which stretches from Senegal to Ethiopia 12 (figure 2), are a major public health problem. Search strategy and selection criteria This paper is not a systematic review of the published work for the Meningitis Vaccine Project (MVP), Advanced Market Commitment (AMC), or the Global Alliance for Vaccines and Immunisation (GAVI). Rather, it is a critical comparison of these initiatives in terms of the development of each. The focus of the Review was therefore to obtain the key facts about the development of these initiatives. We made comparative assessment on this factual basis. The search strategy entailed three elements. First, we identified key documents from the websites of the initiatives we describe: MVP ( the vaccine AMC ( and GAVI ( org). Many of the references obtained are not peer-reviewed journal articles, but working papers and business documents (such as minutes of meetings) provided as online resources through these websites. Second, we contacted four key individuals involved in these initiatives and asked for direction to key resources and for facts to be checked. Third, we identified peer-reviewed journal articles through a search of PubMed between December, 2010, and April, Only a few PubMed-indexed papers directly name the MVP or AMC. We did not further systematically search these databases with wide search terms, but used PubMed to identify key papers when these were suggested to us and made use of the similar articles function in PubMed. We screened articles for relevance on the basis of their contribution of factual information, rather than summarising published opinions related to the initiatives. Lancet 2011; 378: Published Online June 9, 2011 DOI: /S (11) Chatham House Centre on Global Health Security, The Royal Institute of International Affairs, London, UK (J R Hargreaves PhD, C Clift PhD, A Roemer-Mahler PhD, Prof R Smith PhD, Prof D L Heymann MD); London School of Hygiene and Tropical Medicine, London, UK (J R Hargreaves, Prof B Greenwood MD, A Roemer-Mahler, Prof R Smith, Prof D L Heymann); and MSD Wellcome Trust Hilleman Laboratories, Delhi, India (A Goel PhD) Correspondence to: Dr James R Hargreaves, Faculty of Epidemiology and Population Health, London School of Hygiene and Tropical Medicine, Keppel Street, London WC1E 7HT, UK james.hargreaves@lshtm.ac.uk Vol 378 November 26,

2 Panel: Timeline of major events in the development of pneumococcal and meningococcal conjugate vaccines for low-income countries, First trial of a serogroup A+C meningococcal conjugate vaccine in the African meningitis belt (The Gambia) Successful trial of a serogroup A+C meningococcal conjugate vaccine in Niger 3 Major type A epidemic in meningitis belt: around cases and deaths 1997 International Coordinating Group (ICG) for polysaccharide vaccine procurement in the meningitis belt established 1998 First safety and immunogenicity studies of seven-valent pneumococcal conjugate vaccine (which later becomes Prevenar) Monovalent meningitis C conjugate vaccine adopted in routine childhood vaccination in UK, with successful control of serogroup C disease shown subsequently 5, Efficacy of seven-valent conjugate pneumococcal vaccine in American infants reported, with substantial herd effect of immunisation of infants shown subsequently 7, Launch of Meningitis Vaccine Project 2003 Efficacy of a nine-valent pneumococcal conjugate vaccine in South African infants reported Efficacy of a nine-valent pneumnococcal conjugate vaccine in Gambian infants reported 10 Phase 1 studies on MenAfriVac complete Quadrivalent ACYW135 meningococcal vaccine Menactra (Sanofi Pasteur, Lyon, France) licensed 2006 Routine infant immunisation with a seven-valent pneumococcal conjugate vaccine introduced in the UK 2007 AMC for pneumococcal vaccines pilot project launched 2009 GAVI agrees investment case for MenAfriVac ($370 million) AMC legal documents signed Rwanda and The Gambia introduce routine pneumococcal conjugate vaccination into their infant immunisation programmes, made possible by donations of Prevenar to GAVI 2010 GAVI allocates $30 million to support national MenAfriVac campaigns in Burkina Faso, Mali, and Niger MenAfriVac vaccination campaigns in Burkina Faso, Mali, and Niger Quadrivalent ACYW135 meningococcal vaccine Menveo (Novartis, Basel, Switzerland) licensed First AMC-supported delivery of pneumococcal conjugate vaccine in Nicaragua GAVI=Global Alliance for Vaccines and Immunisation. AMC=Advance Market Commitment. Major epidemics occur every years; in , at least people died. 13 Most of these epidemics are caused by meningococci belonging to serogroup A. Polysaccharide vaccines against these bacteria have been available for some time. However, they are not immunogenic in very young children, do not provide long-term immunity in children, and do not prevent nasopharyngeal carriage. 14,15 For N meningitidis, polysaccharide vaccines are shipped and deployed when an outbreak occurs. However, despite improvements in coordination, 16 reactive vaccination is usually only partly effective in containment of an outbreak. Polysaccharide-protein conjugate vaccines could help to reduce the public health burden caused by these pathogens. Major pharmaceutical companies, however, have focused on the development of vaccines for the profitable European and US markets. 10 years ago, conjugate vaccines produced by several companies were available for prevention of serogroup C meningitis in Europe, 5,6 but there was no conjugate vaccine available for the prevention of serogroup A meningitis in Africa. Similarly, the existing seven-valent vaccine to prevent pneumococcal disease did not contain conjugates that would protect against all the most important serotypes in countries that needed the vaccine most, nor was this vaccine affordable to these countries. Major pharmaceutical companies argued that they had had little incentive to invest in these products, since volumes and profit margins in developing country markets were likely to be small. Most low-cost pharmaceutical producers from developing countries did not have the technological capacity to develop conjugate vaccines. MVP In 2001, the Bill & Melinda Gates Foundation awarded $70 million to the Program for Appropriate Technology in Health (PATH) and WHO to establish the MVP and catalyse the development of a low-price conjugate vaccine for N meningitidis serogroup A, with the ultimate goal to eliminate meningitis as a public health problem in sub- Saharan Africa. 17 The project used a so-called push mechanism, with the provision of upfront funding to Vol 378 November 26, 2011

3 <10 10 < < < Figure 1: Pneumococcal deaths in children aged 1 59 months per children younger than 5 years (HIV-negative pneumococcal deaths only) Reproduced from reference 11, with permission from Elsevier. meet a specified target. The MVP used the funds to support clinical research activities (about $35 million), facilitate technology transfer and strengthen conjugate vaccine manufacture ($6 8 million) at the Serum Institute of India Ltd (SIIL, Pune, India), support other vaccine development partners ($8 million), and fund the partnership ($20 million). SIIL also invested $17 million to help to create a dedicated production facility for the new vaccine following the results of phase 1 studies. The project has successfully developed and assured a 10-year supply of a new monovalent N meningitidis serogroup A vaccine, MenAfriVac, at an initial price of $0 40 per dose. By early 2009, GAVI had channelled funds to support roll-out of the vaccine to more than 19 5 million individuals aged 1 29 years in Burkina Faso, Mali, and Niger. Introduction of this vaccine will replace the need for polysaccharide vaccines that are less effective, and should be cost saving even in the short term (data available on request from PATH). AMC for pneumococcal vaccines The pneumococcal AMC was formally agreed in 2007, as a so-called pull mechanism that uses market incentives to persuade companies to invest their own money in the development and manufacture of new vaccines for poor countries. 18 For the AMC pneumococcal pilot, the governments of Italy, the UK, Canada, Russia, and Norway, and the Bill & Melinda Gates Foundation, have committed $1 5 billion to incentivise manufacturers to produce a pneumococcal vaccine to meet a specified product profile including activity against serotypes 1, 5, Mauritania 3 4 million Senegal 12 8 million Côte d Ivoire 19 4 million Guinea 10 2 million Guinea-Bissau 1 8 million The Gambia 1 7 million Mali 15 2 million Niger 15 9 million Burkina Faso 14 9 million Northern Nigeria 60 million Southern Nigeria 83 million Benin 9 5 million Togo 6 8 million Ghana 23 9 million Chad 10 8 million Central African Republic 4 3 million Democratic Republic of Congo 65 million Sudan 39 4 million Figure 2: The meningitis belt Data are the estimated population of each country in Reproduced with permission from PATH ( path.org/menafrivac/meningitis-belt.php) with permission. Copyright 2011, Program for Appropriate Technology in Health (PATH). All rights reserved. and 14 the most frequent isolates in GAVI-eligible countries. 19 Companies that participate in the AMC make legally binding commitments to supply vaccines at a preagreed price (the tail price) after the donor funds have been spent. The AMC donor funds are used to supplement the tail price by paying a top up to manufacturers to bring the price to $7 0 per dose for 20% of supplies until the AMC funds are exhausted. 18 So far Pfizer and GlaxoSmithKline have each signed AMC contracts to Eritrea 5 million Ethiopia 85 million Uganda 33 3 million Kenya 38 million Meningitis belt country Hyperendemic country Non-meningitis belt country Vol 378 November 26,

4 Driven by public demand and government support Advanced price commitment MVP AMC Replicable in future GHPs? Key issues and remaining questions Yes Yes Essential GHPs need to ensure: continued donor engagement; that the priorities of low-income countries shape vaccine agenda; and that low-income countries commitment to vaccine access is strengthened $0 40* per dose for 10 years Maximum $3 50* per dose for 10 years (tail price) Deployed in both projects Technology transfer Yes No Multiple examples exist of which some are described in the text Advanced commitment to supplement purchase price No Yes Unknown in present format, although price supplementation remains central to GAVI and others strategy Price setting is complex and must aim for a minimum price while assuring long-term, stable supply Strengthening emerging and low-cost vaccine manufacturers seen as key to long-term lower prices; risks associated with sole suppliers (as for MenAfriVac) Might favour existing strong companies, entrench their position, and use donor funds to supplement profits; substantial donor commitment is needed; more research needed into effectiveness MVP=Meningitis Vaccine Project. AMC=Advanced Market Commitment for pneumococcal vaccines. GHP=global health partnership. GAVI=Global Alliance for Vaccines and Immunisation. *In both cases prices might rise with inflation over time under agreed rules. Table: Key features of MVP and AMC approaches to development and deployment of new vaccines for low-income countries and their potential for replication provide their new vaccines, PCV13 and PCV10, respectively, initially at the maximum tail price of $3 50. The first doses of new pneumococcal vaccines, supported by the AMC, were delivered in Nicaragua, Yemen, Guyana, and Kenya in late 2010 and early Comparison between the MVP and AMC approaches Public support The table shows the key features of the MVP and AMC approaches to development and deployment of new vaccines for low-income countries. Both the MVP and AMC supported vaccine advances for diseases that cause a substantial public health burden and economic cost in poor countries, and both were instituted because donor funds were leveraged to address these issues. Government support for a meningitis vaccine helped to launch the MVP after a request from African governments for assistance following the epidemic. In 2000, a summit of health ministers resulted in a declaration of support for efforts to develop a lowcost conjugate vaccine. 20 Support for the project was reaffirmed in September, 2008, at the WHO regional committee meeting in Yaounde, Cameroon. 21 Government support is also in place for an affordable pneumococcal vaccine. However, the evolution of the AMC was driven by advocates of innovative financing mechanisms from developed countries. First proposed by economist Michael Kremer, the AMC idea was taken up by the Centre for Global Development in Washington DC, with support from the Bill & Melinda Gates Foundation, and was endorsed in a speech by the then UK s Chancellor of the Exchequer Gordon Brown in November, Italy, as then Chair of the G7, had a key role in getting G8 finance ministers to commission the World Bank and GAVI to do the preparatory work for a pilot AMC. The UK Treasury helped to propel the scheme forward, as it had for another pilot financing mechanism, the International Finance Facility for Immunisation (IFFm). GAVI became the driver for both pilots, launched in 2006 (IFFm) and 2007 (AMC). To ensure informed public support for vaccines is crucial. Global health partnerships will have a growing role in maintaining the commitment of global health donors to vaccines, ensuring that new initiatives are driven by the priorities of low-income countries and strengthening these countries capacity to finance and prioritise vaccine purchase. An example of such work is the initiative of the Sabin Vaccine Institute, which aims to help governments to identify long-term sources of financing and assure a fiscally sustainable national immunisation programme. 23 Advance price commitment Both the MVP and AMC negotiated advance commitments from manufacturers to supply new vaccines at a low price once developed. MenAfriVac was initially sold at $0 40 per dose. This price, which will rise to incorporate inflationary pressures over time, is guaranteed for 25 million doses per year for 10 years. Pfizer and GlaxoSmithKline s new pneumococcal vaccines will be sold initially at $3 50 per dose under a contract to provide 30 million doses each year for 10 years. A supplement of $3 50 per dose is paid from the AMC for about 20% of doses until the donor commitment is exhausted. 18 The tail price could rise with inflation under agreed rules and after assessment by an independent body. 24 From the outset, the MVP sought an advance commitment to provide the vaccine at less than $0 50 per dose, which is close to the estimated manufacturing cost. The programme aimed for this price because governments of the countries of the African meningitis belt felt that any product priced at more than $1 00 per dose would be Vol 378 November 26, 2011

5 too expensive to roll-out. 17 The MVP initially tried but was unable to engage an industrialised country pharmaceutical company already producing conjugate vaccines to develop and supply a serogroup A meningococcal vaccine at an affordable price. 17 Although a product with low manu facturing costs could feasibly be developed in a relatively short time, pharmaceutical companies in Europe and the USA considered not only the costs of research and development but also the opportunity costs of manufacturing a product for developing countries markets to be too high. Ultimately, SIIL agreed to the price commitment in exchange for capital investment from the MVP fund to improve facilities for conjugate vaccine manufacture and technology transfer. From the outset, the AMC approach also sought to guarantee a low tail price for the vaccines that would be developed. The donors originally decided a price of $2 00, 25 which is still estimated by one critic of the AMC to be close to the cost of production. 26,27 However, subsequent analytical work resulted in the starting tail price offer being increased to a maximum of $3 50 on the grounds that this price gave a better incentive to existing and emerging manufacturers. 28 The costs of production are difficult to assess accurately because of commercial confidentiality and variability in methods for allocation of fixed and overhead costs. Both approaches were apparently successful in the short term in achievement of relatively low prices. Some argue, however, that the AMC process missed an opportunity to negotiate a tail price closer to the cost of production, as the MVP did. Whether the $3 50 price negotiated by the AMC will be low enough to sustain access in the long term, or high enough to induce participation by more than two manufacturers, is not yet known. However, the MVP approach also raised questions. Supply of the vaccine at such a low price might leave little incentive for SIIL to continue to produce MenAfriVac after the next 10 years, and the MVP might also have discouraged other innovators since they would be unable to compete with the $0 40 price. Further, a low-cost conjugate quadrivalent or pentavalent meningitis vaccine might ultimately be essential if elimination of meningitis epidemics is to be achieved. Although such products are available, 29 they are too expensive for GAVI or the countries of the meningitis belt at present. Despite the efforts of the MVP, who will supply such a product is unclear. The MVP has received funding from the UK Department for International Development (DfID) to support an expanded partnership with SIIL to develop a polyvalent meningitis protein-conjugate vaccine. Although that collaboration is in its early stages and the polyvalent vaccine will undoubtedly cost more than the monovalent MenAfricVac, the project intends to agree an affordable pricing structure in the same spirit as the original MVP project (personal communication, La Force M, PATH, Seattle, WA, USA). Technology transfer The MVP successfully coordinated a so-called technology transfer between the Center for Biologic Evaluations and Research (CBER) of the US Food and Drug Administration and SIIL. 30 CBER had experience with conjugation chemistry and provided technical support to SIIL in development of a low-cost manufacturing process. SynCo Bio Partners (Amsterdam, Netherlands) were brought into the partnership for contract manufacture of group A polysaccharide, and SIIL supplied tetanus toxoid as a carrier protein necessary for conjugation. By contrast, the AMC offers no provision for technology transfer to emerging suppliers. The transfer of key technologies can be crucial to support vaccine development. Transfer can be difficult to negotiate, however, because it is closely linked to intellectual property rights, and many technologies needed for vaccine development are subject to intellectual property. 31 In the case of the MVP, PATH negotiated a non-exclusive licence for the technology, which it then sublicensed to SIIL. Vaccine manufacturers do not usually accept a non-exclusive sublicence for a key production process; however, three key factors made this possible. First, no other manufacturer was interested in making the vaccine at such a low price. Therefore SIIL did not fear that the non-exclusivity of the licence would generate competition from other manufacturers. Second, PATH provided technical assistance and funds to SIIL for the necessary technology scale-up. Third, an exclusive licence would have been much more expensive because of greater up-front and royalty fees than for a non-exclusive licence. 30 The fact that the MVP was able to license the technology from a public institution, rather than a private company, might also have been crucial. Although the MVP initially approached a pharmaceutical company, BiosYnth (Sienna, Italy), to license the technology, this company did not remain involved throughout the project. 17 Strengthening of emerging and low-cost manufacturers should improve competition and reduce prices in the long term. This strategy was a strength of the MVP, although one unintended outcome of the project is that MenAfriVac is a de-facto sole supplier product, a fact that carries potential risks. Nevertheless, the combination of donor funds and technology transfer has been used in other vaccine development projects. For example, WHO s 2008 global pandemic influenza action plan facilitated the establishment of manufacturing capacity for influenza vaccines in several countries. 32,33 In 2010, GlaxoSmithKline announced an expanded technology transfer collaboration with the Brazilian institution FioCruz to develop and manufacture vaccines. 34 Finally, the Cholera Vaccine Initiative (CHOVI) facilitated transfer of the technology to make oral cholera vaccine to Shantha Biotechnics (Hyderabad, India). 35 Some argue too for a greater focus on public vaccine production. 36 By contrast, critics of the AMC argue that the partnership is skewed towards the interests of the existing Vol 378 November 26,

6 large manufacturers because it provides an incentive to scale up production of vaccines already in development and because it offers no technical support to strengthen low-cost vaccine manufacturers who might have difficulty competing. 37 Both existing AMC agreement holders and new entrants will be able to bid for additional amounts for the next 5 years during a new tender process in At present, 70% of the $1 5 billion has still to be applied for. Both SIIL and Panacea Biotech have registered to participate in the initiative, but when either will have a product eligible for the AMC is not known. Advance commitment to supplement purchase price The AMC offers an advance commitment to supplement the purchase price of new products once they have been developed. By contrast, although the MVP successfully secured a low price, it did not negotiate explicit commitments to purchase, or supplement the purchase of, the end product. In its original conception, an AMC was intended to mimic market incentives. It was postulated that a $3 billion AMC would encourage companies to undertake research towards vaccines for malaria, tuberculosis, or HIV, for which development was scientifically challenging, and that an AMC of this size could provide incentives for investment in research and development equivalent to those prevailing for vaccines meeting the needs of wealthier countries. 38 The idea of late-stage AMCs emerged later when the principal objective was to accelerate the widespread introduction of existing vaccines into markets of developing countries. Thus, the pneumococcal AMC was introduced when Wyeth (now part of Pfizer) and GlaxoSmithKline were in the final stages of developing conjugate vaccines that would provide protection against serotypes circulating in both developed and developing countries. At the time, Wyeth was already manufacturing the existing best selling seven-valent vaccine. The AMC was used to stimulate stages necessary for regulatory approval and investment in manufacture and distribution, so that these products could be made available to developing countries at a much lower price than in developed countries. 38 To our knowledge no plans are in place to replicate the AMC for either early-stage or late-stage research and development, although early AMC documents suggested an intention to start a larger AMC for a malaria vaccine. 39 The present financial situation worldwide has perhaps made the scale of the donor commitment needed seem daunting, and some are sceptical about the appropriateness of this mechanism to support early-stage research. 31,37 Debate about the success of the present pilot is likely to inform future decisions. A design and process evaluation to assess the efficiency and effectiveness of the pneumococcal AMC is planned for However, although the AMC itself might not be replicated, the principle of use of donor funds to contribute to the purchase price of vaccines alongside government money is central to GAVI s overall strategy. Challenges ahead The products supported by the MVP and AMC have the potential to profoundly affect public health. Yet substantial challenges lie ahead. Some of these challenges are scientific, with much to learn about the new vaccines as they are rolled out. Maintenance of public trust will also be essential. Perhaps even greater though are the political and economic challenges facing the roll-out of these vaccines. The MVP and AMC have spurred the development of new products at much lower prices than were previously available. But the experience of the two projects also draws attention to the vulnerability of the present system. In 2010, GAVI celebrated 10 years in which it spent $4 billion strengthening vaccine delivery systems and introducing new and underused vaccines to the poorest countries. 40 But GAVI is now faced with a shortfall of $3 7 billion. The planned introduction of MenAfriVac will use two strategies. First is an initial vaccination campaign of people aged 1 29 years (about 70% of a typical population in a meningitis belt country) to rapidly establish herd immunity. Second is the long-term introduction of the vaccine to protect new birth cohorts. Countries with high rates of routine immunisation could incorporate MenAfriVac into these programmes, whereas countries with low coverage could organise follow-up single-dose campaigns targeting young children every 5 years. The countries of the meningitis belt are, with some exceptions (eg, Nigeria, Cameroon, Ghana), among the poorest in the world. Many receive support from donors such as UNICEF in purchasing vaccines from the Expanded Programme on Immunisation (EPI), and all have received GAVI funds to support the introduction of new and underused vaccines. Donor funds, channelled through GAVI, were anticipated to support the initial roll-out campaigns of MenAfriVac across the African meningitis belt. In June, 2008, the GAVI board approved a meningitis investment case up to a total of $370 million. 41 This plan included the cost of national mass-immunisation campaigns ($246 million) and other activities to introduce the new vaccine, and $55 million to create an interim stockpile of polysaccharide vaccine. However, as a result of growing budget constraints, in 2008 the GAVI board could only approve the commitment of funds up to a maximum of $30 million to support roll-out of MenAfriVac in the three countries (Burkina Faso, Mali, and Niger) and stockpile funds. 42 In early 2011, GAVI approved funding for a further 35 million doses in Nigeria, Chad, and Cameroon (personal communication, La Force M, PATH, Seattle, WA, USA). Donor support was not intended to continue beyond the initial campaign. Ongoing dialogue suggested that immunisation committees of national governments Vol 378 November 26, 2011

7 should then manage the process of financing vaccination of subsequent birth cohorts with use of bilateral and country resources. African ministers of health pledged support for sustained use of the vaccine in the Yaounde Declaration in September, 2008, 21 and evidence of its effectiveness and the low price are hoped to support sustained use of the vaccine. The AMC seems to solve the difficulty of uncertain demand by providing a guarantee to purchase vaccines, but in reality the AMC funds guarantee only the supplement to the purchase price. Although manufacturers also commit to a tail price, there is no guarantee that there will be demand, which depends on the future finances available for vaccine purchase. Thus, the difference between the MVP and AMC approaches in terms of financing the demand for vaccine is more apparent than real. In fact, the AMC poses much greater challenges to GAVI than does the MVP with regard to its financial sustainability because of its magnitude. Whereas the AMC donors fund the $1 5 billion supple ment payable to manufacturers, GAVI itself (with a small contribution from recipient countries of $0 20 per dose for low-income countries) is expected to finance the actual purchase of the vaccines. As a result, GAVI s last published projection is that the AMC donors will disburse $844 million in , but only if GAVI itself spends a further $1 61 billion to finance vaccine purchase. The total cost of the AMC programme ($2 5 billion) would then amount to more than 35% of GAVI s total spending on vaccine programmes in that period. 43 After 2015, there are other threats to the AMC. The AMC was based on achievement of at least 200 million doses every year after a decade. However, GAVI has now adopted new policies which mean that countries with an annual per-head income exceeding $1500 will no longer be eligible for AMC or GAVI funding or to purchase vaccine at GAVI prices. Because this included some major countries, the viability of the AMC was threatened. GAVI s solution to this problem has been to allow countries in this position to continue nevertheless to access AMC funds and GAVI prices (the tail price), but only if they fully finance the purchase themselves. In that scenario GAVI estimates that 200 million doses will be given in 2020, 44 and the AMC funds can be fully used. However, this scenario assumes that graduated countries will be prepared to pay the full GAVI tail price. If not, demand from GAVI-eligible countries will fall to 100 million doses per year in the 2020s. 45 If no additional money is raised from donors then the GAVI-funded AMC expenditure alone could fall short by 68% or $1097 million. 46 The extent of GAVI s commitment to the AMC can be regarded as both a cause and effect of the situation. Although the AMC adds $1 5 billion to GAVI s income, GAVI estimates that between 2010 and 2030 it will, in addition, have to devote more than five times that amount ($8 1 billion) to subsidisation of country purchases, but only if countries also spend $6 2 billion on vaccine purchase. 45 Conclusions The MVP has brought a safe product to the market at a very low price, which should combat a public health problem affecting some of the poorest countries in the world. The AMC has accelerated the development and manufacture of pneumococcal vaccines at a cheaper price than ever before. GAVI has already supported the delivery of about 20 million doses of MenAfriVac and is committed to the roll-out of pneumococcal vaccines, assisted by the $1 5 billion generated by the AMC. These successes give hope to those who believe that global health partnerships can foster a more equitable global public health. Much work still needs to be done to encourage pharmaceutical manufacturers to invest in research into low-cost products for diseases affecting the poorest people. A range of innovative mechanisms such as prizes, a global health impact fund, and priority review vouchers are being investigated by a WHO-sponsored expert working group. 46 Product development partnerships are especially powerful in late-stage development; however, worryingly, investment in these partnerships decreased during Our research suggests that the MVP included components such as technology transfer, capacity building, and price setting from which future versions of an AMC might be able to benefit. But investment in research and development also poses challenges. GAVI continues to accelerate the uptake and use of underused and new vaccines, which was its first strategic aim for Thus, although GAVI did not sponsor the MVP, it was anticipated as central to the initial roll-out of MenAfriVac. GAVI s sponsorship of the AMC is also driven by this aim but has even larger resource implications. Despite GAVI s ambition and high levels of international support, it is unable to commit to financing the full roll-out of the new vaccines before the replenishment meeting in London in June, GAVI s role in bringing together the public, private, and philanthropic sectors is crucial but relies on growing investment from donors, engagement of pharmaceutical companies, and public support, which is a complex balance. For example, although GAVI s resource allocation is driven by demand from countries, some have argued that the presence of manufacturers on GAVI s board is a conflict of interest since the board s decisions are crucial in affecting the choices that countries can make. 49 Alongside continued support of GAVI, attention should also be given to other approaches such as increased co-financing of vaccines, tiered pricing, and revolving funds that could in the short term decrease the financial pressure on GAVI, and in the long term result in increased political and financial engagement by developing countries. Facilitation of the continued engagement of all stakeholders will probably be driven by its success in its Vol 378 November 26,

8 three other strategic aims for : to strengthen the capacity of integrated health systems to deliver immunisation; to increase the predictability of global financing and improve the sustainability of national financing for immunisation; and to shape vaccine markets so that they consistently deliver lower prices for vaccines. Contributors DLH and AG suggested the paper. JRH searched for articles and source information, coordinated inputs, and led the writing of the paper. BG contributed text on the epidemiology and control of N Meningitidis. CC contributed text on the AMC. AR-M contributed text on intellectual property issues. RS contributed text on global health partnerships. All authors contributed to writing and agreed the final draft. Conflicts of interest BG s institution has received a grant from PATH for research into a pneumococcal protein vaccine. CC has received consultancy fees from the WHO Department of Public Health, Innovation and Intellectual Property. AG was an employee of SIIL during the period discussed in the paper. All other authors declare that they have no conflicts of interest. Acknowledgments We thank Marc La Force (MVP), Suresh Jadhav (SIIL), Richard Adegbola (Bill & Melinda Gates Foundation), and Aurelia Nguyen (GAVI) who gave feedback on the paper. While the opinions expressed in the paper are those of the authors, these individuals have provided valuable feedback to help to ensure the accuracy of the information presented. During an internship at Chatham House, Arthy Santhakumar helped to proof read and fact check the report. References 1 Bill & Melinda Gates Foundation. Bill and Melinda Gates pledge $10 billion in call for decade of vaccines. Jan 29, gatesfoundation.org/press-releases/pages/decade-of-vaccines-wecannouncement aspx (accessed Dec 12, 2010). 2 Twumasi PA Jr, Kumah S, Leach A, et al. A trial of a group A plus group C meningococcal polysaccharide-protein conjugate vaccine in African infants. J Infect Dis 1995; 171: Campagne G, Garba A, Fabre P, et al. Safety and immunogenicity of three doses of a Neisseria meningitidis A + C diphtheria conjugate vaccine in infants from Niger. Pediatr Infect Dis J 2000; 19: Rennels MB, Edwards KM, Keyserling HL, et al. Safety and immunogenicity of heptavalent pneumococcal vaccine conjugated to CRM197 in United States infants. Pediatrics 1998; 101: Campbell H, Borrow R, Salisbury D, Miller E. Meningococcal C conjugate vaccine: the experience in England and Wales. Vaccine 2009; 27 (suppl 2): B Trotter CL, Andrews NJ, Kaczmarski EB, Miller E, Ramsay ME. Effectiveness of meningococcal serogroup C conjugate vaccine 4 years after introduction. Lancet 2004; 364: Black S, Shinefield H, Fireman B, et al. Efficacy, safety and immunogenicity of heptavalent pneumococcal conjugate vaccine in children. Northern California Kaiser Permanente Vaccine Study Center Group. Pediatr Infect Dis J 2000; 19: Whitney CG, Farley MM, Hadler J, et al. Decline in invasive pneumococcal disease after the introduction of protein-polysaccharide conjugate vaccine. N Engl J Med 2003; 348: Klugman KP, Madhi SA, Huebner RE, Kohberger R, Mbelle N, Pierce N. A trial of a 9-valent pneumococcal conjugate vaccine in children with and those without HIV infection. N Engl J Med 2003; 349: Cutts FT, Zaman SMA, Enwere G, et al, for the Gambian Pneumococcal Vaccine Trial Group. Efficacy of nine-valent pneumococcal conjugate vaccine against pneumonia and invasive pneumococcal disease in The Gambia: randomised, double-blind, placebo-controlled trial. Lancet 2005; 365: O Brien KL, Wolfson LJ, Watt JP, et al, for the Hib and Pneumococcal Global Burden of Disease Study Team. Burden of disease caused by Streptococcus pneumoniae in children younger than 5 years: global estimates. Lancet 2009; 374: LaForce FM, Ravenscroft N, Djingarey M, Viviani S. Epidemic meningitis due to Group A Neisseria meningitidis in the African meningitis belt: a persistent problem with an imminent solution. Vaccine 2009; 27 (suppl 2): B Harrison LH, Trotter CL, Ramsay ME. Global epidemiology of meningococcal disease. Vaccine 2009; 27 (suppl 2): B Trotter CL, Greenwood BM. Meningococcal carriage in the African meningitis belt. Lancet Infect Dis 2007; 7: Patel M, Lee CK. Polysaccharide vaccines for preventing serogroup A meningococcal meningitis. Cochrane Database Syst Rev 2005; 1: CD WHO International Coordinating Group (ICG) on Vaccine Provision for Epidemic Meningitis Control disease/meningococcal/icg/en/index.html (accessed May 18, 2011). 17 Jodar L, LaForce FM, Ceccarini C, Aguado T, Granoff DM. Meningococcal conjugate vaccine for Africa: a model for development of new vaccines for the poorest countries. Lancet 2003; 361: GAVI. Advanced Market Commitment for Vaccines fact sheet (accessed May 18, 2011). 19 Advance Market Commitments for Vaccines. Target Product Profile (TPP) for the Advance Market Commitment (AMC) for pneumococcal conjugate vaccines. Dec 18, vaccineamc.org/files/tpp_master_table.pdf (accessed April 18, 2011). 20 WHO delegates. Joint recommendations for the development and introduction of conjugate vaccines against meningococcal disease in the African and Eastern Mediterranean regions path.org/files/who-mening-joint-recs.doc (accessed May 18, 2011). 21 Ministers of Health of African countries of the meningitis belt. Yaounde Declaration on elimination of meningococcal meningitis type a epidemics as a public health problem in Africa. September, declaration.pdf (accessed May 18, 2011). 22 HM Treasury. Speech by the RT Hon Gordon Brown MP, Chancellor of the Exchequer at the BBC World Service Trust conference 24 November gov.uk/+/ speeches/press/2004/press_94_04.cfm (accessed May 18, 2011). 23 Sabin Vaccine Institute. Sabin Vaccine Institute convenes global colloquium on sustainable immunization financing. March 28, releases/2011/03/28/sabin-vaccine-institute-convenes-globalcolloquium-sustainable-im (accessed April 18, 2011). 24 Advance Market Commitments for Vaccines. Pneumococcal AMC Inflation Review Application Process. August, (accessed May 18, 2011). 25 Advance Market Commitments for Vaccines. Response of the AMC Donor Committee to the Interim Report of the Economic Expert Group response_2703.pdf (accessed May 18, 2011). 26 Light DW. Saving the pneumococcal AMC and GAVI. Human Vaccines 2011; 7: Light DW. GAVI s Advance Market Commitment. Lancet 2010; 375: AMC Implementation Working Group. Implementation Working Group Report presented to the AMC Donor Committee July 10th, July, IWG10JULY08_2_.pdf (accessed May 18, 2011). 29 Harrison LH, Mohan N, Kirkpatrick P. Meningococcal group A, C, Y and W-135 conjugate vaccine. Nat Rev Drug Discov 2010; 9: Brooke S, Harner-Jay CM, Lasher H, Jacoby E. How public private partnerships handle intellectual property: the PATH experience. In: Krattiger A, Mahoney RT, Nelsen L, et al, eds. Intellectual property management in health and agricultural innovation: a handbook of best practices. Oxford: MIHR, 2007: WHO. Public health,innovation and intellectual property rights. Report of the commission on intellectual property rights, innovation and public health. April, intellectualproperty/report/en/index.html (accessed May 18, 2011). 32 WHO. Global pandemic influenza action plan to increase vaccine supply: progress report Geneva: World Health Organization, Vol 378 November 26, 2011

9 33 WHO. WHO facilitates influenza vaccine technology transfer to developing countries. April 24, mediacentre/news/notes/2007/np18/en (accessed Jan 18, 2011). 34 GlaxoSmith Kline Press Release. GlaxoSmithKline and Fiocruz extend innovative collaboration to research and develop new medicines for neglected tropical diseases. November, htm (accessed May 18, 2011). 35 International Vaccine Institute. The Cholera Vaccine Initiative (CHOVI). May, program.html (accessed April 18, 2011). 36 Birn A-E, Lexchin J. The GAVI Alliance, AMCs and improving immunization coverage through public sector vaccine production in the global south. Human Vaccines 2011; 7: Light DW. Making practical markets for vaccines. Why I decided that the Center for Global Development Report, Making Markets for Vaccines, offers poor advice to government and foundation leaders. PLoS Med 2005; 2: e Levine R, Kremer M, Albright A. Making markets for vaccines: ideas to action. Washington DC: Center for Global Development, Advance Market Commitments for Vaccines. Technical working group on advance market commitments (AMCs) for vaccines. Second meeting, HM Treasury, London, 9th November November, Summary.pdf (accessed May 18, 2011). 40 Lee K, Harmer A. Ten years of the Global Alliance for Vaccines and Immunisation. BMJ 2010; 340: c GAVI. Minutes of GAVI Alliance and Fund Board meeting 25 June June resources/gavi_alliance_25_june_08_final_board_report.pdf (accessed May 18, 2011). 42 GAVI. Minutes of GAVI Alliance and Fund Board meeting 29 October Oct 29, governance/boards/reports/2008_10_29_gavi_alliance_board_ meeting.php (accessed May 18, 2011). 43 GAVI. GAVI financial forecast update November Nov 30, b_Financial_ Forecast_update.pdf (accessed May 18, 2011). 44 Advance Market Commitments for Vaccines. Strategic demand forecast (required supply) version March 11, (accessed May 18, 2011). 45 GAVI. Next steps on the pneumococcal AMC: accounting for the new context. June 16 17, resources/08 Next_Steps_on_the_Pneumococcal_AMC.pdf (accessed May 18, 2011). 46 WHO. Establishment of a consultative expert working group on research and development:financing and coordination. Geneva: World Health Organization, Policy Cures. G-Finder 2010 neglected disease research and development: is the global financial crisis changing R&D? London: Policy Cures, GAVI. GAVI press release. GAVI Alliance donors and partners agree to first pledging conference in June 2011 and announce early commitments. Geneva: GAVI, about/pledging_conference/index.php (accessed May 18, 2011). 49 Berman D, Malpani R. High time for GAVI to push for lower prices. Human Vaccines 2011; 7: 1. Vol 378 November 26,