Accelerating the Introduction of Rotavirus Vaccines into GAVI-Eligible Countries

Transcription

1 Accelerating the Introduction of Rotavirus Vaccines into GAVI-Eligible Countries Investment Case for GAVI Secretariat Submitted by PATH s Rotavirus Vaccine Program in collaboration with WHO and the US CDC October 2006 PATH 1455 NW Leary Way Seattle, Washington USA (206)

2 Contents Executive Summary...1 Part 1: The Proposed Investment...5 Section 1: Description of the Problem...5 1a. Disease description and burden...5 1b. The challenge...6 Section 2: The Objective...7 2a. The expected benefits...7 2b. Policy decisions needed to realize expected benefits...8 2c. Two investments...8 Section 3: Proposal Costs and Funding Needs...9 3a. Vaccine costs: GAVI subsidies b. Vaccine costs: Country co-payments c. Strategic and technical activities to support accelerated introduction...11 Section 4: Financial Sustainability...12 Part 2: Rationale for Investing...14 Section 5: Relevance to GAVI Objectives a. Alignment with GAVI priorities, milestones, and principles b. Target countries...15 Section 6: Expected Public Health Impact of the Investment a. Impact of the investment on burden of disease: Investment b. Impact of the investment on burden of disease: Investment c. Contribution to Millennium Development Goals d. Impact of the investment on burden of disease through 2025: Investments 1 and 2 combined...18 Section 7: Support for Accelerated Introduction a. Support activities, (Investment 1) b. Support activities, (Investment 2) c. Partners and responsibilities...23 Section 8: Constraints and Probability of Success a. Epidemiological and vaccine performance constraints b. Technical constraints c. Institutional constraints...25 Accelerating the Introduction of Rotavirus Vaccines into GAVI-Eligible Countries Page ii

3 8d. Social and cultural constraints e. Vaccine supply security and price f. Critical risks...27 Section 9: Economic Analysis a. Cost-effectiveness analysis b. Sensitivity analysis vaccine cost-effectiveness c. Sensitivity analysis vaccine impact d. Market analysis...31 Part 3: Monitoring and Evaluating Implementation...33 References...35 Annex 1: Annex 2: Annex 3: Annex 4: Annex 5: Annex 6: Annex 7: Annex 8: Annex 9: Annex 10: Annex 11: Annex 12: Key References about Disease and Disease Burden Supplementary Information on Other Interventions for Rotavirus Diarrhea Characteristics of the Two Licensed Rotavirus Vaccines List of GAVI-Eligible Countries by Investment Period Systems Costs Impact Analysis, Demand Forecasting, and Cost-Effectiveness: Methods and Assumptions Alternative Price and Co-financing Scenarios Estimated Vaccine Impact by Country Timeline Details of Activities to Support Accelerated Vaccine Introduction Technical Constraints Harmonization of Economic Analysis Methods for Rotavirus and Pneumococcal Vaccine Investment Cases Accelerating the Introduction of Rotavirus Vaccines into GAVI-Eligible Countries Page iii

4 List of Tables Table 1. Estimated GAVI funding associated with Investments 1 and 2 for Table 2. Estimated cumulative country co-payments associated with Investments 1 and 2 for Table 3. Current status of critical information influencing accelerated introduction of rotavirus vaccines...12 Table 4. Components of accelerated introduction support, Table 5. Addressing critical risks...27 Table 6. Cost per disability-adjusted life year (DALY) averted and cost per death averted for GAVI-eligible countries by region and totals...29 Table 7. Lives saved, DALYs averted, and health care visits averted per 1,000 infants vaccinated, by region and total for GAVI-eligible countries, over the period Table 8. Univariate sensitivity analysis for key variables for the cumulative cost per DALY averted when the price falls from $6.00 to $1.00 per dose over the projected period of 2007 to Table 9. Univariate sensitivity analysis of key variables and their impact on total number of lives saved...31 List of Figures Figure 1. Annual deaths from rotavirus, by region (adapted from Parashar, 2006)...6 Figure 2. Cumulative number of countries adopting rotavirus vaccine, by year: Investments 1 and Figure 3. Infants vaccinated and lives saved through Figure 4. Infants vaccinated and lives saved: Accelerating the Introduction of Rotavirus Vaccines into GAVI-Eligible Countries Page iv

5 Executive Summary The Investment Objective In GAVI-eligible countries, vaccination against rotavirus can prevent childhood deaths caused by the severe diarrhea and dehydration associated with rotavirus disease. By 2015, the use of rotavirus vaccines has the potential to save the lives of nearly 120,000 children per year. Looking beyond 2015, rotavirus vaccine introduction and use in GAVI-eligible countries can, by 2025, prevent nearly 225,000 deaths annually. It is estimated that over the period 2007 to 2025, rotavirus vaccines can, cumulatively: Prevent the deaths of nearly 2.4 million children; Prevent nearly 100 million hospitalizations and clinic visits; Save nearly $500 million in direct medical costs. Rotavirus is a disease of inequity. It infects nearly every child in the world before the age of five years; however, the risk of dying from rotavirus infection is disproportionately borne by children in the developing world. For example, for a child living in the United States, the risk of death due to rotavirus is 1 in 200,000, 1,2 while for a child living in Bangladesh, the risk is a thousandfold higher: 1 in ,4 The establishment of a financing policy for the subsidization of vaccine purchase by GAVI can significantly reduce this inequity. This document outlines a plan whereby staged investments by GAVI beginning in 2007 will lead to accelerated introduction of rotavirus vaccines in most of the world s poorest countries. The Disease Infants and young children with rotavirus infection suffer vomiting, fever, and diarrhea, and for children with severe disease, this combination of symptoms can progress to dehydration and death. An estimated 500,000 children die from rotavirus each year, and over 2 million are hospitalized with pronounced dehydration. 5,6 As noted above, the mortality and morbidity associated with rotavirus infection fall starkly and disproportionately on children in developing countries, with more than 90 percent of the deaths occurring in these countries. Treatment and prevention options that address other causes of diarrhea are significantly less effective for children with severe rotavirus disease. As a result, vaccines represent the best hope for preventing the most severe episodes of rotavirus infection, especially in impoverished regions where access to medical care is limited. Accelerating the Introduction of Rotavirus Vaccines into GAVI-Eligible Countries Page 1

6 The Vaccines Two orally administered, live, attenuated rotavirus vaccines, one manufactured by GlaxoSmithKline (GSK) and one by Merck & Co., have been demonstrated to be efficacious and safe in large-scale clinical trials conducted in North America, Latin America, and the European Union. On the basis of the respective studies, both products were licensed by either the US FDA or the European Medicines Evaluation Agency (EMEA) in In addition, one manufacturer applied for WHO prequalification in January 2006, and the other applied in September Efficacy and safety In 2005, WHO s Strategic Advisory Group of Experts (SAGE) recognized that use of rotavirus vaccines is appropriate in regions of the world where efficacy data has been generated. Further, SAGE acknowledged that the lessons of vaccine introduction and post-marketing surveillance from one region are relevant to other regions. Finally, efficacy data from Asia and Africa should be collected to inform decision-making at both the global and regional levels. Definitive studies evaluating the efficacy of these vaccines in impoverished populations in Asia and Africa are either underway or planned, the results from which are expected by Establishing the efficacy of live, attenuated rotavirus vaccines in representative populations in different regions of the world is important in light of regional differences in efficacy seen with earlier rotavirus candidates, as well as other orally administered, live, attenuated vaccines, including polio and cholera vaccines. Vaccine supply The manufacturers of the currently available vaccines, GSK and Merck, have indicated their willingness to immediately make their respective rotavirus vaccines available at tiered prices. It is estimated that the current manufacturing capacity of either one of these suppliers could provide vaccine supply to meet the anticipated demand in eligible countries through at least Several manufacturers based in developing countries have also initiated development of rotavirus vaccine candidates. Market availability for at least one of these products could begin as early as 2011 and market entry of additional products is projected through 2015, provided these companies have adequate development resources and demand for their products. Cost-effectiveness Rotavirus vaccines are either cost-effective or very cost-effective for all GAVI-eligible countries according to criteria established in the 2002 World Health Report. The cumulative cost per disability-adjusted life year (DALY) averted for the period is $30 for all regions combined, and the average cost per death averted is $600 or less for all regions combined, depending on the price of the vaccine. Accelerating the Introduction of Rotavirus Vaccines into GAVI-Eligible Countries Page 2

7 The Challenges Any widespread vaccine introduction effort in the poorest countries of the world will be challenging. This investment case examines critical risks that could delay or postpone the advancement of the global rotavirus agenda, including epidemiological and product performance constraints; technical, institutional, and cultural constraints; and risks to vaccine supply and price evolution. Activities are proposed to minimize delay and risk and offset many of these potential risks. The realization of the public health impact estimated in this investment case depends on a number of factors, many of which can be influenced by the policy decisions and investments made by GAVI in the coming years. With financial support from GAVI to subsidize the cost of vaccine purchase, as well as the strategic and technical work needed to ensure timely and successful introduction of rotavirus vaccines into country immunization systems, strong and sustained demand for the vaccine can be established. The creation of demand and the availability of financing to purchase these vaccines will actively stimulate the maturation of the market for these vaccines, a market characterized by multiple manufacturers from both industrialized and developing countries contributing adequate supply at affordable and sustainable prices. As a result, the children most vulnerable to the threat posed by rotavirus can realize the life-saving benefits that vaccines can provide. The Proposed Project To realize the public health impact of rotavirus vaccines, this investment case recommends that the GAVI Alliance establish a financing policy to subsidize the purchase of rotavirus vaccines in GAVI-eligible countries beginning in During the period 2007 to 2010, GAVI-eligible countries in Latin America and the European region are expected to apply for subsidization. The use of rotavirus vaccines in these regions will save lives as soon as the vaccines are introduced. In addition to saving lives in these countries, establishing a financing policy in 2007 is critical for catalyzing interest in rotavirus vaccines among international donors, vaccine suppliers, and countries. This interest will positively contribute to the accelerated development of a functioning market for these vaccines, including the achievement of an affordable and sustainable price for rotavirus vaccines. In the absence of this catalytic process, the maturation of the market for rotavirus vaccines will be prolonged, the global agenda slowed, and the public health impact of these vaccines diminished. A second investment decision by GAVI is expected in 2010 and will allow countries in Africa and Asia to apply for subsidization. By 2010, the efficacy of rotavirus vaccines in Asia and Africa will be known. In addition, the public health experience gained from the use of rotavirus vaccine in GAVI-eligible countries in Latin America and the European region, as well as the global experiences with these vaccines, will provide a critical foundation for informed decisionmaking. In addition to subsidizing vaccine purchase, GAVI will need to invest in strategic and technical activities beginning in These activities are critical underpinnings to the successful introduction and sustainable use of rotavirus vaccines. In order to maximize public health impact Accelerating the Introduction of Rotavirus Vaccines into GAVI-Eligible Countries Page 3

8 over time, these activities need to be funded and conducted simultaneously with the ongoing and planned clinical trial activities in Africa and Asia. The Proposed Costs Estimates of the funds required for vaccine subsidization were generated based on the demand forecasting model created for this investment case. The model presupposes a two-stage investment for GAVI, with one decision taken in November 2006 and the second in 2010, once the results from the first investment and from ongoing and planned Phase 3 clinical trials become available. Depending on the prices negotiated with the manufacturers of the rotavirus vaccines, the total costs for subsidy of vaccine purchase by GAVI from 2007 to 2010 are estimated in the range of $13 to $50 million. The costs associated with necessary strategic and technical activities from 2007 to 2010 are estimated at $38 million. Taken together, the investment by GAVI in rotavirus vaccines in this four-year period would be in the range of $51 to $87 million. It should be noted that once the decision is taken to invest in the subsidization of vaccine purchase for countries in Latin America and the European region, continued subsidization beyond 2010 will be required, regardless of whether GAVI decides in 2010 to provide subsidization for the remaining GAVIeligible countries. The costs to health systems for 13 countries adopting vaccine during the period are an estimated $21 million. The GAVI Board s previous commitments to strengthening health systems are expected to adequately support these costs, and thus no additional GAVI funding is requested. Given GAVI s financing policy in GAVI Phase II, countries are expected to co-finance new vaccine introduction. If the co-payment model used for pentavalent vaccine is applied to rotavirus vaccines, countries are expected to provide an estimated $5 million in co-payments between This document sets forth a comprehensive plan with the objectives of generating important evidence for informed decision-making and creating the necessary environment whereby rotavirus vaccines can join the other EPI vaccines in saving the lives of children in many of the world s poorest countries. Beginning in 2007, staged investments by GAVI will stimulate a cascade of events leading to the accelerated introduction and the maturation of the market for these life-saving vaccines. Accelerating the Introduction of Rotavirus Vaccines into GAVI-Eligible Countries Page 4

9 Part 1: The Proposed Investment Section 1: Description of the Problem 1a. Disease description and burden Rotavirus infection, the most common cause of severe dehydrating childhood diarrhea around the world, is particularly dangerous for young children in low-resource countries. A baby in rural India or in a periurban slum of Nigeria, who may have nutritional deficits or may not have ready access to the prompt and intensive medical care needed to treat the disease, is more likely to die from rotavirus than are other children in the industrialized world who suffer from this infection. Rotavirus disease usually begins with vomiting and fever followed by profuse watery diarrhea, which can persist for 3 to 8 days. A young infant can very quickly become dehydrated and listless, while the family anxiously tries to obtain help for their child. As the disease progresses, dehydration intensifies and abdominal pain adds to the misery. Because the vomiting can prevent successful administration of simple oral rehydration, hospitalization is required more often than for other diarrhea episodes. The severe dehydration and electrolyte imbalances from loss of body fluids can lead to death in just a few days after onset. 5,7 Although the predominant mode of transmission is fecal-oral, it appears that other modes of transmission may also be important, given the high rates of infection and the similarity of infection rates in the industrialized and developing worlds. 6 Of the nearly 11 million deaths that occur annually among children under the age of five years, diarrheal disease is the second leading cause. 3,8 Rotavirus infection is estimated to account for 29 to 45 percent of childhood diarrheal deaths globally, 3 and is therefore responsible for more than 500,000 deaths and 2 million hospitalizations of children under age five each year. 3,4 More than 90 percent of rotavirus-related deaths occur in Asia and Africa (see Figure 1). 3,4 In addition to causing loss of life, rotavirus puts a burden on health care systems and on families, particularly through medical costs and lost productivity for the adults tending sick children. 9,10 Abstracts of key references on rotavirus disease and its epidemiology are provided in Annex 1. Accelerating the Introduction of Rotavirus Vaccines into GAVI-Eligible Countries Page 5

10 Figure 1. Annual deaths from rotavirus, by region (adapted from Parashar, 2006) 3 Europe 11,838 United States and Canada 125 Latin America 18,981 Africa 229,701 Asia 289,354 1b. The challenge In contrast to many other diarrheal diseases, prevention and treatment options for rotavirus are limited. New vaccines represent the best opportunity for having a significant impact on this major cause of childhood mortality and illness, but they will not reach those who need them most unless public financing is made available to help countries initially pay for the vaccine and get the technical support they need for successful introduction. Other interventions While improved water and sanitation can lower the incidence of many diarrheal infections, the effect is less pronounced on rotavirus disease, as evidenced by the high incidence of rotavirus illness throughout the world, including countries with modern sanitation systems. Oral rehydration therapy (ORT) is normally effective in replacing the loss of fluids and electrolytes associated with diarrhea, if given early and in sufficient quantity. However, because rotavirus infection is associated with rapid onset of vomiting and severe diarrhea among infants and young children, the effectiveness of ORT as a treatment option is limited. The high rate of vomiting with rotavirus infection is likely to challenge the effectiveness of new oral zinc treatments as well. This leaves intravenous hydration as a mainstay, which requires expensive hospital care not readily accessible to impoverished families. Thus, vaccines are critical for impoverished regions, where resources and timely medical care are limited and where the consequences of infection can be most severe. Detailed information on other interventions for diarrheal disease is provided in Annex 2. Rotavirus vaccines Two live, oral, attenuated vaccines against rotavirus infection one based on a human, monovalent viral strain (GSK s Rotarix ) and one based on a multivalent, bovine reassortant Accelerating the Introduction of Rotavirus Vaccines into GAVI-Eligible Countries Page 6

11 construct (Merck s RotaTeq ) were licensed by WHO-recognized regulatory authorities in GSK s Rotarix vaccine was first approved in Mexico in 2004; it has since been approved by the EMEA in Europe in early 2006 and licensed in more than 70 countries. It has not yet been submitted to the US FDA for approval. Merck s RotaTeq was approved by the FDA and recommended for routine use by the US Advisory Committee on Immunization Practices in February 2006, and registration is proceeding in other countries. General product profiles for these two vaccines are presented in Annex 3. The currently available vaccines have favorable efficacy profiles based on data available to date. Efficacy and safety data associated with the GSK and Merck vaccines were collected primarily in the Americas and Europe. In addition to the protection against rotavirus-specific diarrhea, the vaccines demonstrated an unexpectedly high efficacy against gastroenteritis of any type, suggesting that either a substantial proportion of the diarrhea of unknown etiology is actually due to rotavirus, or rotavirus infection predisposes to other gastrointestinal infections, or both. Less is known about the efficacy of live, oral rotavirus vaccines in impoverished communities with heavy enteric disease burdens in Asia and Africa. GAVI-funded Phase 3 studies in Africa and Asia are either underway or planned, with results expected by In addition to the vaccines developed by multinational pharmaceutical companies, emerging market suppliers in India, China, Brazil, and Indonesia have begun development of their own rotavirus vaccine products. Based on interviews with manufacturers and a report from the Boston Consulting Group, 11 most products are in pre-clinical stages of development, but at least three have completed Phase 1 studies. The first of these products could be available as early as Currently, the development of a market for rotavirus vaccines in impoverished countries faces many risks, including inadequate financing, unpredictable demand, and competing vaccine priorities. Section 8 provides a detailed discussion of risks and constraints. Without GAVI financing for the purchase of vaccine and for the strategic and technical support needed for introduction, low-income countries will not be able to afford the full cost of rotavirus vaccines for years. Investments by GAVI beginning in 2007 are critical to accelerating not only the introduction and use of these life-saving vaccines, but also the development of a sustainable market in which countries express predictable demand and manufacturers offer vaccines at acceptable prices. In the absence of GAVI financial support, rotavirus vaccines will reach only children in high- and middle-income countries, and will not be widely available to the most vulnerable children in the poorest countries, where the disease burden is the greatest. Section 2: The Objective 2a. The expected benefits Investments by GAVI to provide financial subsidization for the purchase of rotavirus vaccines, and to support strategic and technical activities designed to ensure successful adoption and sustained use of the vaccine in GAVI-eligible countries, have the potential to save the lives of an estimated 2.4 million children by Accelerating the Introduction of Rotavirus Vaccines into GAVI-Eligible Countries Page 7

12 In addition, investments by GAVI have the potential to: Contribute to the achievement of Millennium Development Goal 4, by preventing 120,000 childhood deaths annually due to rotavirus disease by Prevent approximately 100 million severe rotavirus illnesses and their related outpatient visits and hospitalizations, with corresponding cost savings of nearly US $500 million between 2007 and Ensure equitable access to this life-saving vaccine in developing countries whose citizens would otherwise have to wait an estimated 10 to 15 years before having the opportunity to protect their children from this disease. Contribute to the goals of GAVI and the Global Immunization Vision and Strategy (GIVS) to accelerate introduction of new vaccines in the developing world, where more than 90 percent of the current rotavirus mortality burden exists. 2b. Policy decisions needed to realize expected benefits In order to realize these public health benefits, investments to subsidize the purchase of rotavirus vaccines and to provide essential strategic and technical support activities will be necessary. Specifically, it is recommended that GAVI establish a financing policy that allows eligible countries to apply for financial subsidization of the purchase price for rotavirus vaccines beginning in In addition, it is recommended that GAVI provide financial support for essential strategic and technical activities intended to ensure successful vaccine introduction and sustainable vaccination programs. 2c. Two investments This investment case recommends establishment of these financing policies by means of two separate investment decisions by GAVI. The first would provide subsidization to GAVI-eligible countries in Latin America and the European region beginning in The second GAVI decision, likely to be taken in 2010, would provide subsidization to countries in the African and Asian regions, once results from ongoing Phase 3 clinical trials in these regions are available and considered favorable for vaccine introduction. Annex 4 lists the individual countries within each proposed investment period. Throughout the remainder of this Investment Case, the subsidy requirements, the strategic and technical activities to support introduction and sustainability, and the projected health impact of rotavirus vaccine introduction are described in the context of these two separate but interrelated GAVI decisions: Investment 1 and Investment 2. Investment 1 Investment 1 involves establishment of a financing policy, beginning in 2007, that allows GAVIeligible countries in Latin America and the European region to receive financial support for the Accelerating the Introduction of Rotavirus Vaccines into GAVI-Eligible Countries Page 8

13 purchase of rotavirus vaccines. It is assumed that once a financing policy for the countries included in Investment 1 is established, GAVI will continue to make that subsidization available through 2015, independent of the later decision taken on Investment 2. The financing requested in Investment 1 also includes funding for strategic and technical activities to support introduction in the countries in these regions over the period 2007 to In addition to investing in strategic and technical activities to support introduction in Latin America and the European region, funds will be used to support activities in Africa and Asia to adequately prepare for accelerated introduction in these regions. To date, Latin America has been the focus of vaccine introduction. Rotarix (GSK) was first licensed in Mexico in 2004, and has now been introduced in Brazil, Panama, Venezuela, El Salvador, and specific states within Mexico. Plans for introduction of RotaTeq (Merck) are also underway. As a result, most GAVI-eligible countries in Latin America (Bolivia, Guyana, Honduras, and Nicaragua) are poised and ready for introduction of rotavirus vaccines. In addition to countries in Latin America, several GAVI-eligible countries in the European region (Georgia, Kyrgyzstan, Ukraine, and Uzbekistan) have also expressed significant interest in introducing rotavirus vaccines. The countries in this region have expressed their interest based on disease burden and the clinical trial results available to date. Investment 2 Assuming acceptable clinical trial results for vaccine efficacy and safety in Africa and Asia, countries in these regions will begin to introduce rotavirus vaccines as early as 2010, after trial data become available in 2009 and the WHO Scientific Advisory Group of Experts (SAGE) adopts a recommendation for the use of rotavirus vaccines in these regions. The financing request for subsidization presented for this second investment decision is estimated for the period 2011 to 2015 (end of GAVI Phase II). Investment 2 is far broader in scope, involving many more eligible countries. The estimated funding includes vaccine subsidies for all GAVI-eligible countries, as well as the strategic and technical activities required to accelerate introduction and sustained use of rotavirus vaccines during this time period. Section 3: Proposal Costs and Funding Needs To fully realize the public health benefits associated with the use of rotavirus vaccines in GAVIeligible countries, funding is requested for two separate categories: Vaccine costs Vaccine costs include GAVI subsidies to countries adopting between 2007 and The price of vaccine has not yet been negotiated with the manufacturers. As a result, the vaccine costs were estimated across a range of possible prices. Currently, the lowest public-sector price for rotavirus vaccines that is publicly known is $14 for a treatment course of the GSK product (two doses for this vaccine) in Brazil. Under the assumption that GAVI will be able to negotiate a price from the manufacturers lower than that of Brazil (a middleincome, non-gavi eligible country), the top of the range of prices was set at $12 per course. For illustrative purposes, the lower estimate was generated using $4 per course. Accelerating the Introduction of Rotavirus Vaccines into GAVI-Eligible Countries Page 9

14 Strategic and technical support costs Strategic and technical activities are necessary to ensure successful adoption and sustained use of rotavirus vaccines in GAVI-eligible countries. These costs are for activities specific to the introduction and sustained use of rotavirus vaccines and do not include the routine program costs that are required for the introduction of any new vaccine. Costs of strategic and technical support for the four-year period have been estimated at $38 million. Support costs for the five-year period are more difficult to estimate, and will depend upon findings from introduction efforts and clinical trials in Since represents both a longer period and a broader scale of vaccine introduction, costs are estimated at $42 million. The projected funding needs for each of these two categories for the two investment decisions are summarized in Table 1. Table 1. Estimated GAVI funding associated with Investments 1 and 2 for Vaccine costs for Investment 1 countries Vaccine costs for Investment 2 countries Strategic and technical support costs Years Years Total $13-$49 million $20-$88 million $33-$137 million $206-$690 million $206-$690 million $38 million $42 million $80 million Total $51-87 million $268-$820 million $319-$907 million Systems costs It is assumed that routine program costs have already been allocated in GAVI immunization services support (ISS) budgets (see Annex 5). 3a. Vaccine costs: GAVI subsidies Financing for the subsidization of the cost of rotavirus vaccines accounts for the majority of the required funding requested in this investment case. Through the front-loading of subsidies for the vaccines at a time when the price of the vaccines is high, compared to later prices that are expected to be lower when the market for these vaccines has matured, GAVI will ensure that children in developing countries will have equitable and timely access to these life-saving vaccines. The funding estimates for GAVI subsidization for the period 2007 to 2015 were generated based on a demand forecasting model and pricing assumptions. The results of the analysis are considered a base case scenario driven by key assumptions including projections of country adoption, initial price, and rate of price decline (see Annex 6 for description of demand forecasting model methods and assumptions). The base case scenario and associated assumptions represent one possible future outcome for the introduction and use of rotavirus vaccines. Realization of the base case scenario relies on factors that are under GAVI s control (e.g., establishing financing policies, developing a supply strategy, and negotiating prices with manufacturers) and factors that are not (e.g., outcome of efficacy studies of rotavirus vaccines in Africa and Asia). Alternative scenarios can also be generated by Accelerating the Introduction of Rotavirus Vaccines into GAVI-Eligible Countries Page 10

15 varying the key assumptions in the model. Comparing the outcomes of alternative scenarios to the base case is useful to support important policy analyses and decision-making for GAVI. According to the country adoption projections included in the estimated demand scenario, new countries will initiate vaccine introduction through 2018 (i.e., beyond the projected end of GAVI Phase II) and peak vaccine usage will be reached a few years later. 3b. Vaccine costs: Country co-payments In addition to the subsidization of vaccine costs provided by GAVI, countries are expected to contribute to the cost of vaccine purchase through co-payment. In July 2006 a proposal was made to the GAVI Alliance Board for a new vaccine financing policy for pentavalent vaccines that would require countries to co-finance the introduction of new vaccines in GAVI Phase II. While many details of this policy have yet to be worked out, GAVI-eligible countries would be stratified into four groups least poor, intermediate, and poorest, plus a group of fragile or post-conflict countries and similar co-financing requirements will be applied to the countries within each group. Estimated co-payments for these countries range from $0.00/dose for postconflict countries to $0.90/dose for the least poor. This co-financing policy was applied to rotavirus vaccines in order to estimate potential country co-payments. Table 2 below presents the cumulative co-payments for all adopting countries estimated using the model and the base case assumptions. Annex 7 provides detailed cofinancing assumptions used in these cost calculations. Table 2. Estimated cumulative country co-payments associated with Investments 1 and 2 for Country copayments Investment 1 Investment 1 Investment 2 Total $5 million $17 million $81 million $103 million It is acknowledged that for many countries, co-payment funds will be provided by bilateral donor contributions at the national level. It is also recognized that countries will be required to completely finance vaccine beyond c. Strategic and technical activities to support accelerated introduction Realizing the health impact described in this Investment Case will require not only a financing policy from GAVI to subsidize the cost of vaccine purchase, but also an investment in strategic and technical activities to support the accelerated and successful introduction of vaccine. Table 3 illustrates current critical information gaps that will delay introduction unless support activities are undertaken to fill these gaps. The ultimate objectives of these support activities will be to limit programmatic delays once GAVI funding for vaccine is available, and to ensure appropriate planning to achieve maximum public health benefit of the GAVI investment. Proposed support activities are fully outlined in Section 7 and are intended to complement ongoing rotavirus disease surveillance and control activities and routine vaccine program activities. Activities to Accelerating the Introduction of Rotavirus Vaccines into GAVI-Eligible Countries Page 11

16 support accelerated introduction will also explore, plan, and implement appropriate linkages between rotavirus vaccine introduction and other health system and policy strengthening activities. Table 3. Current status of critical information influencing accelerated introduction of rotavirus vaccines Region Adoption beginning (year) Number of GAVIeligible countries Disease Burden Level of Information About: Cost- Effectiveness Safety and Efficacy in Clinical Trials Postlicensure Safety and Effectiveness Human Resource and Health Systems Capacity Latin 2007 America Europe * + Asia * Africa * ++: Substantial information available. +: Partial information available. : Little or no information available. *Although data are not available for all key inputs, sensitivity analyses demonstrate that introduction remains cost-effective across a wide range of assumptions (See Section 9c). The majority of costs estimated for Investment 1 include costs to support introduction and sustained use of rotavirus vaccines for countries in Latin America and the European region through Costs are also included for activities from 2007 to 2010 required in preparation for a positive decision on Investment 2 and the subsequent accelerated introduction of rotavirus vaccines in Africa and Asia. The costs for strategic and technical activities that will be included in Investment 2 are for activities from 2011 to 2015 to support introduction and sustained use of rotavirus vaccines in Africa and Asia. Section 4: Financial Sustainability Although there are formidable challenges to achieving a financially sustainable rotavirus vaccine supply in the poorest countries of the world, the realization of this goal is well within reach. Both the global funding landscape and the rotavirus vaccine marketplace are conducive to financiallysustainable country vaccine programs. A GAVI financing policy for rotavirus vaccine subsidies will not only provide necessary funds for vaccine, but will serve as a catalyst for countries and suppliers, stimulating subsequent demand and supply, respectively. Unlike nearly all new vaccines and pharmaceutical products that typically have only one supplier with a single patented product, rotavirus vaccines are currently manufactured by two multinational corporations, and more than ten other manufacturers already have or are considering development of vaccine candidates. Accelerating the Introduction of Rotavirus Vaccines into GAVI-Eligible Countries Page 12

17 Rotavirus vaccines also have an advantage over some other vaccines in terms of the prospects for sufficient, affordable vaccine supply. Unlike malaria and some other diseases, rotavirus affects children across economic sectors throughout the world. For manufacturers of rotavirus vaccine, this translates to a broad market in both developed and developing countries. Large and diverse markets for vaccine products allow manufacturers to engage in tiered pricing from the beginning of the supply period and over time. In addition, emerging suppliers in India, China, Brazil, and Indonesia have begun development of their own rotavirus vaccine products. Market availability for at least one of these products could begin as early as 2011 and market entry of additional products is projected through 2015, provided these companies have adequate resources and demand for their product (see Section 9d). The critical importance of comprehensive Multi-Year Plan (cmyp) development for each adopting country cannot be underestimated. Even at the anticipated mature market price of $1.00 per dose, countries and their national donors must prepare to accept this financial commitment after the end of the subsidization period. However, all 13 Investment 1 countries in Latin America and the European region are categorized as intermediate or least poor countries by income, so are less likely to face significant challenges in taking responsibility for total vaccine price at market maturity, compared to many of the poorest countries in Africa and Asia. Finally, the possibility of a predictable, sustainable vaccine supply may not only provide adoption incentives to countries, but also produce additional benefits, including increased coverage. As countries experience a predictable supply of affordable vaccine, they will be able to make long-term decisions about investments in infrastructure that will enhance delivery efficiency and coverage for all vaccines. Accelerating the Introduction of Rotavirus Vaccines into GAVI-Eligible Countries Page 13

18 Part 2: Rationale for Investing Section 5: Relevance to GAVI Objectives 5a. Alignment with GAVI priorities, milestones, and principles Investing in the introduction of rotavirus vaccine is entirely consistent not only with GAVI s objectives but also with the General principles for use of GAVI resources as approved by the Board in mid Rotavirus vaccines will contribute to the GAVI mission of saving children s lives and protecting people s health through the widespread use of vaccines. It also complements GAVI s strategic objectives to improve access to sustainable immunization services and expand the use of all existing safe and cost-effective vaccines. Administering rotavirus vaccine during clinic visits for DTP vaccination achieves synergy by promoting delivery of other appropriate interventions at immunization contacts and supports national and international accelerated disease control targets for vaccine-preventable diseases. Rotavirus vaccine is one of the new priority vaccines that are the focus of the third core programmatic area for GAVI investment in country support. As one of the near-term vaccines, rotavirus vaccine is well matched to stated GAVI principles and priorities. Funding for this vaccine is consonant with the core principle of supporting countries in achieving the Millennium Development Goals, since it would clearly address Goal 4 by reducing child mortality rates. Widespread introduction of rotavirus vaccine, especially to those GAVI-eligible countries where the need is greatest, has the potential to substantially reduce child deaths due to diarrhea and thereby support the achievement of the Millennium Development Goal 4: to reduce by two-thirds the mortality rate of children under five. GAVI has strongly affirmed its intention to support nationally-defined priorities. At the Sixth International Rotavirus Symposium in 2004 in Mexico City, representatives from three GAVIeligible countries in Latin America were among the 16 Latin American country representatives who signed a declaration: We call upon PAHO and its Revolving Fund for the acquisition of vaccines to work together with bilateral and multilateral agencies, the Global Alliance for Vaccines and Immunization and the manufacturers of vaccines to facilitate the introduction of the rotavirus vaccine, as soon as it becomes available at affordable price for the countries in the region. 12 Investing in rotavirus vaccine further supports the WHO/UNICEF Global Immunization Vision and Strategy (GIVS) for by introducing new vaccines and offering the opportunity to integrate several diarrheal disease control strategies including rotavirus vaccines, ORT, and zinc treatment into a more comprehensive approach. Accelerating the Introduction of Rotavirus Vaccines into GAVI-Eligible Countries Page 14

19 5b. Target countries The order of adoption by GAVI-eligible countries has been estimated as part of a comprehensive demand forecast model. Among the factors contributing to the timing of adoption are: previous experience with newer vaccines such as Hib and hepatitis B, national immunization coverage rates, and country-specific burden of disease. See Annex 6 for demand forecast methods and results. Although all 72 GAVI-eligible countries could potentially adopt rotavirus vaccine given available funding and favorable trial results in Africa and Asia, it is expected that some countries will not adopt the vaccine during the project period due to political, social, or economic instability, or other priorities. In the base case analysis, it is assumed that there are eight GAVIeligible countries that will not introduce rotavirus vaccines. As outlined in Section 2, the remaining 64 GAVI-eligible countries are divided into two investments according to their estimated adoption timeline. Investment 1 includes 13 GAVIeligible countries in Latin America and the European region that would adopt rotavirus vaccine beginning in 2007, and Investment 2 includes 51 countries in Africa and Asia that would begin to introduce in (See Annex 4 for a list of countries included.) For each investment decision, GAVI will need to enact financing policies that provide financial subsidization of vaccine purchase for the respective regions. For a complete description of activities associated with Investments 1 and 2, see Section 7. The recommendation to consider two investment decisions is based on the following: The recommendation by SAGE that a regional and phased approach could be appropriate in those regions where successful Phase 3 trials have been undertaken, and provided that other elements such as appropriate infrastructure and financing mechanisms were available. 13 Regulatory approval has been granted by the EMEA for both currently available rotavirus vaccines. Approval has also been granted for at least one vaccine by several countries in Latin America, based on Phase 3 trials conducted in those regions. In addition, several countries in the European region have expressed interest in introducing rotavirus vaccines based on the available clinical data. One rotavirus vaccine manufacturer (GSK) has applied for WHO prequalification of its product, and it is expected to be prequalified by early The other (Merck) submitted the application in late 2006 for WHO prequalification of its product. Phase 3 trials are being conducted or planned to evaluate the efficacy of the two currently available rotavirus vaccines in representative (impoverished) populations in Africa and Asia. The results from these studies are expected by Based on these factors, it is recommended that GAVI enact a financing policy for the subsidization of rotavirus vaccine purchase for GAVI-eligible countries in Latin America and the European region beginning in A second policy decision regarding Investment 2 will need to be taken in If the results of the clinical trials in Africa and Asia demonstrate that efficacy of the current vaccines is not acceptable, then the policy decision for Investment 2 can be denied (go/no-go decision) or postponed until a more efficacious vaccine for those regions is Accelerating the Introduction of Rotavirus Vaccines into GAVI-Eligible Countries Page 15

20 available. In that case, the costs to GAVI and to the countries in these regions, as well as to their donors, will include only those associated with Investment 1. Figure 2. Cumulative number of countries adopting rotavirus vaccine, by year: Investments 1 and Investment 1 Countries (13 total) Investment 2 Countries (51 total) Figure 2 above shows the cumulative number of countries expected to adopt rotavirus vaccines, by Investment and by year. Twelve of the 13 Investment 1 countries introduce by 2009, while the 51 countries included in Investment 2 are expected to adopt between 2010 and The figure illustrates a steady increase in the total number of countries that will have rotavirus vaccine incorporated into their EPI system over time, starting with four countries in 2007 and finally reaching 64 countries in Section 6: Expected Public Health Impact of the Investment With GAVI funding to subsidize vaccine and the necessary strategic and technical activities to ensure maximum vaccine benefits, the global public health impact of rotavirus vaccine is significant and compelling. The incremental impact of the investments by GAVI associated with the base case scenario are presented in two ways: first, for the GAVI investment periods through 2015, and second, through The projections of public health benefit through a time period that extends beyond the end of GAVI Phase II are relevant for appreciating the potential extent of the impact of that investment. Similar to the concept of an economic investment, the public health return on the front-loading investment by GAVI for subsidization extends well beyond the actual period of the financing policy. Accelerating the Introduction of Rotavirus Vaccines into GAVI-Eligible Countries Page 16

21 6a. Impact of the investment on burden of disease: Investment 1 Vaccine introduction will have considerable impact on mortality and health care costs in Investment 1 (13 countries in Latin America and the European region). Introducing vaccine in these countries as a result of Investment 1 can, by 2015: Prevent the cumulative deaths of more than 30,000 children; Prevent more than 2 million hospitalizations and clinic visits; Save more than $11 million in direct medical costs. The benefits of Investment 1 go well beyond the reduction of mortality and savings of health care utilization in these regions. GAVI s signal to fund rotavirus vaccine as early as possible for Latin America and the European region will begin an essential process of country-level demand and subsequent manufacturer motivation to produce vaccine. In addition, valuable lessons learned in these early-adopter countries can greatly inform future introduction strategies in Investment 2. Without the catalytic and informative experiences from Investment 1, the benefits of Investment 2 would be delayed and likely reduced. 6b. Impact of the investment on burden of disease: Investment 2 With the momentum gained from vaccine introduction in Investment 1 countries, favorable results from African and Asian clinical trials, and a financing policy by GAVI, the potential benefits of rotavirus vaccine on Investment 2 countries are considerable. Introducing vaccine into Investment 2 GAVI-eligible countries can, by 2015: Prevent the cumulative deaths of 340,000 children; Prevent more than 12 million hospitalizations and clinic visits; Save more than $60 million in direct medical costs. The majority of the global health impact on disease burden is realized in Investment 2, primarily because it includes many more GAVI-eligible countries, with larger populations and a much greater share of the global burden of rotavirus disease. However, the benefits of Investment 2 are not to be considered on their own, as they are linked sequentially to Investment 1. Investments 1 and 2 were designed to fit within the GAVI policy decision points as described in Section 2. There is an assumed sequence to the decisions, i.e., that GAVI will enact a financing policy for rotavirus vaccines associated with Investment 1 in 2007 and then Investment 2 in c. Contribution to Millennium Development Goals Introduction of rotavirus vaccine can contribute to Millennium Development Goal 4: Reduce Child Mortality. Specifically the goal is stated as, Reduce by two thirds, between 1990 and 2015, the under-five mortality rate (from By 2015, it is Accelerating the Introduction of Rotavirus Vaccines into GAVI-Eligible Countries Page 17

22 expected that rotavirus vaccine will reduce childhood deaths by nearly 120,000 per year, a 2 percent contribution to overall Millennium Development Goals (see Figure 3). Figure 3. Infants vaccinated and lives saved through 2015 Infants Vaccinated (millions) Lives Saved (thousands) Infants Vaccinated Lives Saved 6d. Impact of the investment on burden of disease through 2025: Investments 1 and 2 combined The decisions associated with Investments 1 and 2 will have significant impact during the investment periods on both morbidity and mortality associated with rotavirus infection; however, the benefits of this investment will continue to grow and accrue over time as vaccine introduction continues and use is sustained. In fact, the very nature of investment involves paying for something now to reap the benefits in the future. Thus, it is of paramount importance to understand the impact of these investments on reductions in childhood morbidity and mortality in future years. To illustrate the long-term impact of rotavirus vaccine introduction and use, the base case scenario was extended to Introducing rotavirus vaccine into GAVI-eligible countries can, by 2025, prevent nearly 225,000 deaths annually. Cumulatively over this time period, the use of rotavirus vaccines is estimated to: Prevent the deaths of nearly 2.4 million children; Prevent nearly 100 million hospitalizations and clinic visits; Save nearly $500 million in direct medical costs. Figure 4 depicts the outcome of a GAVI investment in reaching children and saving lives. Accelerated introduction of rotavirus vaccines, clinically proven to be safe and effective, could save the lives of millions of some 2.4 million infants and children worldwide by See Annex 6 for a complete description of methods and calculations for expected outcomes of vaccine introduction. See Annex 8 for estimated vaccine impact by country. Accelerating the Introduction of Rotavirus Vaccines into GAVI-Eligible Countries Page 18

23 Figure 4. Infants vaccinated and lives saved: Infants Vaccinated (millions) Lives Saved (thousands) Infants Vaccinated Lives Saved Total Infants Vaccinated: 716 million Total Lives Saved: 2.4 million Hospital and Outpatient Visits Avoided: 93 million Section 7: Support for Accelerated Introduction 7a. Support activities, (Investment 1) In addition to implementing a financing policy beginning in 2007 for GAVI-eligible countries in Latin America and the European region (see Timeline, Annex 9), funding of strategic and technical activities is necessary to support accelerated introduction and widespread use of rotavirus vaccines in these countries and to prepare GAVI-eligible countries in Africa and Asia for future vaccine introduction. These technical and strategic activities have been designed to occur in parallel with ongoing Phase 3 trials. One of the important lessons learned from the recent history with new vaccine development and introduction is that activities to support the decision-making process around vaccine introduction must be considered simultaneously with vaccine development. Similar to the lengthy vaccine development and clinical testing process, it can take years to get a vaccine introduced into the sites most in need. In order to compress these timelines, several activities need to occur simultaneously with clinical trial activities to prepare for project demonstration and early adoption. Support activities needed during this period are grouped into three main components: 1. Support activities in GAVI-eligible countries in Latin America and the European region designed to initiate and sustain vaccine introduction in countries in those regions. These activities will also help catalyze future decisions to introduce vaccine and inform on best operational approaches to vaccine introduction in countries in Asia and Africa. Accelerating the Introduction of Rotavirus Vaccines into GAVI-Eligible Countries Page 19

24 2. Support activities in GAVI-eligible countries in Africa and Asia that will enhance decision-making capacity and prepare countries for best courses of action after completion of ongoing vaccine efficacy trials in these regions. 3. Global-level support activities to inform, influence, and help coordinate global policy and financing decisions. Specific activities for each component are detailed in Table 4, next page. Component 1: Activities in Latin America and the European region are focused in three major areas: 1. Enhanced Active Disease Surveillance. Continuation and expansion of rotavirus disease surveillance activities are necessary to confirm the morbidity of rotavirus in representative countries in the region, and to establish pre-introduction vaccine baselines for rotavirus disease incidence and strain distribution. The global and regional coordination of these activities, through the use of previously established surveillance networks with standardized protocols, laboratory worker training, and reporting systems will ensure necessary data precision and quality standards. The ultimate goal of these activities should be to build surveillance systems that can be integrated with other vaccine-preventable disease surveillance networks. (Further details on enhanced disease surveillance activities are contained in Annex 10.) 2. Post-marketing Surveillance. WHO advisory committees, including SAGE and the Global Advisory Committee on Vaccine Safety, recommend that post-marketing surveillance be conducted in countries introducing rotavirus vaccines. The objectives of post-marketing surveillance activities would be to monitor safety of vaccine with respect to intussusception and other adverse events and to assure that vaccine remains effective when taken from clinical trial conditions to widespread use in populations. Post-marketing surveillance activities would be designed to advance a region or countries within a region toward vaccine introduction or to provide evidence that will promote and sustain new vaccination programs in other countries or regions. (Further details on post-marketing surveillance activities are contained in Annex 10.) 3. Demonstration Projects. In 2005, WHO s Strategic Advisory Group of Experts (SAGE) recognized that use of rotavirus vaccines is appropriate in regions of the world where efficacy data has been generated. Further, SAGE acknowledged that the lessons of vaccine introduction and post-marketing surveillance from one region are relevant to other regions. Demonstration projects to evaluate the impact of rotavirus vaccines in early adopting countries under real-world conditions will be essential for introduction of rotavirus vaccine in countries in Africa and Asia and will complement clinical trial results. The information derived from demonstration projects will strengthen disease burden and effectiveness estimates in those early-adopting countries, particularly in the European region where such information is limited. Regional demonstration projects should be planned and implemented early to evaluate not only vaccine impact and safety, but also feasibility, real-world costeffectiveness and affordability under situations of rapid vaccine scale-up. (Further details on demonstration projects are contained in Annex 10.) Accelerating the Introduction of Rotavirus Vaccines into GAVI-Eligible Countries Page 20

25 Table 4. Components of accelerated introduction support, COMPONENT 1: Latin America and the European region Focus Areas Objectives Specific Activities Support rotavirus surveillance in sentinel sites preintroduction Design and implement surveillance for safety Design and implement vaccine effectiveness studies Continue rotavirus disease and strain surveillance postintroduction Disease Surveillance Post- Marketing Surveillance Demonstration Project Establish robust disease burden estimates and data on strain distribution to allow measurement of impact of introduction. Evaluate vaccine introduction Build and sustain confidence in vaccination programs Catalyze vaccine introduction in other countries and regions Identify potential strain replacement post-vaccination Identify logistical health system constraints to vaccine scale-up (human resource capacity, cold chain, transportation, integration of services) Provide real world costs and benefits Measure the reduction in disease burden (public health impact). Stimulate country and regional vaccine introduction efforts COMPONENT 2: Africa and Asia Focus Areas Objectives Specific Activities Disease Surveillance Confirm morbidity of rotavirus in representative countries in region to demonstrate need and stimulate demand for vaccine introduction Establish pre-vaccination disease incidence and strain distribution to allow measurement of impact of introduction Design and implement demonstration project Identify significant programmatic deficiencies in vaccine delivery and make recommendations for successful vaccine delivery strategies Identify and communicate results to allow countries to prepare for vaccine introduction Strengthen and expand rotavirus disease surveillance Train laboratory workers in rotavirus detection methods Communicate results to local and global public health communities Clinical Trials* Establish vaccine safety and efficacy in impoverished settings Design and implement clinical trials Identify and communicate vaccine safety and efficacy estimates Effectiveness Study Establish safety and effectiveness of human monovalent vaccine construct in impoverished settings in Asia COMPONENT 3: Global Activities Focus Areas Objectives Specific Activities Policy Development/ Support Financing Support Demand/ Supply Monitoring Project Management and Administration Strengthen expertise in decision-making for rotavirus and diarrheal disease control programs and policies Create favorable political/social environment for vaccine introduction Ensure appropriate and timely decisions so vaccine is made available as early as possible Procure adequate funding for key support activities at country, regional, and global levels Increase probability of sustainable vaccine supply Ensure overall coordination of rotavirus activities, strategic focus, global communication, and consensus building Ensure accountability for all funding, agreements, and results Design and implement effectiveness study Identify and communicate vaccine safety and effectiveness estimates Generate rotavirus and diarrheal disease information, tools, and guidelines for stakeholders in various media Organize meetings/workshops for key stakeholders Generate tools for rotavirus decision-making and planning Participate in processes to develop key consensus documents Further refine cost-effectiveness and, especially for planning support for introduction in Africa and Asia, vaccine investment estimates Identify and respond to additional funding sources for vaccine (e.g., Advanced Market Commitments) to augment GAVI funding and expand impact. Develop, refine, and disseminate strategic forecast of global market, supply, and demand Identify and disseminate key demand drivers Support Rotavirus Supply Working Group efforts with multinational and potential developing country suppliers Oversee administration of project activities Communicate with GAVI Board and other stakeholders on key project components Coordinate key partners performing different rotavirus-related activities Provide scientific/technical guidance as needed Develop contractual and budgetary agreements Coordinate communications of overall strategies and role of rotavirus within the context of other new vaccine introductions *These trials are already fully funded by GAVI through the original Rotavirus ADIP and a supplemental grant to the ADIP. Accelerating the Introduction of Rotavirus Vaccines into GAVI-Eligible Countries Page 21

26 Component 2: Activities in Africa and Asia are focused on complementing ongoing clinical trials in GAVI-eligible countries in those regions and preparing countries for decision-making once the results of these trials become available. 1. Enhanced Active Disease Surveillance. Similar to activities outlined in Component 1 (and Annex 10). 2. Vaccine Effectiveness Study. The ongoing clinical trial activities will provide Phase 3 efficacy data for a multivalent, bovine reassortant rotavirus vaccine construct (Merck s RotaTeq ) in impoverished settings in Africa and Asia, and for a human, monovalent rotavirus strain (GSK s Rotarix ) in Africa. However, only Phase 2 data will be available on the human, monovalent rotavirus strain in GAVI-eligible countries in Asia. As GSK licensure is expected in impoverished settings in Asia in the coming year, data from a Phase 4 effectiveness study in that setting could inform SAGE on the performance of this vaccine and accelerate vaccine uptake in that region of the world. In addition, designing the study to maximize practicality and simulate public health practices, and/or evaluate additional outcomes such as mortality reduction and herd immunity effects of the vaccine, would provide additional real world data to allow refined assessments of overall impact and cost. Component 3: Global level activities are focused in four major areas: 1. Policy Development/Support. Regional and global support is necessary to generate technical and program recommendations and guidelines, incorporating key lessons learned from strategic surveillance activities and demonstration projects in early adopter countries. Advocacy and awareness-building activities would be designed to create and strengthen regional and international expertise in decision-making for rotavirus and diarrheal disease control programs and policies. Additional key activities include organizing meetings and workshops for key stakeholders, developing decision-making/planning tools, and contributing to consensus documents. 2. Financing Support. Financing support is necessary to assure that GAVI, the G8, the World Bank, and other key donors have the necessary information to make decisions about funding rotavirus vaccines and vaccine programs. This will be accomplished through continued development and refinement of cost-effectiveness and vaccine investment estimates, using updated information on disease burden, vaccine safety and effectiveness, and health systems impacts. 3. Demand/Supply Monitoring. Demand/supply monitoring activities will increase the probability of a sustainable vaccine supply. Such activities include developing and refining strategic forecasts of supply and demand, and will involve collaboration and informationsharing with multinational and developing-country vaccine manufacturers. Required activities for demand refinement include country-level assessments of anticipated demand in countries that may adopt in the future as well as post-introduction assessments of early adopters. The latter activity will lead to a greater understanding of demand behavior. Credible demand estimates will be regularly communicated to vaccine suppliers throughout the country adoption period. Accelerating the Introduction of Rotavirus Vaccines into GAVI-Eligible Countries Page 22

27 4. Project Management. A coordinating body should be identified and funded to provide leadership for all activities and monitor their progress. The responsibilities of this coordinating body will include overseeing administration of project activities, communicating with the GAVI Board and other stakeholders on key components, coordinating the efforts and financing of key partners and subcontractors, and providing technical guidance as appropriate. The coordinating body will also need to work with other groups introducing new vaccines, particularly pneumococcal and Hib vaccines, so that all efforts are synchronized and projects can share their findings. 7b. Support activities, (Investment 2) In , the period financing cost estimates and strategy needs will be refined based on clinical trial results and accumulated experience from introduction in Latin America and the European region. Assuming successful clinical trial data in Africa and Asia and reassuring post-marketing surveillance information from Latin America and the European region, support activities will be focused in Africa and Asia and include postmarketing surveillance of vaccine safety and effectiveness, in addition to introduction of vaccine and continued support for enhanced disease surveillance. While the intent and design of these activities will be similar to those outlined in Table 4 above, the scope will be broader given the much larger number of GAVI-eligible countries in Africa and Asia. As in , globallevel activities and rigorous management of support activities will be necessary to assure efficient use of expertise, personnel, and funds (see Timeline, Annex 9). 7c. Partners and responsibilities Designing and implementing workplans to deliver the necessary strategic and technical support will require multiple public health partners working in a coordinated manner in close cooperation with the GAVI Secretariat. Together, the partners involved in this effort need to contribute a variety of skills and experiences, including both technical (e.g., disease surveillance; postmarketing surveillance; clinical trial design and conduct; policy development communication) and managerial (e.g., ability to work with multiple partners and create flexible working relationships to enhance each partner s varying strengths; effectively manage contracts and provide financial oversight; establish effective public-private partnerships; work within a project milestone framework). In addition to working closely with the GAVI Secretariat, it will be necessary to coordinate the strategic and technical activities together with WHO. WHO, through its global mandate from the countries, will play a role at both the global and regional levels in preparing and assisting countries with the decisions to introduce new vaccines and the potential implementation of rotavirus vaccine introduction. At the global level, WHO will facilitate policy development and support for rotavirus vaccine introduction through global- and regional-level advisory meetings and through the processes of vaccine pre-qualification and standardization of assays, related processes, and regulatory oversight of new vaccines. Generic standardized protocols for safety and surveillance for vaccine Accelerating the Introduction of Rotavirus Vaccines into GAVI-Eligible Countries Page 23

28 impact and AEFI (adverse events following immunization) are under development and will be initially field tested and implemented through a Global Sentinel Network in selected countries. At the regional level, WHO will facilitate and coordinate regional surveillance networks and develop a rotavirus-specific component within the Vaccine Preventable Diseases (VPD) Surveillance Framework for routine country-level surveillance as vaccines are introduced. Regional reference laboratories should be integrated into the VPD Surveillance Framework for support of the rotavirus-specific analysis and characterization. Additionally, regional strengthening and support for the national regulatory authorities will occur. Introduction of a new vaccine is accompanied by country-level activities including program support costs, EPI strengthening and training, routine AEFI surveillance, and routine VPD surveillance. Programmatic experience in vaccine introduction lies with the countries. Finally, cmyps will need to be developed and will include rotavirus and other new and under-utilized vaccine introduction. Section 8: Constraints and Probability of Success Any wide scale vaccine introduction effort in the poorest countries of the world will be challenging. This section discusses the most important constraints facing the activities outlined and suggests ways to mitigate them. Anticipating challenges and risks allows for advance planning and consideration of parallel activities that may offset some of their effects. 8a. Epidemiological and vaccine performance constraints Data deficiencies. The efficacy of rotavirus vaccines in impoverished settings in Africa and Asia is not yet known. However, Phase 3 clinical trials in these settings with the currently licensed vaccines are ongoing or will begin soon, and cost-effectiveness analyses have shown that rotavirus vaccine would be a highly cost-effective intervention even if the vaccines prevent only 50% of severe rotavirus disease. The testing of two different vaccine constructs increases the changes of having at least one cost-effective vaccine option for the developing world. In addition to the primary outcome of efficacy against severe rotavirus disease, the clinical trials have also been designed to answer important additional questions. Thus, even in a scenario in which the vaccine is not optimally efficacious, global understanding of rotavirus disease and prevention will increase, and future prevention efforts will advance. Annex 10 provides detail on activities designed to occur in parallel with Phase 3 trials. Adverse events following immunization. Safety surveillance is critically important to identify adverse events, including intussusception, that may manifest as vaccine is introduced in routine vaccination programs to large numbers of children with varied vaccine schedules. Cases of natural intussusception will occur by chance following vaccination, and will raise concerns about possible causal associations with vaccine. Therefore, systemic safety surveillance with strict quality standards is essential to identify rare adverse events, and to prevent misinterpretation of temporal results as causal, with loss of confidence in the vaccine program. Surveillance expertise and communication efforts are necessary commensurate to this risk (see Annex 10 for detail). Accelerating the Introduction of Rotavirus Vaccines into GAVI-Eligible Countries Page 24

29 8b. Technical constraints Competing priorities and affordability. A possible technical constraint is that of vaccines for multiple diseases becoming available for use in the near future with insufficient demand or capacity to absorb them. A coordinated effort is needed among groups working to introduce new vaccines, particularly rotavirus, pneumococcal, and Hib vaccines. The relative benefits and demand for each of these vaccines will differ by country and by region, and affordability will be a challenge. In order to optimize the provision of as many vaccines as possible for children who need them, coordination of the efforts of the various groups focusing on disease-specific vaccines will be vital in order to share results and lessons learned and to develop common messages that promote the optimal use of all vaccines. In addition, negotiation with multinational suppliers will be critical to achieving appropriate initial prices. Cold chain limitations. The vaccines produced by the two multinational manufacturers currently employ presentations and packaging that occupy significantly more space than traditional antigens and will be difficult for existing cold chain systems in developing countries to accommodate. For example, whereas multi-dose presentations of BCG, DPT, OPV, HepB, Hib and measles vaccines occupy <10 cm 3 per dose, the two current rotavirus vaccines by GlaxoSmithKline and Merck, occupy 123 cm 3 and 60 cm 3 per dose, respectively. Public and private sector collaboration will be needed to make changes in order to meet cold chain constraints in developing countries, and both manufactures have voiced a willingness to do so. For further information, please refer to Annex 11. Program constraints. GAVI-eligible countries are by definition among the poorest in the world and must cope with competing health problems, under-funded systems, and under-trained personnel all of which can limit the capacity to successfully absorb new vaccines. Improvements in coverage rates for all vaccines in GAVI-eligible countries would significantly increase the public health benefit that could be realized from the introduction and use of rotavirus vaccines. Funding constraints/financial sustainability. Identifying the financial resources necessary not only for the co-payment during the investment periods, but also the full costs of the vaccine, even at the market mature price, will be challenging for GAVI-eligible countries. Adequate supply. Development of vaccines by additional manufacturers beyond the two multinationals is vital to reducing vaccine cost over time and to ensuring adequate global supply. Efforts to encourage additional supply are underway outside the scope of this project. GAVI s commitment of funds will in itself provide significant motivation to vaccine manufacturers to scale up production and will encourage new manufacturers to enter the market. 8c. Institutional constraints GAVI. GAVI s own decision-making and administrative processes for establishing financing policies recommended in this Investment Case may introduce delays critical to vaccine introduction and other interdependent activities and timelines. At a minimum, delays could increase demand uncertainty for manufacturers and funding uncertainty for project implementers. Accelerating the Introduction of Rotavirus Vaccines into GAVI-Eligible Countries Page 25

30 WHO. Since the WHO prequalification process requires up to 18 months, any significant delays could lead to corresponding delays in the ability of UN agencies to purchase vaccine. WHO is working to remove any obstacles to timely prequalification. Coordinating body. In order to ensure the success of GAVI s investment in rotavirus vaccines, a coordinating institution must assume a central role, fully accountable for the success or failure of each activity, strategy, and partner contribution. This coordinating body must bring technical expertise, strong relationships with partner/affiliate institutions, accountability to GAVI, and the ability to manage and maximize funds and successfully coordinate multiple subcontracted partners. Above all, the coordinating body must be able to analyze results quickly and impartially, so that activities may be adjusted as needed and GAVI may fulfill its role of investing in vaccine and associated activities most likely to bring about widespread health improvement in poor countries. 8d. Social and cultural constraints Effective communication and managing expectations. Diarrheal disease is recognized as an important health problem for many of the GAVI-eligible countries; however, knowledge and awareness of rotavirus as an etiological agent of a large percentage of severe diarrheal episodes in infants and young children is low. At best, rotavirus vaccines will prevent only a portion of all acute, severe diarrhea, which is the easily recognized clinical syndrome. At the individual level, parents or physicians may falsely interpret a child who received rotavirus vaccine and then presents with diarrhea as a vaccine failure, even though the diarrhea is likely due to another cause. This highlights the need for developing communication strategies that place the role of rotavirus vaccines into an appropriate context of overall diarrheal disease management. Another way to manage this risk is to support research on improved point-of-care diagnostics for rotavirus infection. Such diagnostics, while technically feasible, are likely outside the scope of this project. 8e. Vaccine supply security and price Ensuring adequate supply to meet demand over time is a risk that all vaccine markets face, especially in the early years of market development. In the case of rotavirus vaccines, currently two multinational manufacturers have expressed interest in supplying their products to GAVIeligible countries at differential prices. In addition, several developing-country manufacturers are engaged in the development of vaccine products with constructs similar to those of the multinational manufacturers. At this point, there is insufficient clinical and country-demand evidence to establish a clear preference for one product, or category of products, over the other. The multinational manufacturers have signalled that meeting significant supply requirements (e.g., beyond 2011) would require capital investments to increase manufacturing capacity. Availability of supply would have a lead-time of 3-5 years from the time of the investment decision. The successful development of vaccines by additional suppliers beyond the two multinationals is vital to reducing vaccine cost over time and to ensuring adequate global supply. The expression Accelerating the Introduction of Rotavirus Vaccines into GAVI-Eligible Countries Page 26

31 of GAVI s commitment to the rotavirus market through the early establishment of a financing policy will motivate vaccine manufacturers to continue investing in product development and production scale-up, as well as encourage new manufacturers. In light of the strategic importance of ensuring adequate supply to meet demand at sustainable prices, GAVI should proactively develop and exercise a supply strategy that employs modern business tactics. 8f. Critical risks Table 5. Addressing critical risks (see also Annex 10) Risk Risk Rating Risk Minimization Serious adverse events are associated with one or both rotavirus vaccine constructs. One or both rotavirus vaccine constructs are not efficacious in preventing severe rotavirus gastroenteritis in developing countries. Gaps occur in GAVI funding at critical decision points: 2006 Investment 1 decision 2010 Investment 2 decision 2015 GAVI phase-out Clinical trial findings are incomplete due to unforeseen events (such as influenza Low probability with high consequence. In July 1999, a rhesus rotavirus tetravalent vaccine (RotaShield) was associated with development of intussusception among vaccine recipients in the US, leading to the suspension of vaccine use and ultimately the cessation of research and marketing activities worldwide. Large placebo-controlled clinical trials have not demonstrated an association between the current GSK and Merck rotavirus vaccines and intussusception. Given this reassurance, the potential for association with a serious adverse event is low, but real, as the vaccine is introduced to larger numbers of children. See further discussion in Annex 10. The consequences of a real or perceived risk are substantial, however, and highlight the need for monitoring, careful risk-benefit calculations, and crisis communication plans. Moderate probability with moderate consequence. Live, oral rotavirus vaccines may be less efficacious in impoverished populations due to host differences, higher prevalence of co-infections, sociocultural differences, or differences in rotavirus serotype distribution. However, even if rotavirus vaccines are only moderately efficacious (50%), the impact may be substantial, given the high incidence of rotavirus disease and its severe consequences in the developing world. See further discussion in Annex 10. Low to moderate probability, but high consequence. Activities could lose critical momentum in 2007 or 2010, causing delay in vaccine benefits to countries, or cause them to falter at the point where support from GAVI is replaced by other sources. Low to moderate probability, but high consequence. The investment is proposed in two stages to allow GAVI s careful consideration of findings before reinvesting in Surveillance activities are proposed to identify potential adverse events and prevent misinterpretation of findings. Risks may be offset somewhat by the fact that with two different vaccine constructs, one may prove unsafe, but not the other. Communication activities are proposed to disseminate accurate information, respond to inaccurate information, and develop appropriate messages in the event of a crisis. The investment is proposed in two stages to allow GAVI s careful consideration of findings before reinvesting in Risks may be offset somewhat by the fact that two different vaccine constructs are being tested. Clinical trials and proposed activities for technical support of GAVI s investment are designed to have identified some of the reasons why vaccines are ineffective, should they be found as such. Testing in multiple countries in two regions offsets concerns about lower efficacy in specific populations (e.g., high HIV prevalence). Communication: Even if the vaccine is not as efficacious as in other regions, it may still have a substantial impact. To minimize funding gaps in 2007: plan for the possibility of a one-year costextension of the rotavirus ADIP. 2010: compile what is known from clinical trials, with activities geared to multiple outcomes. 2015: focus on both supply and demand to ensure vaccines will be affordable and available. Mitigate risk by conducting trials in multiple sites. Plan for several possible trial outcomes, so that time is not lost. Accelerating the Introduction of Rotavirus Vaccines into GAVI-Eligible Countries Page 27

32 Risk Risk Rating Risk Minimization pandemic, political unrest). Over time, vaccine price fails to fall to $1. Low to moderate probability, but high consequence. After GAVI funding ends in 2015, demand may decrease substantially if price is unaffordable. 2007: Negotiate with multinational suppliers to achieve lowest initial price. Ongoing: Monitor emerging supplier progress in development and production to ensure timely availability of supply; advocate for additional support to accelerate these timelines if needed. Ongoing: Communicate closely with all manufacturers to ensure adequate supply for current and anticipated demand. Although any effort to introduce vaccines into some of the world s poorest countries will be challenging, balanced against the risks and constraints noted above is the extremely high cost of doing nothing. To help monitor project progress and provide for evaluation and course corrections, this investment case proposes a mid-term funding decision by GAVI in 2010, the point at which clinical trials outcomes will become known, early-adopter countries will have introduced rotavirus vaccines, and many proposed activities will be underway. For a detailed timeline of all proposed activities, see Annex 9. Section 9: Economic Analysis 9a. Cost-effectiveness analysis Vaccination of infants in low-income countries is considered cost-effective, 14 and rotavirus vaccine is no exception. In recent months, several cost-effectiveness studies of rotavirus vaccination have been conducted to estimate the health and economic impact of vaccination on populations in Asia, Latin America, and in low-and middle-income countries throughout the world. 9,10,15,16 All of the studies have concluded that rotavirus vaccination will be cost-effective when compared with well-established benchmarks such as the 2002 World Health Report. This report suggests that interventions with an incremental cost-effectiveness ratio cost per disability-adjusted life year (DALY) of less than the per capita Gross Domestic Product (GDP) are considered very cost-effective and those less than three times the per capita GDP are considered cost-effective. 17 Emory University has evaluated the cost-effectiveness of vaccine in GAVI-eligible countries. The estimates of cost-effectiveness (see Table 6) are based on a comprehensive set of parameters including rotavirus mortality estimates, vaccine efficacy, vaccine coverage rates, timing of vaccine, likelihood of vaccination in those most at-risk, direct treatment costs, and vaccine and related administration costs, as they change over time. A more detailed description of the methods employed in the cost-effectiveness analysis can be found in Annex 6, and a comparison of these methods to the pneumococcal vaccine cost-effectiveness analysis can be found in Annex 12. The rotavirus vaccine provides good value for the investment and is either cost-effective or very cost-effective for all GAVI countries. Using a price for GSK s 2-dose vaccine of $6 per dose, the rotavirus vaccine costs from $65 to $360 per DALY averted, depending on WHO region. At the projected market mature price of $1, rotavirus vaccine is very cost-effective for GAVI countries, Accelerating the Introduction of Rotavirus Vaccines into GAVI-Eligible Countries Page 28

33 ranging from $10 per DALY averted in Sub-Saharan Africa to $50 per DALY averted in the Eastern Mediterranean Region. Over the projected period 2007 to 2025, a rotavirus vaccine would cost $30 per DALY averted and $600 per death averted for all GAVI countries, capturing the cumulative costs and benefits of introducing the rotavirus vaccine. It is expected that during this time, Investment 2 countries with higher burden of disease will adopt the vaccine, and the price will fall to $1 per dose. At that price, rotavirus vaccines represent a very cost-effective and equitable intervention for GAVI-eligible countries in all regions of the world. Table 6. Cost per disability-adjusted life year (DALY) averted and cost per death averted for GAVIeligible countries by region and totals WHO Region Cost/DALY averted ($6.00/dose) Cost/DALY averted ($1.00/dose) Cumulative Cost/DALY averted for the period 2007 to 2025 Average per capita GDP* Cumulative cost per death averted for the period AMR $240 $15 $85 $900 $450 EUR $160 $20 $65 $1180 $700 AFR $65 $10 $20 $480 $380 EMR $360 $50 $20 $750 $500 SEAR $125 $25 $35 $740 $820 WPR $190 $30 $65 $580 $1,000 GLOBAL $100 $15 $30 $690 $600 *Weighted average 2005 GDP per capita for GAVI-eligible countries within each region and total. Source: IMF, World Economic Outlook Database, April 2006 Table 7 illustrates the impact of vaccine on disease and health-system burden, with estimates of the number of lives saved, DALYs averted, and health care visits averted per 1,000 infants vaccinated, by WHO region. It is important to note the variability in impact by region. There is more than a 3-fold difference between the region with the highest potential vaccine impact (AFR) and the lowest (AMR). This gap is largely driven by baseline rotavirus mortality in the regions, and is not a reflection of vaccine efficacy. Table 7. Lives saved, DALYs averted, and health care visits averted per 1,000 infants vaccinated, by region and total for GAVI-eligible countries, over the period Number of lives saved per 1,000 vaccinated DALYs averted per 1,000 vaccinated Number of hospitalizations and outpatient visits averted per 1,000 vaccinated WHO Region AMR EUR AFR EMR SEAR WPR GLOBAL Accelerating the Introduction of Rotavirus Vaccines into GAVI-Eligible Countries Page 29

34 These ratios are multiplied by the number of infants vaccinated (estimated from the demand forecast) to estimate the total impact of vaccine on lives saved, DALYs, health care visits and health care costs avoided (see Section 6). 9b. Sensitivity analysis vaccine cost-effectiveness Changes in assumptions for the key variables have very little impact on the cost-effectiveness of the rotavirus vaccine. Using the global estimate of cost-effectiveness for a rotavirus vaccine, univariate sensitivity analyses were conducted to assess the impact of variations in vaccine efficacy, rotavirus mortality, relative coverage, health system costs, and timing of the vaccination on the cost per DALY averted. Varying the estimates for the ranges shown in Table 8 demonstrates that the cost-effectiveness of the vaccine can decline to a low of $27 per DALY averted when rotavirus mortality is increased by 25 percent, or it can increase to $57 per DALY averted if vaccine efficacy is 50%. Even at the highest cost-effectiveness ratio of $57 per DALY averted, the rotavirus vaccine remains a very cost-effective intervention in GAVI eligible countries for the projected period of 2007 to Table 8. Univariate sensitivity analysis for key variables for the cumulative cost per DALY averted when the price falls from $6.00 to $1.00 per dose over the projected period of 2007 to 2025 Variable Base case value Range or alternate scenario Cost/DALY averted (range) Vaccine efficacy 85% 50%-100% $30 ($57 to $29) Rotavirus mortality Varies by country ± 25% $30 ($27 to $45) Relative coverage 90% 50% - 90% ($47 to $35) Health system costs 0.50/dose $0.25-$1.50 $30 ($27 to $50) Timing of vaccination Current On-time Current: $30 On-time: $27 9c. Sensitivity analysis vaccine impact Vaccine efficacy, baseline rotavirus mortality rates, relative coverage, and timing of vaccination are key drivers influencing the estimate of lives saved due to rotavirus vaccination. Although the base case scenario includes the best estimates for all of these variables, they are estimates, so it is important to subject the analysis to changes in key drivers and evaluate their impact on outcomes. Vaccine efficacy. Although initial results of Phase 2 trials in Asia look promising, there is still uncertainty regarding vaccine efficacy among impoverished populations in Africa and Asia at this time. Therefore, it is important to estimate the impact of a rotavirus vaccine with a range of efficacy values. The base case analysis assumes 85 percent efficacy based on existing clinical trial data from the GSK vaccine (range 70-94%). A broader range between 50% and 100% resulted in an estimated 1.4 to 2.8 million lives saved (see Table 9). Accelerating the Introduction of Rotavirus Vaccines into GAVI-Eligible Countries Page 30

35 Rotavirus mortality. Baseline disease mortality estimates for all countries were varied 25 percent higher and lower, resulting in a range of million lives saved. Relative coverage. Even in the worst-case scenario where only 50 percent of the children most at risk of dying from rotavirus were vaccinated, introduction would still save 1.7 million lives and efforts could simultaneously focus on reaching these children to maximize the impact. Timing of vaccination. If vaccines were given to infants on time (best case), according to labelling guidelines, an estimated 2.6 million lives could be saved compared to 2.4 million using current, real dosing behavior. Estimates of vaccine impact on lives saved remain significant and compelling for a range of values of key factors in the analysis. Table 9. Univariate sensitivity analysis of key variables and their impact on total number of lives saved Variable Base case value Range or alternate scenario Lives Saved Vaccine efficacy 85% 50%-100% 2.4 million ( million) Rotavirus mortality Varies by country ± 25% 2.4 million ( million) Relative coverage 90% 50% - 90% million Timing of vaccination Current On-time Current: 2.4 million On-time: 2.6 million 9d. Market analysis Realizing the public health gains of rotavirus vaccine requires that an adequate supply of efficacious, safe, and affordable vaccine be available to meet the demand from developing countries. To achieve this goal, it is critical that a functional market for rotavirus vaccines develop as quickly as possible. A mature market ideally includes several manufacturers from both developed and developing countries that contribute WHO-prequalified vaccines in sufficient quantities in a competitive fashion. Currently, the rotavirus market includes the participation of two multinational vaccine manufacturers, GSK and Merck. Both of the multinational manufacturers have signalled their interest in providing vaccine to GAVI-eligible countries at differential prices. The multinationals long-term commitment to provide adequate volume to meet demand of the GAVI-eligible countries is not entirely clear at this time; however, estimates of their manufacturing capacity and stated interests suggest that they could likely satisfy the estimated demand of fewer than 20 million doses total over the next 3 to 4 years. Both manufacturers have indicated a willingness to consider adding manufacturing capacity (i.e., fill-finish capacity) that could increase the available supply for developing-country markets; however, capital investments would need to be made with a lead time of 3-5 years before capacity was available. Both manufacturers have indicated that before such capital investments would be undertaken, strong signals from GAVI regarding long-term commitments to purchase vaccines (e.g., price-volume-time contracts) would be necessary. Accelerating the Introduction of Rotavirus Vaccines into GAVI-Eligible Countries Page 31

36 Emerging suppliers in India, China, Brazil, and Indonesia have begun development of their own rotavirus vaccine products. Potential candidates include the 116E monovalent strain under development by Bharat Biotech International, Ltd., the RV3 strain under development by BioFarma, and the UK bovine-human reassortant vaccine, which has been licensed for development by the US National Institutes of Health (NIH) to seven companies in Brazil, China, and India. The UK bovine-human reassortant vaccine has a profile similar to the Merck RotaTeq vaccine. Market availability for at least one of these products could begin as early as 2011 and market entry of additional products is projected through 2015, provided these companies have adequate resources and demand for their product. Supply is estimated to increase over time, with adequate product to meet GAVI-eligible country demand within eight years of initial market introduction. Through 2011, it is estimated that multinationals likely have capacity to meet the relatively modest demand of GAVI-eligible countries. To ensure adequate supply to meet projected demand in GAVI-eligible countries beyond this period, whether rotavirus vaccine is supplied by multinational or emerging suppliers or a combination of the two, it will be critical for GAVI to develop and implement a robust supply strategy beginning in 2006 in order to ensure adequate vaccine availability in the future. Accelerating the Introduction of Rotavirus Vaccines into GAVI-Eligible Countries Page 32

37 Part 3: Monitoring and Evaluating Implementation The ultimate goal of introducing rotavirus vaccine in developing countries is the measurable reduction of morbidity and mortality from rotavirus disease. Towards that end, there are various success and process indicators that should be measured, including vaccine impact and programmatic impact. Given that this may be a challenge, particularly in the early stages, a detailed evaluation plan should be carefully outlined by the coordinating body and partners responsible for vaccine introduction. Broad guidelines and indicators are proposed below. Investment 1 The goal of Investment 1 is to initiate the introduction process and catalyze broader, more accelerated introduction, particularly in Africa and Asia. Definition of success Rotavirus vaccine coverage meeting or exceeding a high percentage of DPT3 coverage by at least one year after introduction in all countries that introduce the vaccine by the end of Investment 1. Reduction in hospitalization for rotavirus demonstrated through use of standardized protocol in at least one country in each region Near the completion of Investment 1, a recommendation for rotavirus vaccine introduction from WHO s SAGE, and subsequently a global recommendation from the World Health Assembly. Milestones Addition of rotavirus to the WHO/UNICEF Joint Reporting Form. Standardized surveillance systems established in all GAVI-eligible countries in Latin America and the European region in order to determine rotavirus hospitalization rates pre- and postvaccine introduction, as well as mechanisms for adverse events reporting in place and underway in one or more countries in each of the two regions. Completion and dissemination of Phase 3 clinical trials results from Asia and Africa. Ongoing disease surveillance in Africa and Asia to establish rates and patterns of rotavirus disease pre-vaccine introduction. Applications by countries to GAVI for rotavirus vaccine funding. Logistical assessment completed in one or more countries in each region. Accelerating the Introduction of Rotavirus Vaccines into GAVI-Eligible Countries Page 33

38 Roles and responsibilities The coordinating body will be responsible for compiling the data from the surveillance teams. WHO and UNICEF will be responsible for reporting coverage data. WHO will be responsible for developing standardized protocols. Investment 2 Definition of success Within one year of introduction, rotavirus vaccine coverage that meets or exceeds a high percentage of DPT3 coverage in those GAVI-eligible countries in AFRO, SEARO, WPRO, and EMRO that choose to introduce the vaccine. Reductions in severe rotavirus morbidity and mortality proportionate to coverage demonstrated through use of standardized protocol in at least one country in each region. Successfully applying lessons learned from Investment 1 and making modifications to introduction process as needed. Milestones Standardized surveillance guidelines and protocols in place in countries. Refinements to cost-effectiveness estimates and introduction strategies based on Investment 1. Decision by countries to introduce rotavirus vaccine as expressed in multi-year plans and/or through applications to GAVI for vaccine funding. Standardized surveillance protocols established in all GAVI-eligible countries in AFRO, SEARO, WPRO, and EMRO in order to determine hospitalization rates pre- and post- vaccine introduction, as well as protocols for adverse events reporting in place and underway in one or more countries in each region. Applications by countries to GAVI for rotavirus vaccine funding. Introduction and availability of the vaccine. Logistical assessment done in one or more countries in each region. Roles and responsibilities The coordinating body will be responsible for compiling the data from the surveillance teams. WHO and UNICEF will be responsible for reporting coverage data. Accelerating the Introduction of Rotavirus Vaccines into GAVI-Eligible Countries Page 34

39 References 1 Parashar UD, Holman RC, Clarke MJ, Bresee JS, Glass RI. Hospitalizations associated with rotavirus diarrhea in the United States, 1993 through 1995: surveillance based on the new ICD-9-CM rotavirusspecific diagnostic code. J Infect Dis 1997;177: Glass RI, Kilgore PE, Holman RC, et al. The epidemiology of rotavirus diarrhea in the United States: surveillance and estimates of disease burden. J Infect Dis 1996;174 (Suppl 1):S5-S11. 3 Parashar UD, Gibson CJ, Bresee JS, Glass RI. Rotavirus and severe childhood diarrhea. Emerg Infect Dis 2006; 12(2): Parashar UD, Hummelman EG, Bresee JS, Miller MA, Glass RI. Global illness and deaths caused by rotavirus disease in children. Emerg Infect Dis 2003; 9(5): Dormitzer P. Rotaviruses. In: Mandell G, Bennett J, Dolin R, editors. Mandell, Douglas, and Bennett's principles and practice of infectious diseases. Philadelphia: Elsevier, 2005: Parashar UD, Bresee JS, Gentsch JR, Glass RI. Rotavirus. Emerg Infect Dis 1998; 4(4): Carlson JA, Middleton PJ, Szymanski MT, Huber J, Petric M. Fatal rotavirus gastroenteritis: an analysis of 21 cases. Am J Dis Child 1978; 132(5): Bryce J, Boschi-Pinto C, Shibuya K, Black RE. WHO estimates of the causes of death in children. Lancet 2005; 365(9465): Fischer TK, Anh DD, Antil L, Cat ND, Kilgore PE, Thiem VD et al. Health care costs of diarrheal disease and estimates of the cost-effectiveness of rotavirus vaccination in Vietnam. J Infect Dis 2005; 192(10): Podewils LJ, Antil L, Hummelman E, Bresee J, Parashar UD, Rheingans R. Projected costeffectiveness of rotavirus vaccination for children in Asia. J Infect Dis 2005; 192 Suppl 1:S133-S Boston Consulting Group. Final Report, Global Vaccine Supply, The Changing Role of Suppliers Rotavirus and Rotavirus Vaccines. Proceedings of the Sixth International Rotavirus Symposium, Mexico City: July 7-9, p See 14 World Bank. Investing in Health. The World Development Report Washington, DC, World Bank, 1993) 15 Walker, D. and R. Rheingans, Cost effectiveness of rotavirus vaccines. Expert Review of Pharmacoeconomics & Outcomes Research, (5): p Rheingans R, et al., Healthcare Costs of Rotavirus Gastroenteritis and Cost-Effectiveness of Vaccination in Developing Countries (unpublished), World Health Organization. World Health Report 2002: Chapter 5 - Some strategies to reduce risk. In: World Health Organizaton; p ) Accelerating the Introduction of Rotavirus Vaccines into GAVI-Eligible Countries Page 35

40 Annex 1 Key References about Disease and Disease Burden (1) Bresee JS, Parashar UD, Widdowson MA, Gentsch JR, Steele AD, Glass RI. Update on rotavirus vaccines. Pediatr Infect Dis J 2005; 24(11): Rotavirus was discovered in 1973, and 10 years later the first report of a rotavirus vaccine clinical trial appeared. This update reviews the epidemiology of rotavirus infections, assesses past and current vaccines and presents ideas for implementation of vaccination programs in developed and developing countries. (2) Bryce J, Boschi-Pinto C, Shibuya K, Black RE. WHO estimates of the causes of death in children. Lancet 2005; 365(9465): BACKGROUND: Child survival efforts can be effective only if they are based on accurate information about causes of deaths. Here, we report on a 4-year effort by WHO to improve the accuracy of this information. METHODS: WHO established the external Child Health Epidemiology Reference Group (CHERG) in 2001 to develop estimates of the proportion of deaths in children younger than age 5 years attributable to pneumonia, diarrhoea, malaria, measles, and the major causes of death in the first 28 days of life. Various methods, including single-cause and multi-cause proportionate mortality models, were used. The role of undernutrition as an underlying cause of death was estimated in collaboration with CHERG. FINDINGS: In , six causes accounted for 73% of the 10.6 million yearly deaths in children younger than age 5 years: pneumonia (19%), diarrhoea (18%), malaria (8%), neonatal pneumonia or sepsis (10%), preterm delivery (10%), and asphyxia at birth (8%). The four communicable disease categories account for more than half (54%) of all child deaths. The greatest communicable disease killers are similar in all WHO regions with the exception of malaria; 94% of global deaths attributable to this disease occur in the Africa region. Undernutrition is an underlying cause of 53% of all deaths in children younger than age 5 years. INTERPRETATION: Achievement of the millennium development goal of reducing child mortality by two-thirds from the 1990 rate will depend on renewed efforts to prevent and control pneumonia, diarrhoea, and undernutrition in all WHO regions, and malaria in the Africa region. In all regions, deaths in the neonatal period, primarily due to preterm delivery, sepsis or pneumonia, and birth asphyxia should also be addressed. These estimates of the causes of child deaths should be used to guide public-health policies and programmes. (3) Cunliffe NA, Kilgore PE, Bresee JS, Steele AD, Luo N, Hart CA et al. Epidemiology of rotavirus diarrhoea in Africa: a review to assess the need for rotavirus immunization. Bull World Health Organ 1998; 76(5): Rapid progress towards the development of rotavirus vaccines has prompted a reassessment of the disease burden of rotavirus diarrhoea in developing countries and the possible impact of these vaccines in reducing diarrhoeal morbidity and mortality among infants and young children. We examined the epidemiology and disease burden of rotavirus diarrhoea among hospitalized and clinic patients in African countries through a review of 43 published studies of the etiology of diarrhoea. The studies were carried out from 1975 through 1992, and only those in which a sample Annex 1 Accelerating the Introduction of Rotavirus Vaccines into GAVI-Eligible Countries Page A1-1

41 of more than 100 patients with diarrhoea were specifically screened for rotavirus by using an established diagnostic test were included. Rotavirus was detected in a median of 24% of children hospitalized for diarrhoea and in 23% who were treated as outpatients; 38% of the hospitalized patients with rotavirus were < 6 months and 81% were < 1 year of age. Rotavirus was detected year-round in nearly every country and generally exhibited distinct seasonal peaks during the dry months. In 5 countries where rotavirus strains had been G-typed, 74% of strains were of one of the four common serotypes (G1 to G4), G1 was the predominant serotype, and 26% were non-typeable. This cumulative experience from 15 African countries suggests that rotavirus is the most important cause of severe diarrhoea in African children and that most strains in circulation today belong to common G types that are included in reassortant vaccines. Wherever large numbers of cases of rotavirus diarrhoea occur early in infancy, immunization at birth may protect the children before their first symptomatic infection. (4) Glass RI, Parashar UD. The promise of new rotavirus vaccines. N Engl J Med 2006; 354(1): (5) Kane EM, Turcios RM, Arvay ML, Garcia S, Bresee JS, Glass RI. The epidemiology of rotavirus diarrhea in Latin America. Anticipating rotavirus vaccines. Rev Panam Salud Publica 2004; 16(6): OBJECTIVE: To assess the disease burden and characterize the epidemiology of rotavirus diarrhea in Latin America. METHODS: We conducted a literature review of studies of children < 5 years of age who were hospitalized or seen as outpatients for diarrhea and for whom rotavirus was sought as the etiologic agent of the diarrhea. This review included inpatient and outpatient studies published since 1998 that included at least 100 children and reported surveillance activities lasting at least 12 consecutive months. RESULTS: A total of 18 inpatient and 10 outpatient studies met the criteria for inclusion in this review. Rotavirus was detected in a median of 31% of inpatients (range, 16%-52%) and 30.5% of outpatients (range, 4%-42%). The median detection rate was higher in studies that used an enzyme-linked immunosorbent assay (ELISA) (inpatients 38%, outpatients 33%) versus less sensitive methods of detection. The age distribution of rotavirus disease varied among countries, with 65%-85% of children hospitalized in the first year of life. Most countries had rotavirus admissions year round, and rotavirus generally exhibited a winter seasonal peak in both temperate and tropical climates. CONCLUSIONS: The heavy burden of disease attributable to rotavirus in Latin America suggests that vaccines currently being tested could have considerable impact in preventing hospitalizations, clinic visits, and deaths. The findings of the young age distribution of patients highlight the importance of early immunization for the success of a vaccine program. The data suggest that future surveillance for rotavirus diarrhea in Latin America should use a standardized surveillance protocol with an ELISA for detection. Data from surveillance studies will be critical to monitor the impact of the future introduction of vaccines. (6) Parashar UD, Gibson CJ, Bresse JS, Glass RI. Rotavirus and severe childhood diarrhea. Emerg Infect Dis 2006; 12(2): Studies published between 1986 and 1999 indicated that rotavirus causes approximately 22% (range 17%-28%) of childhood diarrhea hospitalizations. From 2000 to 2004, this proportion increased to 39% (range 29%-45%). Application of this proportion to the recent World Health Organization estimates of diarrhea-related childhood deaths gave an estimated 611,000 (range 454, ,000) rotavirus-related deaths. Annex 1 Accelerating the Introduction of Rotavirus Vaccines into GAVI-Eligible Countries Page A1-2

42 (7) Podewils LJ, Antil L, Hummelman E, Bresee J, Parashar UD, Rheingans R. Projected costeffectiveness of rotavirus vaccination for children in Asia. J Infect Dis 2005; 192 Suppl 1:S133-S145. BACKGROUND: New rotavirus vaccines may soon be licensed, and decisions regarding implementation of their use will likely be based on the health and economic benefits of vaccination. METHODS: We estimated the benefits and cost-effectiveness of rotavirus vaccination in Asia by using published estimates of rotavirus disease incidence, health care expenditures, vaccine coverage rates, and vaccine efficacy. RESULTS: Without a rotavirus vaccination program, it is estimated that 171,000 Asian children will die of rotavirus diarrhea, 1.9 million will be hospitalized, and 13.5 million will require an outpatient visit by the time the Asian birth cohort reaches 5 years of age. The medical costs associated with these events are approximately 191 million US dollars; however, the total burden would be higher with the inclusion of such societal costs as lost productivity. A universal rotavirus vaccination program could avert approximately 109,000 deaths, 1.4 million hospitalizations, and 7.7 million outpatient visits among these children. CONCLUSIONS: A rotavirus vaccine could be cost-effective, depending on the income level of the country, the price of the vaccine, and the cost-effectiveness standard that is used. Decisions regarding implementation of vaccine use should be based not only on whether the intervention provides a cost savings but, also, on the value of preventing rotavirus disease-associated morbidity and mortality, particularly in countries with a low income level (according to 2004 World Bank criteria for the classification of countries into income groups on the basis of per capita gross national income) where the disease burden is great. (8) Ruiz-Palacios GM, Perez-Schael I, Velazquez FR, Abate H, Breuer T, Clemens SC et al. Safety and efficacy of an attenuated vaccine against severe rotavirus gastroenteritis. N Engl J Med 2006; 354(1): BACKGROUND: The safety and efficacy of an attenuated G1P[8] human rotavirus (HRV) vaccine were tested in a randomized, double-blind, phase 3 trial. METHODS: We studied 63,225 healthy infants from 11 Latin American countries and Finland who received two oral doses of either the HRV vaccine (31,673 infants) or placebo (31,552 infants) at approximately two months and four months of age. Severe gastroenteritis episodes were identified by active surveillance. The severity of disease was graded with the use of the 20-point Vesikari scale. Vaccine efficacy was evaluated in a subgroup of 20,169 infants (10,159 vaccinees and 10,010 placebo recipients). RESULTS: The efficacy of the vaccine against severe rotavirus gastroenteritis and against rotavirus-associated hospitalization was 85 percent (P<0.001 for the comparison with placebo) and reached 100 percent against more severe rotavirus gastroenteritis. Hospitalization for diarrhea of any cause was reduced by 42 percent (95 percent confidence interval, 29 to 53 percent; P<0.001). During the 31-day window after each dose, six vaccine recipients and seven placebo recipients had definite intussusception (difference in risk, per 10,000 infants; 95 percent confidence interval, to 2.18; P=0.78). CONCLUSIONS: Two oral doses of the live attenuated G1P[8] HRV vaccine were highly efficacious in protecting infants against severe rotavirus gastroenteritis, significantly reduced the rate of severe gastroenteritis from any cause, and were not associated with an increased risk of intussusception. Annex 1 Accelerating the Introduction of Rotavirus Vaccines into GAVI-Eligible Countries Page A1-3

43 (9) Vesikari T, Matson DO, Dennehy P, Van Damme P, Santosham M, Rodriguez Z et al. Safety and efficacy of a pentavalent human-bovine (WC3) reassortant rotavirus vaccine. N Engl J Med 2006; 354(1): BACKGROUND: Rotavirus is a leading cause of childhood gastroenteritis and death worldwide. METHODS: We studied healthy infants approximately 6 to 12 weeks old who were randomly assigned to receive three oral doses of live pentavalent human-bovine (WC3 strain) reassortant rotavirus vaccine containing human serotypes G1, G2, G3, G4, and P[8] or placebo at 4-to-10-week intervals in a blinded fashion. Active surveillance was used to identify subjects with serious adverse and other events. RESULTS: The 34,035 infants in the vaccine group and 34,003 in the placebo group were monitored for serious adverse events. Intussusception occurred in 12 vaccine recipients and 15 placebo recipients within one year after the first dose including six vaccine recipients and five placebo recipients within 42 days after any dose (relative risk, 1.6; 95 percent confidence interval, 0.4 to 6.4). The vaccine reduced hospitalizations and emergency department visits related to G1-G4 rotavirus gastroenteritis occurring 14 or more days after the third dose by 94.5 percent (95 percent confidence interval, 91.2 to 96.6 percent). In a nested substudy, efficacy against any G1-G4 rotavirus gastroenteritis through the first full rotavirus season after vaccination was 74.0 percent (95 percent confidence interval, 66.8 to 79.9 percent); efficacy against severe gastroenteritis was 98.0 percent (95 percent confidence interval, 88.3 to 100 percent). The vaccine reduced clinic visits for G1-G4 rotavirus gastroenteritis by 86.0 percent (95 percent confidence interval, 73.9 to 92.5 percent). CONCLUSIONS: This vaccine was efficacious in preventing rotavirus gastroenteritis, decreasing severe disease and health care contacts. The risk of intussusception was similar in vaccine and placebo recipients. Annex 1 Accelerating the Introduction of Rotavirus Vaccines into GAVI-Eligible Countries Page A1-4

44 Annex 2 Supplementary Information on Other Interventions for Rotavirus Diarrhea Oral rehydration therapy ORT, the giving of appropriate fluid by mouth to correct dehydration, was widely introduced to fight cholera in the developing world in 1979, relying initially on a pre-packaged oral rehydration solution (ORS) consisting of an electrolyte-balanced mixture of sodium and sugar that was mixed with water. Other carbohydrates and combinations, including a recently approved low-osmolarity solution (1) and home fluids have been proven to be effective options for ORT. While the use of ORT has significantly reduced mortality due to diarrhea, (2) there are constraints on its impact for diarrhea generally and for rotavirus in particular. The impact of ORT is generally limited by its suboptimal usage in low-income countries, with reported rates on DHS surveys as low as 18 percent in some countries and up to 73 percent in others. (3) The effectiveness of ORT in treating rotavirus diarrhea is limited because, in both developed and developing countries, approximately 80 percent of infants and children who present with rotavirus are vomiting, which limits their ability to consume sufficient ORT to correct dehydration. A study from Zambia found that many parents actually stop giving ORT to children when they are vomiting, possibly believing that it is ineffective or that it is actually triggering the vomiting. (4) In Bangladesh, even when children were given ORT at home, those who were vomiting before they arrived at a clinic were 58 times more likely to become dehydrated. (5) Zinc supplementation Oral zinc, given either prophylactically or as part of case management, has been shown to reduce the burden of diarrheal disease although not specifically diarrhea caused by rotavirus. A metaanalysis of controlled trials (6) and a subsequent trial in India (7) have shown modest reductions in incidence and severity of diarrheal episodes after continuous or short-course administration of zinc. In addition to these modest preventive effects, it is now widely accepted that zinc supplements administered to children who already have diarrhea will substantially reduce the duration and severity of the current episode, reduce the incidence of subsequent episodes, and reduce the use of antibiotics and other medicines for treating diarrhea. (8-11) The challenge in using this therapy for rotavirus is, as with ORT, the high rate of vomiting and difficulty in keeping orally ingested substances in the stomach long enough to be absorbed. For prevention, behavior change around handwashing and household hygiene could also be expected to have some effect, (12-13) but is difficult to promote and sustain such change. Moreover, rotavirus infects nearly all the world s children before age 5, regardless of home hygiene. These challenges, along with the limited benefits expected from general water and sanitation improvements, leave new vaccines as the primary strategy for significantly reducing the toll of rotavirus-associated death and illness. Annex 2 Accelerating the Introduction of Rotavirus Vaccines into GAVI-Eligible Countries Page A2-1

45 References (1) World Health Organization. The treatment of diarrhoea: A manual for physicians and other senior health workers, 4th rev Geneva, World Health Organization. (2) Victora CG, Bryce J, Fontaine O, Monasch R. Reducing deaths from diarrhoea through oral rehydration therapy. Bull World Health Organ 2000; 78(10): (3) Stallings R. Child morbity and treatment patterns. Calverton, MD: ORC Macro, (4) Ng'andu NH, Nkowane BM. The management of diarrhoea in young children in a rural community in Zambia. J Trop Med Hyg 1988; 91(4): (5) Ahmed FU, Karim E. Children at risk of developing dehydration from diarrhoea: a casecontrol study. J Trop Pediatr 2002; 48(5): (6) Bhutta ZA, Black RE, Brown KH, Gardner JM, Gore S, Hidayat A et al. Prevention of diarrhea and pneumonia by zinc supplementation in children in developing countries: pooled analysis of randomized controlled trials. Zinc Investigators' Collaborative Group. J Pediatr 1999; 135(6): (7) Bhandari N, Bahl R, Taneja S, Strand T, Molbak K, Ulvik RJ et al. Substantial reduction in severe diarrheal morbidity by daily zinc supplementation in young north Indian children. Pediatrics 2002; 109(6):e86. (8) Baqui AH, Black RE, El Arifeen S, Yunus M, Chakraborty J, Ahmed S et al. Effect of zinc supplementation started during diarrhoea on morbidity and mortality in Bangladeshi children: community randomised trial. BMJ 2002; 325(7372):1059. (9) Baqui AH, Black RE, El Arifeen S, Yunus M, Zaman K, Begum N et al. Zinc therapy for diarrhoea increased the use of oral rehydration therapy and reduced the use of antibiotics in Bangladeshi children. J Health Popul Nutr 2004; 22(4): (10) Bhandari N, Mazumder S, Taneja S, Dube B, Black RE, Fontaine O et al. A pilot test of the addition of zinc to the current case management package of diarrhea in a primary health care setting. J Pediatr Gastroenterol Nutr 2005; 41(5): (11) Bhutta ZA, Bird SM, Black RE, Brown KH, Gardner JM, Hidayat A et al. Therapeutic effects of oral zinc in acute and persistent diarrhea in children in developing countries: pooled analysis of randomized controlled trials. Am J Clin Nutr 2000; 72(6): (12) Luby SP, Agboatwalla M, Feikin DR, Painter J, Billhimer W, Altaf A, Hoekstra RM. Effect of handwashing on child health: a randomised controlled trial. Lancet. 2005;366(9481): (13) Luby SP, Agboatwalla M, Painter J, Altaf A, Billhimer WL, Hoekstra RM. Effect of intensive handwashing promotion on childhood diarrhea in high-risk communities in Pakistan: a randomized controlled trial. JAMA. 2004;291(21): Annex 2 Accelerating the Introduction of Rotavirus Vaccines into GAVI-Eligible Countries Page A2-2

46 Annex 3 Characteristics of the Two Licensed Rotavirus Vaccines Rotarix (GSK) RotaTeq (Merck) Origin Human monovalent Bovine pentavalent Strain G1, P(8) G1, G2, G3, G4, P(8) Dosage 2 doses 3 doses Timing With DTP1, DTP2 With DTP1, DTP2, DTP3 Presentation Lyophilized; reconstituted Liquid Administration Oral; applicator Oral; squeeze tube Storage 2-8 C 2-8 C Coadministration Phase 2 & 3 Safety & Efficacy Trials OPV, IPV, DTaP, DTwP HepB, Hib, PCV-7 n=63,225 healthy infants USA, Canada, Latin America (11), Taiwan, Singapore, Hong Kong, Belgium, Germany, Finland, South Africa, Bangladesh, Sweden, Taiwan IPV, DTaP, DTwP HepB, Hib, PCV-7 Licensure EMEA-2006 FDA-2006 n=70,301 healthy infants USA, Mexico, Costa Rica, Jamaica, Guatemala, Puerto Rico, Taiwan, Belgium, Finland, Germany, Italy Efficacy vs. rotavirus gastroenteritis 85% vs. severe rotavirus gastroenteritis and 100% vs. more severe episodes 98% vs. severe G1-G4 rotavirus gastroenteritis Efficacy vs. gastroenteritis from any cause 40% vs.severe gastroenteritis of any cause; 42% vs. hospitalization for severe gastroenteritis Intussusception No association No association 59% vs. hospitalization for diarrhea of any cause in first year of life Annex 3 Accelerating the Introduction of Rotavirus Vaccines into GAVI-Eligible Countries Page A3-1

47 Annex 4 List of GAVI-Eligible Countries by Investment Period (64 total) Investment 1 Countries (13) Investment 2 Countries (51) AMRO: 1. Bolivia 2. Cuba 3. Guyana 4. Honduras 5. Nicaragua EURO: 1. Armenia 2. Azerbaijan 3. Georgia 4. Kyrgyzstan 5. Moldova 6. Tajikistan 7. Ukraine 8. Uzbekistan AFRO: 1. Benin 2. Burkina Faso 3. Cameroon 4. Chad 5. Comoros 6. Côte d Ivoire 7. Eritrea 8. Ethiopia 9. Gambia 10. Ghana 11. Guinea 12. Guinea-Bissau 13. Kenya 14. Lesotho 15. Liberia 16. Madagascar 17. Malawi 18. Mali 19. Mauritania 20. Mozambique 21. Niger 22. Nigeria 23. Rwanda 24. São Tomé 25. Senegal 26. Sierra Leone 27. Tanzania 28. Togo 29. Uganda 30. Zambia 31. Zimbabwe EMRO: 1. Djibouti 2. Pakistan 3. Somalia 4. Sudan 5. Yemen SEARO: 1. Bangladesh 2. Bhutan 3. India 4. Indonesia 5. Myanmar 6. Nepal 7. Sri Lanka 8. Timor Leste WPRO: 1. Cambodia 2. Kiribati 3. Lao, PDR 4. Mongolia 5. Papua New Guinea 6. Solomon Islands 7. Vietnam Annex 4 Accelerating the Introduction of Rotavirus Vaccines into GAVI-Eligible Countries Page A4-1

48 Annex 5 Systems Costs Table 1 includes the estimated systems costs of introducing rotavirus vaccine in 13 countries in the Latin American and European regions, between 2007 and These costs were estimated using the GIVS (Global Immunization Vision and Strategy) costing model. The model was built based on data from more than 40 countries' Financial Sustainability Plans, used together with data and methods from WHO-CHOICE * and projections of vaccine prices, as well as information on recommended "best practices" for scaling up immunization. This model was designed primarily for global strategic budgeting. More specific cost and budgeting work will be done at the country level using comprehensive multi-year plans (cmyp), in preparation for vaccine introduction. In Table 1, costs are allocated by category. Cold chain costs represent approximately 50% of total systems costs. This is primarily because rotavirus vaccines and their packaging are larger than existing antigens, so some countries will need to expand their cold chain capacity. Costs for the remaining categories are consistent with introduction costs for previously introduced vaccines (e.g. Hep B and Hib). Table 1. Program costs for introducing the rotavirus vaccine into 13 GAVI eligible countries in the AMR and EUR regions for the period Cost category GAVI Total Costs (US$) Cold Chain $11,142,494 Training and Supervision $5,711,794 Vehicles and Transport $3,236,015 Social mobilization and awareness raising $388,514 Surveillance, M&E $243,525 Waste management $178,114 Overhead $750,232 Total program costs $21,650,688 * Choosing Interventions that are Cost-Effective (see Annex 5 Accelerating the Introduction of Rotavirus Vaccines into GAVI-Eligible Countries Page A5-1

49 Annex 6 Impact Analysis, Demand Forecasting, and Cost-Effectiveness: Methods and Assumptions Section 7 of the Investment Case estimates the impact of vaccine introduction on lives saved, health care utilization averted, and related medical cost savings. These estimates are the result of a comprehensive evaluation that relies on key RVP project findings and includes demand forecasting and cost-effectiveness analyses. Two primary models to calculate results were used: Demand Forecasting Model (software developed by Applied Strategies, Inc., San Mateo, California). This model calculates how much vaccine would be needed, how many children would likely be vaccinated, and the cost of vaccine to both the donors and countries, based on data and assumptions entered into the model. Cost Effectiveness Model (reported by Rheingans et al., Emory University). The Rheingans model estimates lives saved and health care costs averted per 1,000 infants vaccinated. Combining results of these models allows an estimation of the overall impact of accelerated rotavirus vaccine introduction on mortality and health care utilization. Donor and country vaccine cost estimates come from the demand forecast model alone. A description follows of the modeling methods and key assumptions that led to the results. Assumptions: Demand Forecast Analysis Demand forecasting, as the name implies, is a prediction of future demand based on current data and assumptions. The results of one scenario (base case) are presented in this annex. The following paragraphs explain the inputs to the demand forecast, including the values used in the base case analysis and the rationale for any assumptions made. Framework To estimate demand, countries were divided into two categories. Investment 1 countries were considered countries that could adopt rotavirus vaccine based on currently available burden of disease and clinical trial data. Investment 2 countries included those likely to adopt vaccine based on data from ongoing or planned clinical trials, anticipated in 2008 or Investment 1 includes the GAVI-eligible countries in Latin America and the European region. Both of these regions have ongoing surveillance activities, a recognition of the burden of rotavirus disease, and access to data from clinical trials that were conducted in either their own populations or representative groups. Investment 2 includes the remaining GAVI-eligible countries in Asia and Africa. In the baseline model, the year of introduction into Investment 2 countries is 2010, when clinical trial results from these regions are expected and appropriate policy recommendations have been made. In Annex 6 Accelerating the Introduction of Rotavirus Vaccines into GAVI-Eligible Countries Page A6-1

50 addition to trial data, disease surveillance activities and awareness-raising will be essential to ensuring adoption in these regions. Population data The source of population data used in the analysis is UN Population Data 2004, births through Vaccine coverage rates It is important to estimate the potential coverage rate for rotavirus vaccine in each country. We used DTP3 coverage rates from WHO ICE-T : Immunization Coverage Estimates and Trajectories.[1] DTP3 was selected as a suitable representation of potential coverage because it is expected that rotavirus vaccines will be given on the same schedule as DTP. Doses per course We expect that both a 2-dose and a 3-dose vaccine will be available in We estimated a global average of 2.5 doses per course in our base case analysis (a 50/50 market share for the two vaccines) throughout the duration of the model. Initial vaccine market price No formal negotiations between GAVI and the manufacturers have begun. Therefore, the initial vaccine market price in 2007 is not known. For estimating the vaccine subsidy costs required of GAVI for Investment 1 ( ), a range of possible vaccine prices was used. Currently, the lowest public-sector price for rotavirus vaccines that is publicly known is $14 for a treatment course of the GSK product (two doses for this vaccine). Under the assumption that GAVI will be able to negotiate a price from the manufacturers lower than that of Brazil (a middle-income, non- GAVI eligible country), the top of the range of prices was set at $12 per course. For illustrative purposes, the lower estimate was generated using $4 per course (see Table 1). Table 1. GAVI costs for two time periods for Investment 1 countries across a range of initial prices (US$ millions) $Price/course Total $ $ $ $ $ $ $ $ $ Annex 6 Accelerating the Introduction of Rotavirus Vaccines into GAVI-Eligible Countries Page A6-2

51 The price per course rather than the price per dose was calculated first so that regardless of the number of doses per course, the course price would remain the same. It is assumed that the two multinational vaccine manufacturers will price and market their vaccines competitively. Other key assumptions include: Price Dynamics: Regardless of starting price, price remains constant through 2011, drops to 94 percent of the starting price in 2012, then drops to 75 percent in 2013 (see price dynamics assessment below). For starting prices from $12 to $11 per course, the price drops to $1.00 per dose in 2018 and prices decrease in even increments between 2014 and For example, if the price starts at $12 it drops $1.60 per year from 2014 through For starting prices $10 to $4 per course, the price drops to $1.00 per dose in 2017 and prices decrease in even increments between 2014 and GAVI Portion of Costs: Based on co-financing assumptions in new GAVI policy. Country co-financing level by income categories: - Least poor = $0.50 (2007-8), $0.60 (2009), $0.70 (2010), $0.80 ( ) - Intermediate = $0.20 ( ), $0.40 ( ) - Poorest = $0.10 ( ), $0.20 ( ) - Fragile = $0 ( ) GAVI pays the difference between market price and country co-finance. Wastage factor We assumed a 5 percent wastage rate for a single-dose oral vaccine. We varied this in the sensitivity analysis from 2 to 10 percent and found that the impact of varying the wastage factor on overall doses demanded was nominal. Price dynamics assessment Regardless of the initial price negotiated between GAVI and the manufacturers, it is projected that a market equilibrium price of $1.00 per dose will be achieved. The average global vaccine price over time represents a blended vaccine market of both the higher-priced products from multinationals and the lower-priced products that are anticipated to be made available by developing-country manufacturers in the future. It is anticipated that the first five years of Annex 6 Accelerating the Introduction of Rotavirus Vaccines into GAVI-Eligible Countries Page A6-3

52 vaccine will be provided exclusively by Merck and GSK, and thereafter the market will include a growing share of vaccine from developing-country suppliers. The first projected decline in price is projected to occur in 2012, when one or more emerging country manufacturers are expected to enter the market with a product that is less expensive than those produced by the two multinationals. Between 2012 and 2015 the entry of four to eight additional emerging suppliers is anticipated, based on analyses from the BCG Global Supply study, RVP s own analysis, and from a report written by an independent consultant. In each of those years, the average price decreases due to increasing supply and price competition, until it reaches $2.00 per dose in Country introduction criteria Estimating demand requires some prediction about which countries will adopt vaccine, and the timing of their adoption. Countries with relatively high DTP3 coverage rates that have introduced hepatitis B and/or Hib vaccine, that have a significant burden of rotavirus disease, and that have expressed an interest in adopting rotavirus vaccine, were considered likely earlyadopters. Countries that met most but not all of these criteria were next in the adoption schedule. This criteria-based prediction process continued until all countries were included. A total of eight countries that, for reasons of political instability and/or very poor vaccine adoption history, would likely never adopt, were excluded from the modeling. The excluded countries accounted for approximately 10 percent of the birth cohort for the GAVI-eligible countries. Market equilibrium price The market equilibrium price of the vaccine (lowest price achieved at market maturity) was set at $1.00. This was based on a cost-of-goods analysis conducted by an independent consultant. The analysis suggests that the cost of goods for developing-country manufacturers is below $1.00 per dose and a price of $1.00 would include sufficient return on investment for developing-country manufacturers. Funding strategy The baseline funding strategy included donor subsidy through 2015 with countries responsible for a modest copayment based on income category. The donor would pay the difference between the co-payment and the market price. Total vaccine cost would decline over time, and in 2015, countries would be responsible for the entire cost of the vaccine. Annex 6 Accelerating the Introduction of Rotavirus Vaccines into GAVI-Eligible Countries Page A6-4

53 Results: Demand Forecast Analysis Figure 1 below is an estimate of vaccine demand for GAVI-eligible countries in Latin America and the European region. Once maximum coverage rates are reached, approximately 6 million doses will be required annually. Introduction of vaccine would begin in 2007 for some countries, with others adopting vaccine in and Figure 1. Doses Demanded (Investment 1) 7 6 Demand in Doses (millions) AMR EUR Figure 2 shows the number of doses demanded for all countries included in the analysis (Investments 1 and 2). These demand figures include 64 of the 72 GAVI-eligible countries, as it is expected that some countries will not adopt due to political instability and/or past history of poor vaccine adoption. Once maximum vaccine coverage rates are reached, 160 million doses per year will be required for these countries. Annex 6 Accelerating the Introduction of Rotavirus Vaccines into GAVI-Eligible Countries Page A6-5

54 Figure 2. Forecasted Demand for GAVI-eligible Countries (Investments 1 and 2) Demand in Doses (millions) AMR EUR AFR EMR SEAR WPR *assumption: 8 countries do not adopt due to political, social or economic instability Assumptions: Health Impact Results Estimates of health impact are drawn from RVP findings and the work of Rheingans, et al.[2] In the Rheingans study, estimates of the costs, lived saved, and health care utilization averted with the introduction of rotavirus vaccine were compared to estimates in which there was no vaccine. These estimates were based on rotavirus mortality data from Parashar, et al.[3], vaccine efficacy from clinical trials[4], vaccine coverage rates from Demographic and Health Survey data on DTP1 and 2, and a relative coverage estimate that accounts for the potentially higher mortality rate in children who do not have access to vaccines. Rheingans then tailored this analysis to GAVI-eligible countries. The following paragraphs give more specific descriptions of the methods, assumptions, and data used by Rheingans, et al. in this analysis. Mortality rates for rotavirus Disease burden was estimated as the expected number of rotavirus-associated deaths during the first five years of life for a single birth cohort in GAVI-eligible countries. Parashar, et al. estimated country-specific mortality attributed to rotavirus gastroenteritis in children under age five.[3] Using the annual number of all deaths for children under five in each country, the authors estimated the proportion of those deaths attributed to diarrhea and the proportion of diarrheal deaths attributed to rotavirus, based on a review of published surveillance studies. Annex 6 Accelerating the Introduction of Rotavirus Vaccines into GAVI-Eligible Countries Page A6-6

55 Vaccine efficacy Vaccine efficacy estimates in the analysis were derived from clinical trial data of a liveattenuated, monovalent human rotavirus vaccine administered in two doses (Rotarix ). The reduction in the number of rotavirus-related events was estimated based on the proportion of children receiving one or two doses, and on vaccine efficacy data. The vaccine had 85 percent efficacy in preventing severe rotavirus gastroenteritis resulting in hospitalization (and is assumed to be the same for cases resulting in death).[4] Efficacy against rotavirus gastroenteritis resulting in an outpatient visit was estimated as the reported mean of the efficacy against severe (85 percent)[4] and any (70 percent) rotavirus gastroenteritis. The efficacy of receiving only one dose was assumed to be 70 percent of the efficacy of a full course.[5] Because efficacy data for Africa and Asia are not yet available, and because real world vaccine effectiveness can vary, even from clinical trials conducted in the same region, a range of vaccine efficacy from 70 to 100 percent was considered in the sensitivity analysis. See Section 9b of the investment case for results. Relative coverage In addition, the cost-effectiveness model accounted for the extent to which vaccination reaches the population at greatest risk of severe outcomes, given the possibility that children at risk of rotavirus mortality may have less access to routine vaccination. This was done by incorporating a factor for relative coverage, reflecting access to vaccination in children experiencing rotavirusassociated death compared to the cohort as a whole. Since few data exist regarding the vaccine coverage of children who die from diarrheal diseases, the model assumed that children who die from rotavirus gastroenteritis were 90 percent as likely to be vaccinated as compared to other children. This variable was further examined in the sensitivity analysis to evaluate the impact on the cost-effectiveness of vaccination. Calculation of total lives saved We estimated the total lives saved in GAVI-eligible countries by taking the number of lives saved per 1,000 vaccinated for each region (see Section 9, Table 4) and multiplying by our demand forecast estimates of number of infants vaccinated by region during the project period of This calculation yields 2.4 million saved lives. Calculation of hospitalizations and outpatient visits averted We estimated the total hospitalizations and outpatient visits averted due to vaccination for rotavirus in GAVI-eligible countries by taking the number of visits averted per 1,000 vaccinated for each region (see Section 9, Table 4) and multiplying by our demand forecast estimates of number of infants vaccinated by region during the project period of This calculation yields nearly 100 million visits averted. Annex 6 Accelerating the Introduction of Rotavirus Vaccines into GAVI-Eligible Countries Page A6-7

56 Calculation of direct medical costs averted The economic costs of rotavirus gastroenteritis were estimated from the healthcare system perspective; therefore, costs borne by individuals such as lost productivity and wages of the caretakers, non-medical expenses (e.g., transport, additional diapers, etc.), and treatment at informal medical settings (e.g., traditional healer or pharmacy) were not included. For hospitalized patients, the direct medical cost was calculated by combining patient information on resource use and unit cost of a hospital bed day, diagnostic tests, and medications, as described in the following equation: Medical cost = (Length of stay x Per diem cost) + Cost of diagnostics + Cost of medication The direct medical cost of outpatient visits was calculated in a similar manner, excluding the multiplier for length of stay, since outpatients do not stay more than one day at the clinic. The average cost for hospitalizations and outpatient visits combined for all regions is $5.00 per visit. Thus, the number of visits averted is multiplied by $5.00 to obtain the total direct medical costs averted as a result of rotavirus vaccination. Annex 6 Accelerating the Introduction of Rotavirus Vaccines into GAVI-Eligible Countries Page A6-8

57 References [1] Wolfson, LJ, WHO ICE-T : Immunization and Coverage Estimates and Trajectories. WHO Department of Immunization, Vaccines & Biologicals, [2] Rheingans R, et al., Healthcare Costs of Rotavirus Gastroenteritis and Cost-Effectiveness of Vaccination in Developing Countries (unpublished), [3] Parashar UD, Hummelman EG, Bresee JS, Miller MA, Glass RI. Global illness and deaths caused by rotavirus disease in children. Emerging Infectious Diseases 2003;9(5): [4] Velazquez FR, slide presentation at ESPID (the European Society for Pediatric Infectious Diseases), Vallencia, Spain, May [5] RVP personal communication with clinical trial researchers. Annex 6 Accelerating the Introduction of Rotavirus Vaccines into GAVI-Eligible Countries Page A6-9

58 Annex 7 Alternative Price and Co-financing Scenarios Vaccine prices and co-financing policies both have a significant impact on costs to donors and recipient countries. Initial vaccine price will have the greatest impact on GAVI, and the rate at which the price declines over time has substantial impact on both GAVI and countries, particularly if the decline is slow and delayed increasing overall costs by nearly $1 billion. Co-financing policies must strike a balance between affordability in the short-term and financial sustainability in the long-run. Many countries will face substantially higher budget requirements once GAVI funding expires. These increases need to be anticipated to ensure a smooth transition and sustainability. Now is the time to implement appropriate financing strategies and policies to influence these critical factors and guarantee the greatest opportunity for rotavirus vaccine to reduce childhood mortality. Vaccine Price Scenarios Many questions still exist around the price of rotavirus vaccine and also the expected rate of decline in price over time. A range of vaccine prices and their impact on donor and country costs, is represented in the estimated vaccine costs presented in Section 3, Table 1. Here, we have modeled the impact of the rate of price decline on donor and country costs using two price scenarios. Both scenarios are variations of a base case that assumes an initial price of $10 per course, declining to $2.50 per course by The base case is primarily illustrative, and is established so that we can compare other scenarios to it, to determine the relative impact of changes in the rate of price decline. Description of the scenarios 1. More rapid price decline. This model assumes an optimistic development and scaling-up capacity of developing-country manufacturers resulting in lower-cost supply of vaccine earlier in the timeline. 2. Slower and delayed price decline. This model assumes there is a delay in supply from developing-country manufacturers that causes a delay in availability of lower-cost products and assumes a slower rate of decline over time. In total, this model assumes a three-year delay in reaching a price that equals country willingness-to-pay ($1.00/dose). Discussion The results of each scenario and the base case are presented in Table 1. Annex 7 Accelerating the Introduction of Rotavirus Vaccines into GAVI-Eligible Countries Page A7-1

59 Table 1. Results of alternative price scenarios, compared to the base case Investment 1 & 2 subsidies ( ) Copays from countries and their donors ( ) Total ( ) Base Case $655 million $1.67 billion $2.33 billion Rapid Price Decline $541 million $1.62 billion $2.16 billion Slower/Delayed Price Decline $942 million $2.28 billion $3.22 billion The scenarios involve changes in the rate of price decline. A more rapid decline in price reduces donor subsidies by approximately $100 million compared to the base case scenario. A slower and delayed price decline has a more significant impact on donor subsidy requirements, increasing the potential funding envelope to nearly $1 billion, an increase of nearly $300 million in subsidy payments over the base case. In addition, the delayed price decline increases copay requirements by more than $500 million. The overall funding envelope required is nearly $1 billion more than the base case scenario. The impact of delayed price decline highlights the importance of developing strategies that will bring new suppliers, particularly emerging country suppliers, to the marketplace as soon as possible, as they are key to driving down the vaccine price. This requires a number of simultaneous strategies including push or pull funding for suppliers, demand creation at the country level, and early signalling of subsidy funding by GAVI and other donors. Co-financing Analysis In July 2006 the GAVI Alliance Board approved a proposed new vaccine financing policy that will require countries to co-finance the introduction of new and under-used vaccines in Investment 2. While many details of this policy have yet to be worked out, the overall structure is clear: GAVI-eligible countries will be stratified into four groups least poor, intermediate, and poorest, plus a group of fragile or post-conflict countries and specific co-financing requirements will be applied to the countries within each group. We have modelled two co-financing scenarios for this investment case based on the new vaccine financing policy proposal. However, this investment case covers the period from 2007 through 2025, while the proposal suggests levels of co-financing only through 2010, at which time the co-financing proposal will be re-evaluated. This analysis explains the co-financing assumptions used in developing these scenarios, including the values used in the base case and the impact on selected countries. This analysis also gives examples of how these co-financing assumptions impact the costs to GAVI and to countries and their donors. As a reminder, the initial price of $4.00 per dose was projected to decrease over time, reaching the market equilibrium price of $1.00 in We assume countries (and/or their donors) will pay the full $1.00 per dose beginning in However, in 2016, post-gavi Investment 2, we expect there to be some type of financing available. These assumptions are detailed in the country-specific examples. It is also important to note that the following scenarios are based on predictions of the future, so need to be interpreted as illustrative. The exact figures and timelines will vary. Annex 7 Accelerating the Introduction of Rotavirus Vaccines into GAVI-Eligible Countries Page A7-2

60 Least Poor Countries The new vaccine financing policy proposes that the least poor group of GAVI countries (those with a 2005 GNI per capita over $1,000) be required to co-finance a gradually increasing amount toward a target set between $0.70 and $0.95 per dose by For the base case scenario we set the co-financing requirement at $0.50 for , $0.60 for 2009, and $0.70 for For 2011 through 2015 we increased the co-financing to $0.80 per dose. For example, Honduras is an Investment 1 country that we assume will introduce the vaccine in 2007 and will be fully scaled up in Table 2 shows the costs through 2017 for Honduras using the base case co-financing assumptions. The cost of subsidies increases through 2009 then decreases through The cost of the country co-finance increases through 2011, remains steady through 2016, then increases 25 percent in 2017 when the country is expected to pay the full $1.00 per dose. Table 2. Vaccine Costs for Least Poor Country (e.g., Honduras) by Financing Source (US$1,000s) Subsidies-GAVI Phase II 612 1,242 1,830 1,796 1,743 1,608 1, Subsidies-Post GAVI Phase II Country Co-finance Total Cost 699 1,419 2,153 2,177 2,179 2,045 1,637 1,363 1, Intermediate Countries The new vaccine financing policy proposes that the intermediate group of GAVI countries (those with a 2005 GNI per capita less than $1,000 and not classified by the United Nations as Least Developed Countries) be requested to co-finance a fixed amount of between $0.20 and $0.50 per dose by This amount would be increased after For the base case scenario we set the co-financing requirement at $0.20 for For 2011 through 2015 we doubled the cofinancing to $0.40 per dose. For example, Uzbekistan is an Investment 1 country which we assume will introduce the vaccine in 2008 and will be fully scaled up in Table 3 shows the costs through 2017 for Uzbekistan using the base case co-financing assumptions. The cost of subsidies increases through 2010 and decreases through Country co-financing increases through 2011, remains steady through 2016, and then jumps more than 200 percent in 2017 when the country is expected to pay the full $1.00 per dose, from $635,000 to $1.57 million. Annex 7 Accelerating the Introduction of Rotavirus Vaccines into GAVI-Eligible Countries Page A7-3

61 Table 3. Uzbekistan Vaccine Costs by Financing Source (US$1,000s) Subsidies-GAVI Phase II 2,051 4,112 6,184 5,873 5,479 4,264 3,406 2,567 Subsidies-Post GAVI Phase II 1,745 - Country Co-finance ,569 Total Cost 2,159 4,328 6,509 6,526 6,134 4,919 4,055 3,209 2,380 1,569 Another example of an intermediate country: Pakistan is an Investment 2 country which we assume will introduce vaccine in 2014 and will be fully scaled up in Table 4 shows the costs through 2017 for Pakistan using the base case co-financing assumptions. The cost of subsidies increases through The cost of the country co-finance also increases through 2016 then in 2017 increases 3.4 times from $3.2 million to $10.9 million, when the country is expected to pay the full $1.00 per dose. Table 4. Pakistan Vaccine Costs by Financing Source (US$1,000s) Subsidies-GAVI Phase II 5,465 8,447 Subsidies-Post GAVI Phase II 8,835 - Country Co-finance 1,041 2,112 3,213 10,859 Total Cost 6,506 10,559 12,047 10,859 Poorest Countries The new vaccine financing policy proposes that the poorest group of GAVI countries (those classified by the United Nations as Least Developed Countries) be requested to co-finance a fixed amount of between $0.10 and $0.25 per dose by This amount would be increased after For the base case scenario we set the co-financing requirement at $0.10 for For 2011 through 2015 we doubled the co-financing to $0.20 per dose. For example, Bangladesh is an Investment 2 country which we assume will introduce the vaccine in 2010 and will be fully scaled up in Table 5 shows the costs through 2017 for Bangladesh using the base case co-financing assumptions. Subsidy costs increase through 2012, and then decrease through The cost of the country co-finance increases sharply through 2012, and then increases slowly through In 2017 the country co-finance increases 5 times, from $1.9 million to $9.8 million, when the country is expected to pay the full $1.00 per dose. Annex 7 Accelerating the Introduction of Rotavirus Vaccines into GAVI-Eligible Countries Page A7-4

62 Table 5. Bangladesh Vaccine Costs by Financing Source (US$1,000s) Investment 2 11,832 23,337 33,096 26,415 21,923 17,333 Post-Investment 2 12,645 - Country Co-finance 303 1,228 1,865 1,887 1,906 1,926 1,945 9,825 Total Cost 12,135 24,565 34,960 28,302 23,829 19,259 14,591 9,825 Discussion Although the details of the proposed co-financing strategy for GAVI Phase II must still be developed, the objective is financial independence at the country level. Therefore, the policy will require a balance between affordable co-financing and long-term country sustainability. From the results of this analysis, we see a sharp increase in country-borne costs, especially for the poorest and intermediate countries, beginning in In our three country examples, the size of this increase from 2016 to 2017 ranged from 2.5- to 5-fold. The proposed copays may be very affordable and lead to high demand for vaccine, increasing the probability of reaching maximum benefits including millions of lives saved. However, the subsequent increase in costs to countries post-gavi Phase II needs to be anticipated to ensure a smooth transition and sustainability of rotavirus vaccination in each country. So, as countries apply for vaccine and begin vaccine introduction, plans to engage their national donors early in the process will be critical so that the significant benefits of rotavirus vaccination will not be delayed or compromised. Annex 7 Accelerating the Introduction of Rotavirus Vaccines into GAVI-Eligible Countries Page A7-5

63 Annex 8 Estimated Vaccine Impact by Country The following table provides estimates of the number of lives that can be saved with introduction of rotavirus vaccine, by country. These estimates are derived from our cost-effectiveness and demand forecast modeling and they represent results from our base case scenario. Estimated deaths averted through 2025 Estimated deaths averted through 2025 Country Country India 716,469 Sierra Leone 12,408 Bangladesh 165,369 Guinea 11,539 Nigeria 139,613 Cambodia 9,863 Pakistan 129,923 Tajikistan 6,712 Indonesia 114,004 Sri Lanka 6,680 Kenya 98,743 Guinea-Bissau 6,423 Ethiopia 85,618 Togo 6,225 Uganda 84,230 Bolivia 6,001 Tanzania 80,797 Azerbaijan 5,181 Ghana 50,357 Honduras 5,163 Malawi 47,365 Mauritania 5,150 Mali 46,870 Somalia 4,956 Vietnam 42,656 Liberia 4,517 Mozambique 38,847 Gambia 4,013 Burkina Faso 34,804 Kyrgyzstan 3,879 Myanmar 29,008 Nicaragua 3,699 Benin 28,879 Bhutan 2,950 Cameroon 28,769 Lao PDR 2,406 Zambia 28,732 Lesotho 2,211 Rwanda 28,195 Papau New Guinea 2,099 Niger 26,785 Cuba 1,576 Madagascar 25,061 Moldova 1,495 Senegal 24,908 Georgia 1,411 Nepal 24,842 Timor-Leste 1,307 Yemen 24,228 Armenia 1,274 Uzbekistan 22,935 Mongolia 1,189 Zimbabwe 20,244 Comoros 1,174 Côte d'ivoire 18,563 Djibouti 511 Sudan 18,421 Guyana 284 Eritrea 13,893 Solomon Islands 240 Ukraine 13,446 Sao Tome and Principe 164 Chad 13,375 Kiribati 31 TOTAL: 2,388,680 Annex 8 Accelerating the Introduction of Rotavirus Vaccines into GAVI-Eligible Countries Page A8-1

64 Annex 9: Timeline of Components Required to Assure Accelerated Introduction of Rotavirus Vaccines PRE-PROJECT INVESTMENT CASE PROJECT Investment 1 Investment GAVI investment decisions ( ) Latin America Clinical trials* Surveillance Logistics support Post-marketing activities Demonstration project Eastern Europe Clinical trials* Surveillance Logistics support Post-marketing activities Demonstration project Asia Surveillance Clinical trials ** Effectiveness study Logistics support Post-marketing activities Africa Surveillance Clinical trials ** Logistics support Post-marketing activities Global Investment case Development Refinement Demand/supply monitoring Forecast Estimation Refinement Policy development/support Project management & admin. Ongoing monitoring * These trials were not funded through the rotavirus ADIP but had significant impact on ADIP activities. ** These trials are funded through a GAVI grant supplemental to the original rotavirus ADIP. Page A9-1

65 Annex 10 Details of Activities to Support Accelerated Vaccine Introduction Rotavirus surveillance activities are critical to demonstrate the need and stimulate demand for rotavirus vaccines. Surveillance must continue after vaccine introduction to evaluate vaccine performance, sustain confidence in the program, and catalyze vaccine introduction in other countries and regions, particularly in Africa and Asia where the potential impact is greatest. Both safety and effectiveness are key components of postmarketing surveillance. Background Decisions regarding a new public health intervention (such as the introduction of a new vaccine) require information on the disease burden and epidemiology and the expected impact and costeffectiveness of the new intervention. Once introduced, public health programs require continuous monitoring and feedback, to maintain high quality and maximal impact in a changing environment. The impact of the vaccine must be demonstrated in different settings, particularly in developing countries with the greatest burden of rotavirus disease as well as the greatest challenges to vaccine performance. During the evaluation phase, monitoring is dependent on two key items: the number of doses of vaccine delivered to the target group (vaccination coverage) and the reduction of disease against which the vaccines are targeted (disease surveillance). Rotavirus disease surveillance provides key data both to establish the burden of disease and the need for vaccination, and to measure the impact of vaccination on disease incidence and on the dynamics of rotavirus strain circulation. Without appropriate disease surveillance systems, vaccine safety and effectiveness in the general population cannot be properly ascertained. Post-marketing surveillance for safety and studies for effectiveness should be implemented soon after vaccine introduction, using existing rotavirus disease surveillance systems as a platform. Post-marketing surveillance activities may be conducted in a few individual countries per region. Selected countries should be broadly representative of GAVI-eligible countries in the region, although it is recognized that in some regions, middle-income countries which are not GAVIeligible may be the only countries with sufficient infrastructure to conduct particular activities. Before activities are initiated, standardized protocols should be developed for various types of post-marketing surveillance in order to increase scientific rigor, to allow comparisons between countries and regions, and to facilitate participation in surveillance activities by countries not selected for specific project activities. Enhanced active disease surveillance Under the current, GAVI-funded Rotavirus Vaccine Program, rotavirus disease surveillance in hospital sentinel sites is operating in over 30 GAVI-eligible countries in Latin America, the European region, Asia, and Africa under a generic protocol developed by WHO and CDC. The Annex 10 Accelerating the Introduction of Rotavirus Vaccines into GAVI-Eligible Countries Page A10-1

66 ultimate goal is to have this core rotavirus surveillance framework included as part of the WHO Vaccine-Preventable Disease Surveillance Network. For diseases that occur frequently (as does rotavirus diarrhea), aggregate reporting through a disease notification system may be adequate, without in-depth investigation of each case that occurs nationally. The objective of disease notification and aggregate reporting is to monitor the overall trend of the disease as well as outline specific high risk areas or populations. The data required for program monitoring often follows the same pattern as aggregate disease surveillance data in existing systems such as the WHO polio or measles surveillance networks. WHO recommends that each country have sufficient sentinel surveillance sites before vaccine introduction in order to provide representative data for the country (the number may vary depending on the size and population diversity in the country). Surveillance in well-defined populations (to provide adequate denominators) and high ascertainment of eligible cases (to provide adequate numerators) should be conducted in representative populations in each region to provide accurate disease incidence rates. These data can then be linked to national data to provide burden estimates for all representative populations in each country. As described in this framework, current rotavirus surveillance activities are being conducted at sentinel sites in each country (the number of sites varies depending on size of country and geographic diversity), and these allow for overall monitoring of disease trends and viral strain prevalence through focused studies without overwhelming the limited capacity of national surveillance systems. Because the greatest efficacy of rotavirus vaccines has been against severe rotavirus disease, existing surveillance focuses on severe outcomes such as hospitalizations. It will be important to assure the continued presence of high-quality regional reference laboratories that can perform strain surveillance to monitor circulating strain diversity and possible strain replacement after vaccine introduction. These reference laboratories also provide training to workers from laboratories within individual countries and provide quality control oversight for individual country laboratories conducting routine surveillance in the region. Maintenance of these regional networks up to and past vaccine introduction is critical in order to provide background data on disease burden, and potentially intussusception (see below), to compare with post-introduction rates. In addition to providing a platform for post-marketing surveillance, these networks foster in-country rotavirus expertise and advocacy efforts. Post-marketing surveillance of vaccine safety In 1998, a rhesus rotavirus tetravalent vaccine (RotaShield) was licensed in the United States. In July 1999, the vaccine was associated with development of intussusception among vaccine recipients, leading to the suspension of vaccine use, and ultimately the cessation of research and marketing activities for this vaccine construct worldwide. While the lack of association of the current GSK and Merck vaccines with intussusception in clinical trials is reassuring, children in those trials received their first dose of rotavirus vaccine within the strictly defined time period of 6-12 weeks of age. In the RotaShield experience, the incidence of intussusception was associated with the first dose of vaccine being given at an older age, and infants older than 90 days of age accounted for 80% of intussusception cases. Thus, safety surveillance is critically important to identify adverse events, including intussusception, that may manifest as vaccine is introduced to Annex 10 Accelerating the Introduction of Rotavirus Vaccines into GAVI-Eligible Countries Page A10-2

67 larger numbers of children with varied vaccine schedules. The Global Advisory Committee on Vaccine Safety (GAVCS) recommends post-marketing surveillance for safety and for vaccine impact in countries that intend to introduce the vaccine, especially where (a) the national surveillance system for adverse event reporting is not robust and (b) infants may get vaccine at older ages than recommended by EPI. In addition, there are concerns about misinterpretation of temporal associations as causal. A perceived risk may be as damaging to a vaccine program as an actual risk. Cases of natural intussusception will occur by chance following vaccination, and will raise concerns about possible causal associations with vaccine. Therefore, systemic safety surveillance with strict quality standards is essential to identify rare adverse events, and to prevent misinterpretation of temporal results as causal, with loss of confidence in the vaccine program. Post-marketing surveillance of vaccine safety, with particular attention to intussusception, will include adaptation and dissemination (including translation) of a generic protocol for field use, and technical and financial support to implement the protocol. In conjunction with technical partners at the Royal Children s Hospital at Melbourne, Australia, and the US CDC, WHO is currently developing such a protocol. The revised version of the generic protocol will be presented to the Global Advisory Committee for Vaccine Safety (GAVCS), and to additional experts in rotavirus vaccines and surveillance systems, for their input in December The primary objectives of the WHO generic protocol are: To determine the incidence of intussusception following rotavirus vaccination, by standard age groups and according to the type and dose of rotavirus vaccine and the timing of immunization. To determine the incidence of other gastrointestinal side effects in relationship with rotavirus vaccination To identify signals of other rare adverse events potentially related to rotavirus vaccination. The protocol will be designed to identify and validate potential cases of intussusception, and to establish if the event is vaccine-associated. In this protocol, safety data will be linked to existing passive Adverse Events Following Immunization (AEFI) surveillance activities (where these exist). In addition to the passive system, active surveillance systems for intussusception and other adverse events will be developed. Sites that participate in active surveillance sites should have: Demographically and geographically well-described populations. Access to health care and capacity to diagnose and treat or transfer cases of intussusception. Accurate ascertainment of vaccine coverage levels. Knowledge of baseline incidence of intussusception. Annex 10 Accelerating the Introduction of Rotavirus Vaccines into GAVI-Eligible Countries Page A10-3

68 Skills necessary to collect and manage data. The Brighton collaboration clinical case definition for intussusception will serve as the case definition for surveillance purposes. Adverse event episodes will be calculated according to vaccine characteristics (type, dose, vaccine lot), interval between receipt of vaccine and diagnosis of event, and classification of intussusception. In many cases additional resources and technical support will be required to strengthen AEFI surveillance. Further, where resources permit, active safety surveillance components of the postmarketing surveillance of vaccine safety protocol will be implemented. Resources for implementation will be needed for training of relevant staff, ensuring timely and effective investigation of serious adverse events (including provision of technical expertise when needed), and database development and skills for data analysis and reporting. Other necessary components of safety surveillance plans will include determining baseline (pre-vaccine introduction) rates of intussusception, and developing and implementing crisis communication plans. Post-marketing surveillance of vaccine impact Clinical trials are performed in select populations under controlled circumstances, and nearly all participants receive the full vaccine series according to the recommended schedules. In clinical trials conducted thus far in middle and high-income countries, both of the currently available vaccines have demonstrated excellent efficacy. It is not possible, however, to predict how these results will translate into population impact, or if one vaccine may have advantages over another under program and field conditions or in areas with unique rotavirus strains. In addition, clinical trials are constrained in their ability to assess rare outcomes. For example, a reduction in death due to rotavirus vaccine will be difficult to demonstrate in the on-going clinical trials in developing countries, due to the large sample size that would be required, and the improved access to care and quality of care that is provided in a clinical trial situation. The impact of rotavirus vaccines on the important outcome of death may be better ascertained in the postmarketing time period. Studies to ensure that the vaccine is performing as is expected could be conducted in the early phases of introduction in 2-3 countries in each region. A number of different study designs may be appropriate to evaluate effectiveness of rotavirus vaccines after introduction into the routine EPI program. Such designs include monitoring longitudinal data pre and post-introduction, examining national diarrheal disease statistics, and performing case control studies. The final choice of design for a specific population will depend on the data and resources available, the setting, the stage of the vaccination program (level of vaccination coverage and rate of uptake), and the precise objective of the study. CDC and WHO are preparing a generic protocol for monitoring the impact of rotavirus vaccination on disease burden and viral strains. This protocol will be reviewed by stakeholders in December 2006 and should be available for use shortly thereafter. The protocol will provide a systematic framework for addressing questions of effectiveness and strain characterization in countries that implement rotavirus vaccination through a uniform, standardized approach that will allow for comparison of data across regions. Annex 10 Accelerating the Introduction of Rotavirus Vaccines into GAVI-Eligible Countries Page A10-4

69 Following introduction of rotavirus vaccines, the impact of vaccination on disease could be demonstrated by monitoring trends in diarrhea and rotavirus disease burden at sentinel sites that are already conducting rotavirus surveillance as part of the networks describe above. Ideal sites would be hospitals with known catchment areas with higher vaccine coverage. Any observed reduction in disease trends would need to be interpreted in conjunction with vaccination coverage rates. For success of such efforts, it will be important to establish surveillance at least 2-3 years before vaccine introduction to provide appropriate pre-vaccination data for comparison. Alternatively, data from passive surveillance systems (e.g., national diarrheal hospitalization data or infant mortality data) may also be useful, particularly if vaccine coverage is high and reporting patterns stable. However, such studies would be limited by potential problems of comparability of disease data pre- and post-introduction. For example, reporting and testing trends can change from year to year, as can the severity of rotavirus epidemics, and other changes in treatment and prevention of diarrhea in general may also change with time. One way to overcome this limitation is to compare vaccine-type rotavirus strains and non-vaccine-type rotavirus strains pre- and postintroduction. Examining seasonality and age-specific rates of disease may give additional insights into the impact of vaccination. The reduction in outcomes should be proportional to the vaccination coverage rates in the region, and will be seen in infants younger than 1 year of age in the first year of vaccine introduction, in those younger than 2 years of age in the second year of the program, and in incrementally increasing age groups during successive years of the vaccination program. Monitoring of disease trends in age groups that are not targeted for vaccination may also demonstrate potential indirect beneficial effects (herd immunity) of vaccination. Monitoring secular trends in diarrhea- and rotavirus-associated health outcomes to demonstrate impact of vaccination can be challenging. A fairly high level of vaccine coverage may need to be achieved before impact may be visible through these ecologic methods. Alternatively, density case-control studies can be performed rapidly, within the first year of vaccine introduction, at low cost, with few participants and in areas where coverage is suboptimal and pre-introduction disease incidence data are sparse. Additionally, case-control studies could be designed to analyze effectiveness of rotavirus vaccine against specific circulating strains, or specific outcomes of interest, such as death. The most critical design elements for case-control studies include the definition, selection, and availability of controls that are representative of the source population, and accurate ascertainment of disease and vaccination status. Combined with data on vaccine coverage, these vaccine effectiveness studies can provide indirect estimates of overall diseaseburden reduction in the country attributable to the program. However, correct design of these epidemiologic studies is of paramount importance, since they are particularly susceptible to bias and misleading conclusions, again stressing the importance of the generic protocols in development. Demonstration projects International public health authorities have emphasized the importance of demonstrating the performance of new rotavirus vaccines in routine vaccination programs. Studies should be designed to identify significant programmatic deficiencies of rapid vaccine scale-up on health systems, including human resource capacity, cold chain capacity, transportation, and integration Annex 10 Accelerating the Introduction of Rotavirus Vaccines into GAVI-Eligible Countries Page A10-5

70 with other services. For example, the introduction of rotavirus vaccine in certain developed countries has highlighted the impact of vaccine packaging on cold chain requirements (see Annex 11). The lessons learned from demonstration projects in the more resource-constrained developing world may serve as the basis for recommendations to countries on successful vaccine delivery strategies, and for tools to facilitate such introduction. The dissemination of such information and tools should allow countries to optimally prepare for vaccine introduction. In addition to the operational aspects, demonstration projects provide the opportunity to further evaluate vaccine safety, effectiveness and impact, using the standardized protocols being developed by WHO and described above. Data from these studies provide inputs to refine riskbenefit ratios and cost-effectiveness estimates. Further, these field evaluations could provide valuable data to address specific issues such as the effectiveness of less-than full dose series or delayed immunization and assessment of potential indirect benefits (e.g., herd immunity) of vaccination. As vaccine is introduced during the time frame, we envision one demonstration project in each early adopter region, Latin America and the European region. The ultimate goal of such studies is to stimulate the introduction and routine use of vaccines in other countries in the region, and in the world, especially those in Africa and Asia, where vaccination is expected to have the greatest impact. Annex 10 Accelerating the Introduction of Rotavirus Vaccines into GAVI-Eligible Countries Page A10-6

71 Annex 11 Technical Constraints Current presentations of rotavirus vaccines present significant challenges to existing cold chain capacity in developing countries. Current manufacturers are exploring changes to packaging and/or presentation that will reduce the overall impact on cold chain capacity in developing countries. GAVI has the ability to further reduce impact through its policies regarding the use of ISS funding, partnering with manufacturers to identify joint solutions, and through purchasing requirements. The current presentations of the two available rotavirus vaccines may present significant challenges to existing cold chain capacity in developing countries. Specific cold-chain limitations might cause some countries to postpone adoption of rotavirus vaccines, and will depend on: Age of the cold chain equipment at all levels. Mix of electric, gas, kerosene, and solar cold chain brands/models. Management, maintenance, and replacement capacity. Proportion of equipment out of service. Degree of national autonomy and/or dependence on donors for cold chain replacement. Both manufacturers are engaged in activities to revise the presentations, which will reduce the strain associated with their current presentations. GAVI should work with the manufacturers in partnership in order to jointly identify sustainable solutions for reducing the impact of these vaccines on the cold chain. GSK s Rotarix The current formulation of GSK s Rotarix vaccine has been delivered to middle-income Latin American countries in boxes containing 25 mono-dose vials, diluent applicators, and connectors. If the complete boxes are stored intact at peripheral level, 2 doses of vaccine require an additional 246 cm 3 or 3.1 times as much refrigerator space as a full course of the traditional vaccines combined. The additional cold chain capacity required would only be 25 cm 3 or 32% if the diluent could be stored outside the cold chain until it requires cooling just prior to reconstitution. However, since there are different lot numbers on vaccine and diluent, health workers are reluctant to separate the contents of the boxes in case there is a need to investigate an adverse event. Therefore, it is important that the manufacturer synchronizes the lot numbers on vaccine and diluent so that, as is normal practice with other antigens, the diluent can be transported outside the cold chain. Annex 11 Accelerating the Introduction of Rotavirus Vaccines into GAVI-Eligible Countries Page A11-1

72 GSK is in the process of developing and testing a liquid formulation. If successfully developed and registered, the liquid formulation may mitigate some of the problems described. It is recommended that GAVI work with GSK now with the goal of identifying the minimum packaging requirements to meet regulatory requirements prior to the finalization of the presentation, including the external box and any delivery devices. Merck s Rotateq Merck s Rotateq vaccine has a familiar presentation, similar to OPV, in plastic squeezedropper vials and will be delivered in boxes containing 10 mono-dose vials. However, the current mono-dose vials have 75 percent empty space and very large caps. Three doses of vaccine will require an additional 178 cm 3 or 2.3 times as much refrigerator space as a full course of the traditional vaccines combined. Merck has stated publicly that they are committed to reconfiguring the packaging to minimize impact on the cold chain capacity within regulatory constraints. The company welcomes a collaborative approach with the public sector to ensure that the concerns and issues of developing countries are appropriately addressed. Role of GAVI GAVI has a potentially critical role to play in mitigating the impact of rotavirus vaccines on the cold chain in GAVI-eligible countries. ISS funding. GAVI has committed to make funds available to countries to assist with the expansion of the cold chain necessary to accommodate new vaccines. It is important that these investments be used in a fashion that optimizes new cold chain capacity, taking into consideration GAVI s future projections for new vaccines. For example, funding for cold chain expansion should not be limited to the needs of a single new vaccine, but based on the projected needs across the range of potential vaccines that countries may be adopting in the next several years. Dialogue with vaccine manufacturers. Early discussions with vaccine manufacturers with the goal of identifying packaging and presentations that reduce the per-dose volume of vaccine destined for developing countries are important. Both of the current manufacturers are exploring options to reduce the impact of their products, and the manufacturers themselves have been quite receptive. GAVI should also begin engaging with the developing-country manufacturers soon so that packaging and presentation options can be considered during development. For all of these discussions, GAVI will play a key role in providing the manufacturers with consolidated input from the public sector, including the expressed needs of the developing-country-based users. Purchasing requirements. Another option for GAVI to influence the manufacturers is to clearly express packaging and presentation preferences in the purchasing requirements. Once again, the success of this approach is dependent on timely and accurate information about the optimal product requirements, taking into consideration field-based input. Annex 11 Accelerating the Introduction of Rotavirus Vaccines into GAVI-Eligible Countries Page A11-2

73 Comparison of Storage Capacity Needs for Rotarix and Standard EPI Vaccines Current packaging of Rotarix vaccines presents serious space constraints with regard to transport in the cold chain and storage at health facilities. Packaged together with a connector, applicator, and diluent, one dose of Rotarix vaccine takes up space that could hold nearly 45 doses of polio vaccine. Apart from the vaccine itself, refrigeration is not necessary for these other components, which comprise nearly 90% of the total package volume. Vaccine volume per dose Polio: 2.5 cm 3 /dose (10-dose vial)* Measles: 1.5 cm 3 /dose (20-dose vial)* Rotarix : - Contents include vaccine, diluent, applicator, connector: cm 3 /dose - Vaccine only: 11.4 cm 3 /dose *Source: WHO. Guidelines on the international packaging and shipping of vaccines. 2002; WHO/V&B/ Vaccine store at rural hospital, Mozambique 1 pack polio vaccine (upper shelf) = 100 doses (16 packs visible = 1600 doses) 1 pack measles vaccine = 500 doses (5 packs visible = 2500 doses) Storage also includes doses of DPT and other EPI vaccines. District vaccine store, Brazil 1 pack Rotarix = 25 doses, including diluent (25 packs visible = 625 doses in standard refrigerator) Note: Despite current Rotarix packaging that includes vaccine and diluent within the same box, it is not necessary to refrigerate diluent while transporting or storing. Annex 11 Rotavirus Vaccine Investment Case Page A11-3