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Accelerating the Introduction of Rotavirus Vaccines into GAVI

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					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 98107 USA
 (206) 285-3500
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.......................................................................... 10
       3b. Vaccine costs: Country co-payments ................................................................ 11
       3c. 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................................................................... 14
       5a. Alignment with GAVI priorities, milestones, and principles ............................... 14
       5b. Target countries ................................................................................................ 15
   Section 6: Expected Public Health Impact of the Investment...................................... 16
       6a. Impact of the investment on burden of disease: Investment 1 .......................... 17
       6b. Impact of the investment on burden of disease: Investment 2 .......................... 17
       6c. Contribution to Millennium Development Goals ................................................ 17
       6d. Impact of the investment on burden of disease through 2025:
       Investments 1 and 2 combined ............................................................................... 18
   Section 7: Support for Accelerated Introduction.......................................................... 19
       7a. Support activities, 2007-2010 (Investment 1).................................................... 19
       7b. Support activities, 2011-2015 (Investment 2).................................................... 23
       7c. Partners and responsibilities ............................................................................. 23
   Section 8: Constraints and Probability of Success...................................................... 24
       8a. Epidemiological and vaccine performance constraints ..................................... 24
       8b. Technical constraints ........................................................................................ 25
       8c. Institutional constraints ...................................................................................... 25



Accelerating the Introduction of Rotavirus Vaccines into GAVI-Eligible Countries                                                   Page ii
       8d. Social and cultural constraints........................................................................... 26
       8e. Vaccine supply security and price ..................................................................... 26
       8f. Critical risks ........................................................................................................ 27
   Section 9: Economic Analysis ..................................................................................... 28
       9a. Cost-effectiveness analysis............................................................................... 28
       9b. Sensitivity analysis—vaccine cost-effectiveness............................................... 30
       9c. Sensitivity analysis—vaccine impact ................................................................. 30
       9d. Market analysis ................................................................................................. 31
Part 3: Monitoring and Evaluating Implementation ......................................................... 33
References...................................................................................................................... 35


Annex 1:               Key References about Disease and Disease Burden
Annex 2:               Supplementary Information on Other Interventions for Rotavirus Diarrhea
Annex 3:               Characteristics of the Two Licensed Rotavirus Vaccines
Annex 4:               List of GAVI-Eligible Countries by Investment Period
Annex 5:               Systems Costs
Annex 6:               Impact Analysis, Demand Forecasting, and Cost-Effectiveness: Methods
                       and Assumptions
Annex 7:               Alternative Price and Co-financing Scenarios
Annex 8:               Estimated Vaccine Impact by Country
Annex 9:               Timeline
Annex 10:              Details of Activities to Support Accelerated Vaccine Introduction
Annex 11:              Technical Constraints
Annex 12:              Harmonization of Economic Analysis Methods for Rotavirus and
                       Pneumococcal Vaccine Investment Cases




Accelerating the Introduction of Rotavirus Vaccines into GAVI-Eligible Countries                                                        Page iii
List of Tables

Table 1. Estimated GAVI funding associated with Investments 1 and 2
for 2007-2015..................................................................................................................10

Table 2. Estimated cumulative country co-payments associated with
Investments 1 and 2 for 2007-2015 ................................................................................ 11

Table 3. Current status of critical information influencing accelerated introduction
of rotavirus vaccines ....................................................................................................... 12

Table 4. Components of accelerated introduction support, 2007-2010 .......................... 21

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 2007-2025 .............................................................................................. 29

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 .............................................................................. 30

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 2........................................................................................................ 16

Figure 3. Infants vaccinated and lives saved through 2015 ............................................ 18

Figure 4. Infants vaccinated and lives saved: 2007-2025 ............................................... 19




Accelerating the Introduction of Rotavirus Vaccines into GAVI-Eligible Countries                                                    Page iv
 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 thousand-
fold higher: 1 in 250.3,4

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
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 2006. In addition, one manufacturer
applied for WHO prequalification in January 2006, and the other applied in September 2006.

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 2009.
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
2011.

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 2007-2025 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
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 2007. 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 decision-
making.

In addition to subsidizing vaccine purchase, GAVI will need to invest in strategic and technical
activities beginning in 2007. 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
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 GAVI-
eligible countries.

The costs to health systems for 13 countries adopting vaccine during the period 2007-2010 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 2007-2010.

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
 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
Figure 1. Annual deaths from rotavirus, by region (adapted from Parashar, 2006)3

                                                           United States
                                     Europe                and Canada
                                      11,838                    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
construct (Merck’s RotaTeq®)—were licensed by WHO-recognized regulatory authorities in
2006. 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 2009.

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 2011.

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 2025.




Accelerating the Introduction of Rotavirus Vaccines into GAVI-Eligible Countries             Page 7
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 2015.
• 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 2025.
• 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 2007.

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 2007. 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 GAVI-
eligible 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
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 2010.
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 GAVI-
eligible countries, funding is requested for two separate categories:
• Vaccine costs—Vaccine costs include GAVI subsidies to countries adopting between 2007
  and 2015. 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 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.



Accelerating the Introduction of Rotavirus Vaccines into GAVI-Eligible Countries               Page 9
• 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 2007-10
  have been estimated at $38 million. Support costs for the five-year period 2011-2015 are more
  difficult to estimate, and will depend upon findings from introduction efforts and clinical trials
  in 2007-2010. Since 2011-2015 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 2007-2015

                                     Years 2007-2010            Years 2011-2015          Total
 Vaccine costs for                     $13-$49 million            $20-$88 million   $33-$137 million
 Investment 1 countries
 Vaccine costs for
                                             ------             $206-$690 million   $206-$690 million
 Investment 2 countries
 Strategic and technical
                                         $38 million                $42 million        $80 million
 support costs
 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
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 post-
conflict 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 co-
financing assumptions used in these cost calculations.

Table 2. Estimated cumulative country co-payments associated with Investments 1 and 2
for 2007-2015
                           Investment 1             Investment 1             Investment 2       Total
                             2007-2010                2011-2015                2007-2015
 Country co-                  $5 million              $17 million              $81 million   $103 million
 payments

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 2015.

3c. 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
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

                                                                       Level of Information About:
                                                                                                                            Human
                               Number                                                  Safety and           Post-          Resource
               Adoption       of GAVI-                                                 Efficacy in       licensure        and Health
               beginning       eligible                                Cost-            Clinical        Safety and         Systems
 Region          (year)       countries      Disease Burden        Effectiveness          Trials       Effectiveness       Capacity

 Latin
 America
                  2007             6
                                                 ++                   ++                ++                   –                –
 Europe           2008             8
                                                  +                   +*                 +                   –                –
 Asia             2010            22
                                                 ++                   +*                   –                 –                –
 Africa           2010            36
                                                  +                   +*                   –                 –                –
++: 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 2015. 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 financially-
sustainable 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
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
 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-2005. 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 GAVI-
eligible 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 2006-2015 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
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 GAVI-
eligible 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 GAVI-
eligible 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 2010. (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 2007. 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 2009.

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 2007. A second policy decision regarding Investment 2 will need
to be taken in 2010. 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
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 2

   70


   60


   50


   40


   30


   20


   10


   0
        2007    2008    2009      2010     2011     2012     2013   2014    2015     2016     2017     2018    2019      2020


                               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 2018. 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 2018.

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
2025. 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
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 2010.

6c. 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 www.un.org/millenniumgoals/). By 2015, it is




Accelerating the Introduction of Rotavirus Vaccines into GAVI-Eligible Countries             Page 17
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

                       40                                                                          140
  Infants Vaccinated




                       35                                                                          120




                                                                                                         Lives Saved
                       30




                                                                                                         (thousands)
                                                                                                   100
       (millions)




                       25
                                                                                                   80
                       20
                                                                                                   60
                       15
                                                                                                   40
                       10
                       5                                                                           20

                       0                                                                           0
                            2006    2007   2008   2009   2010   2011   2012   2013   2014   2015


                                   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 2025. 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 2025. 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
Figure 4. Infants vaccinated and lives saved: 2007-2025


                                       70                                                                                                         250
       Infants Vaccinated (millions)




                                                                                                                                                        Lives Saved (thousands)
                                       60
                                                                                                                                                  200
                                       50

                                       40                                                                                                         150

                                       30                                                                                                         100
                                       20
                                                                                                                                                  50
                                       10

                                        0                                                                                                         0
                                            2006 2007 2008 2009 2010 2011 2012 2013 2014 2015 2016 2017 2018 2019 2020 2021 2022 2023 2024 2025


                                                     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, 2007-2010 (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
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 cost-
   effectiveness 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
             Table 4. Components of accelerated introduction support, 2007-2010

COMPONENT 1: Latin America and the European region
Focus Areas        Objectives                                                                Specific Activities
Disease            • Establish robust disease burden estimates and data on strain            • Support rotavirus surveillance in sentinel sites pre-
Surveillance         distribution to allow measurement of impact of introduction.            introduction
Post-              •   Evaluate vaccine introduction                                         • Design and implement surveillance for safety
Marketing          •   Build and sustain confidence in vaccination programs                  • Design and implement vaccine effectiveness studies
Surveillance       •   Catalyze vaccine introduction in other countries and regions          • Continue rotavirus disease and strain surveillance post-
                   •   Identify potential strain replacement post-vaccination                  introduction

Demonstration      • Identify logistical health system constraints to vaccine scale-up       • Design and implement demonstration project
Project              (human resource capacity, cold chain, transportation, integration of    • Identify significant programmatic deficiencies in vaccine
                     services)                                                                 delivery and make recommendations for successful vaccine
                   • Provide “real world” costs and benefits                                   delivery strategies
                   • Measure the reduction in disease burden (public health impact).         • Identify and communicate results to allow countries to
                   • Stimulate country and regional vaccine introduction efforts               prepare for vaccine introduction
COMPONENT 2: Africa and Asia
Focus Areas        Objectives                                                                Specific Activities
Disease            • Confirm morbidity of rotavirus in representative countries in region    • Strengthen and expand rotavirus disease surveillance
Surveillance         to demonstrate need and stimulate demand for vaccine                    • Train laboratory workers in rotavirus detection methods
                     introduction                                                            • Communicate results to local and global public health
                   • Establish pre-vaccination disease incidence and strain distribution       communities
                     to allow measurement of impact of introduction
Clinical Trials*   • Establish vaccine safety and efficacy in impoverished settings          • Design and implement clinical trials
                                                                                             • Identify and communicate vaccine safety and efficacy
                                                                                               estimates
Effectiveness      • Establish safety and effectiveness of human monovalent vaccine          • Design and implement effectiveness study
Study                construct in impoverished settings in Asia                              • Identify and communicate vaccine safety and effectiveness
                                                                                               estimates
COMPONENT 3: Global Activities
Focus Areas        Objectives                                                                Specific Activities
Policy             • Strengthen expertise in decision-making for rotavirus and diarrheal     • Generate rotavirus and diarrheal disease information, tools,
Development/         disease control programs and policies                                     and guidelines for stakeholders in various media
Support            • Create favorable political/social environment for vaccine               • Organize meetings/workshops for key stakeholders
                     introduction                                                            • Generate tools for rotavirus decision-making and planning
                   • Ensure appropriate and timely decisions so vaccine is made              • Participate in processes to develop key consensus
                     available as early as possible                                            documents
Financing          • Procure adequate funding for key support activities at country,         • Further refine cost-effectiveness and, especially for planning
Support              regional, and global levels                                               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.
Demand/            • Increase probability of sustainable vaccine supply                      • Develop, refine, and disseminate strategic forecast of global
Supply                                                                                         market, supply, and demand
Monitoring                                                                                   • Identify and disseminate key demand drivers
                                                                                             • Support Rotavirus Supply Working Group efforts with
                                                                                               multinational and potential developing country suppliers
Project            • Ensure overall coordination of rotavirus activities, strategic focus,   • Oversee administration of project activities
Management           global communication, and consensus building                            • Communicate with GAVI Board and other stakeholders on
and                • Ensure accountability for all funding, agreements, and results            key project components
Administration                                                                               • 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
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 information-
   sharing 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
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, 2011-2015 (Investment 2)
In 2009-10, the 2011-2015 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, 2011-2015 support activities will be focused in Africa and Asia and include post-
marketing 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 2007-2010, global-
level 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; post-
marketing 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
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
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 cm3 per dose, the two current rotavirus vaccines by
GlaxoSmithKline and Merck, occupy 123 cm3 and 60 cm3 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
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 GAVI-
eligible 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
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       Low probability with high consequence.                   The investment is proposed in two stages to
 associated with one or both                                                               allow GAVI’s careful consideration of findings
                                  In July 1999, a rhesus rotavirus tetravalent vaccine
 rotavirus vaccine constructs.                                                             before reinvesting in 2010.
                                  (RotaShield) was associated with development of
                                  intussusception among vaccine recipients in the          Surveillance activities are proposed to identify
                                  US, leading to the suspension of vaccine use and         potential adverse events and prevent
                                  ultimately the cessation of research and marketing       misinterpretation of findings.
                                  activities worldwide. Large placebo-controlled
                                                                                           Risks may be offset somewhat by the fact that
                                  clinical trials have not demonstrated an association
                                                                                           with two different vaccine constructs, one may
                                  between the current GSK and Merck rotavirus
                                                                                           prove unsafe, but not the other.
                                  vaccines and intussusception. Given this
                                  reassurance, the potential for association with a        Communication activities are proposed to
                                  serious adverse event is low, but real, as the           disseminate accurate information, respond to
                                  vaccine is introduced to larger numbers of children.     inaccurate information, and develop appropriate
                                  See further discussion in Annex 10.                      messages in the event of a crisis.
                                  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.
 One or both rotavirus vaccine    Moderate probability with moderate consequence.          The investment is proposed in two stages to
 constructs are not efficacious                                                            allow GAVI’s careful consideration of findings
                                  Live, oral rotavirus vaccines may be less
 in preventing severe rotavirus                                                            before reinvesting in 2010.
                                  efficacious in impoverished populations due to host
 gastroenteritis in developing
                                  differences, higher prevalence of co-infections,         Risks may be offset somewhat by the fact that
 countries.
                                  sociocultural differences, or differences in rotavirus   two different vaccine constructs are being tested.
                                  serotype distribution. However, even if rotavirus
                                                                                           Clinical trials and proposed activities for
                                  vaccines are only moderately efficacious (50%),
                                                                                           technical support of GAVI’s investment are
                                  the impact may be substantial, given the high
                                                                                           designed to have identified some of the reasons
                                  incidence of rotavirus disease and its severe
                                                                                           why vaccines are ineffective, should they be
                                  consequences in the developing world. See further
                                                                                           found as such.
                                  discussion in Annex 10.
                                                                                           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.
 Gaps occur in GAVI funding       Low to moderate probability, but high                    To minimize funding gaps in
 at critical decision points:     consequence.
                                                                                           2007: plan for the possibility of a one-year cost-
 2006—Investment 1 decision       Activities could lose critical momentum in 2007 or       extension of the rotavirus ADIP.
                                  2010, causing delay in vaccine benefits to
 2010—Investment 2 decision                                                                2010: compile what is known from clinical trials,
                                  countries, or cause them to falter at the point where
                                                                                           with activities geared to multiple outcomes.
 2015—GAVI phase-out              support from GAVI is replaced by other sources.
                                                                                           2015: focus on both supply and demand to
                                                                                           ensure vaccines will be affordable and available.
 Clinical trial findings are      Low to moderate probability, but high                    Mitigate risk by conducting trials in multiple sites.
 incomplete due to unforeseen     consequence.
                                                                                           Plan for several possible trial outcomes, so that
 events (such as influenza
                                                                                           time is not lost.




Accelerating the Introduction of Rotavirus Vaccines into GAVI-Eligible Countries                                            Page 27
 Risk                             Risk Rating                                        Risk Minimization
 pandemic, political unrest).
 Over time, vaccine price fails   Low to moderate probability, but high              2007: Negotiate with multinational suppliers to
 to fall to $1.                   consequence.                                       achieve lowest initial price.
                                  After GAVI funding ends in 2015, demand may        Ongoing: Monitor emerging supplier progress in
                                  decrease substantially if price is unaffordable.   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
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 GAVI-
eligible countries by region and totals
                                                             Cumulative                         Cumulative cost per
                  Cost/DALY            Cost/DALY        Cost/DALY averted           Average      death averted for
  WHO              averted              averted         for the period 2007        per capita    the period 2007-
  Region         ($6.00/dose)         ($1.00/dose)            to 2025                GDP*              2025
  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 2007-2025
                                                                                Number of hospitalizations and
                     Number of lives saved           DALYs averted per         outpatient visits averted per 1,000
 WHO Region           per 1,000 vaccinated            1,000 vaccinated                     vaccinated
 AMR                            1.4                        49                                   141
 EUR                            2.3                        79                                   147
 AFR                            5.1                        174                                  132
 EMR                            2.9                        98                                   133
 SEAR                           3.0                        103                                  139
 WPR                            1.9                        63                                   139

 GLOBAL                         3.4                        117                                  137




Accelerating the Introduction of Rotavirus Vaccines into GAVI-Eligible Countries                               Page 29
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 2025.

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
                                                            Range or alternate     Cost/DALY averted
 Variable                        Base case value                scenario                (range)
                                                                                          $30
 Vaccine efficacy                        85%                     50%-100%
                                                                                      ($57 to $29)
                                                                                          $30
 Rotavirus mortality             Varies by country                 ± 25%
                                                                                      ($27 to $45)
 Relative coverage                       90%                     50% - 90%            ($47 to $35)
                                                                                          $30
 Health system costs                  0.50/dose                 $0.25-$1.50
                                                                                      ($27 to $50)
                                                                                      Current: $30
 Timing of vaccination                 Current                    On-time
                                                                                      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
Rotavirus mortality. Baseline disease mortality estimates for all countries were varied
25 percent higher and lower, resulting in a range of 1.8-2.9 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
                                                            Range or alternate
 Variable                        Base case value                scenario              Lives Saved
                                                                                        2.4 million
 Vaccine efficacy                        85%                     50%-100%
                                                                                    (1.4 – 2.8 million)
                                                                                        2.4 million
 Rotavirus mortality             Varies by country                 ± 25%
                                                                                    (1.8 – 2.9 million)
 Relative coverage                       90%                     50% - 90%           1.7 – 2.4 million
                                                                                   Current: 2.4 million
 Timing of vaccination                 Current                    On-time
                                                                                   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
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
 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 post-
  vaccine 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
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
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7
 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):477-479.
8
 Bryce J, Boschi-Pinto C, Shibuya K, Black RE. WHO estimates of the causes of death in children.
Lancet 2005; 365(9465):1147-1152.
9
 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):1720-1726.
10
  Podewils LJ, Antil L, Hummelman E, Bresee J, Parashar UD, Rheingans R. Projected cost-
effectiveness of rotavirus vaccination for children in Asia. J Infect Dis 2005; 192 Suppl 1:S133-S145.
11
  Boston Consulting Group. Final Report, Global Vaccine Supply, The Changing Role of Suppliers.
2006.
12
 Rotavirus and Rotavirus Vaccines. Proceedings of the Sixth International Rotavirus Symposium,
Mexico City: July 7-9, 2004. p. 49.
13
     See http://www.who.int/wer/2006/wer8101.pdf
14
  World Bank. Investing in Health. The World Development Report 1993. Washington, DC, World Bank,
1993)
15
  Walker, D. and R. Rheingans, Cost–effectiveness of rotavirus vaccines. Expert Review of
Pharmacoeconomics & Outcomes Research, 2005. 5(5): p. 593-601.
16
 Rheingans R, et al., Healthcare Costs of Rotavirus Gastroenteritis and Cost-Effectiveness of
Vaccination in Developing Countries (unpublished), 2005.
17
 World Health Organization. World Health Report 2002: Chapter 5 - Some strategies to reduce risk. In:
World Health Organizaton; 2002. p. 100-144.)




Accelerating the Introduction of Rotavirus Vaccines into GAVI-Eligible Countries                    Page 35
                                                    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):947-952.

      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):1147-1152.

      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 2000-03, 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):525-537.

      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
      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):75-77.

(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):371-377.

      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):304-306.

      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
      454,000-705,000) rotavirus-related deaths.




Annex 1
Accelerating the Introduction of Rotavirus Vaccines into GAVI-Eligible Countries                   Page A1-2
(7) Podewils LJ, Antil L, Hummelman E, Bresee J, Parashar UD, Rheingans R. Projected cost-
    effectiveness 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):11-22.

      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, -0.32 per 10,000 infants; 95 percent confidence interval, -2.91 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
 (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):23-33.

    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
                                                    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 meta-
analysis 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
                                                  References


   (1)    World Health Organization. The treatment of diarrhoea: A manual for physicians and
          other senior health workers, 4th rev. 2005. 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):1246-1255.
   (3)    Stallings R. Child morbity and treatment patterns. Calverton, MD: ORC Macro, 2004.
   (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):199-201.
   (5)    Ahmed FU, Karim E. Children at risk of developing dehydration from diarrhoea: a case-
          control study. J Trop Pediatr 2002; 48(5):259-263.
   (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):689-697.
   (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):440-442.
 (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):685-687.
 (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):1516-1522.
 (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):225-33.
 (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):2547-54.




Annex 2
Accelerating the Introduction of Rotavirus Vaccines into GAVI-Eligible Countries           Page A2-2
                                                    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

 Co-                  OPV, IPV, DTaP, DTwP                            IPV, DTaP, DTwP
 administration
                      HepB, Hib, PCV-7                                HepB, Hib, PCV-7
 Phase 2 & 3           n=63,225 healthy infants                       n=70,301 healthy infants
 Safety & Efficacy
 Trials               USA, Canada, Latin America (11), Taiwan,        USA, Mexico, Costa Rica, Jamaica,
                      Singapore, Hong Kong, Belgium,                  Guatemala, Puerto Rico, Taiwan, Belgium,
                      Germany, Finland, South Africa,                 Finland, Germany, Italy
                      Bangladesh, Sweden, Taiwan
 Licensure            EMEA-2006                                       FDA-2006

 Efficacy vs.         85% vs. severe rotavirus gastroenteritis and    98% vs. severe G1-G4 rotavirus
 rotavirus            100% vs. more severe episodes                   gastroenteritis
 gastroenteritis
 Efficacy vs.         40% vs.severe gastroenteritis of any cause;     59% vs. hospitalization for diarrhea of any
 gastroenteritis      42% vs. hospitalization for severe              cause in first year of life
 from any cause       gastroenteritis
 Intussusception      No association                                  No association




Annex 3
Accelerating the Introduction of Rotavirus Vaccines into GAVI-Eligible Countries                           Page A3-1
                                                    Annex 4
              List of GAVI-Eligible Countries by Investment Period
                                                    (64 total)


Investment 1 Countries (13)                          Investment 2 Countries (51)

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




Annex 4
Accelerating the Introduction of Rotavirus Vaccines into GAVI-Eligible Countries                  Page A4-1
                                                      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 2010. 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 2007-2010

         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 http://www.who.int/choice/en/)



Annex 5
Accelerating the Introduction of Rotavirus Vaccines into GAVI-Eligible Countries                       Page A5-1
                                                    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 2009.

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
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
2025.

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 2007. 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 (2007-2015), 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                  2007-2010                    2011-2015          Total
           $12                         49.6                         88.6            138.2
           $11                         45.1                         80.1            125.2
           $10                         40.5                         69.9            110.4
            $9                         36.0                         61.6             97.6
            $8                         31.5                         53.3             84.8
            $7                         26.9                         45.1             72.0
            $6                         22.4                         36.9             59.3
            $5                         17.9                         28.6             46.5
            $4                         13.3                         20.4             33.7



Annex 6
Accelerating the Introduction of Rotavirus Vaccines into GAVI-Eligible Countries             Page A6-2
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 2018. For example, if the price starts at
  $12 it drops $1.60 per year from 2014 through 2018.

• 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 2017.

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 (2011-15)

  - Intermediate = $0.20 (2007-2010), $0.40 (2011-15)

  - Poorest = $0.10 (2007-2010), $0.20 (2011-15)

  - Fragile = $0 (2007-15)


• 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
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 2015.

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 early-
adopters. 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
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 2008-09 and 2012.

Figure 1. Doses Demanded (Investment 1)

                               7



                               6
  Demand in Doses (millions)




                               5



                               4



                               3



                               2



                               1



                               0
                                   2006   2007   2008   2009   2010   2011   2012   2013   2014   2015   2016   2017   2018   2019   2020   2021   2022   2023   2024   2025


                                                                                              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
Figure 2. Forecasted Demand for GAVI-eligible Countries (Investments 1 and 2)

                                180


                                160


                                140
   Demand in Doses (millions)




                                120


                                100


                                 80


                                 60


                                 40


                                 20


                                 0
                                      2006 2007 2008 2009 2010 2011 2012 2013 2014 2015 2016 2017 2018 2019 2020 2021 2022 2023 2024 2025


                                                     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
Vaccine efficacy
Vaccine efficacy estimates in the analysis were derived from clinical trial data of a live-
attenuated, 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 rotavirus-
associated 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
2007-2025. 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 2007-2025. This calculation
yields nearly 100 million visits averted.




Annex 6
Accelerating the Introduction of Rotavirus Vaccines into GAVI-Eligible Countries            Page A6-7
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
References
[1]      Wolfson, LJ, WHO ICE-T®: Immunization and Coverage Estimates and Trajectories.
         WHO Department of Immunization, Vaccines & Biologicals, 2005.

[2]      Rheingans R, et al., Healthcare Costs of Rotavirus Gastroenteritis and Cost-Effectiveness
         of Vaccination in Developing Countries (unpublished), 2005.

[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):565-72.

[4]      Velazquez FR, slide presentation at ESPID (the European Society for Pediatric Infectious
         Diseases), Vallencia, Spain, May 2005.

[5]      RVP personal communication with clinical trial researchers.




Annex 6
Accelerating the Introduction of Rotavirus Vaccines into GAVI-Eligible Countries         Page A6-9
                                                    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 2017. 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
Table 1. Results of alternative price scenarios, compared to the base case

                                                 Investment 1        Copays from countries
                                                 & 2 subsidies         and their donors         Total
                                                  (2007-2015)            (2007-2025)         (2007-2025)
 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 2017. We assume countries (and/or their donors) will
pay the full $1.00 per dose beginning in 2017. 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
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 2010. For the base case scenario we set
the co-financing requirement at $0.50 for 2007-2008, $0.60 for 2009, and $0.70 for 2010. 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 2009. 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 2015. 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)
                          2007     2008      2009     2010      2011     2012      2013    2014    2015      2016    2017
 Subsidies-GAVI
 Phase II                 612      1,242     1,830    1,796     1,743    1,608     1,201   927     654
 Subsidies-Post GAVI
 Phase II                                                                                                    381     -

 Country Co-finance       87       177       323      381       436      436       437     436     436       435     544

 Total Cost               699      1,419     2,153    2,177     2,179    2,045     1,637   1,363   1,089     816     544


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 2010. This amount would be increased after 2010. For the base case scenario we set the
co-financing requirement at $0.20 for 2007-10. For 2011 through 2015 we doubled the co-
financing 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 2010. 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 2015. 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
Table 3. Uzbekistan Vaccine Costs by Financing Source (US$1,000s)
                          2008     2009      2010     2011      2012     2013      2014    2015    2016      2017
 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       108      216       325      653       654      656       649     642     635       1,569

 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 2017. Table 4 shows the
costs through 2017 for Pakistan using the base case co-financing assumptions. The cost of
subsidies increases through 2015. 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)
                          2014     2015      2016      2017
 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 2010. This amount would be increased
after 2010. For the base case scenario we set the co-financing requirement at $0.10 for 2007-10.
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 2012. 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 2015. The cost of the country co-finance increases sharply through
2012, and then increases slowly through 2016. 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
Table 5. Bangladesh Vaccine Costs by Financing Source (US$1,000s)
                          2010     2011      2012      2013     2014      2015     2016     2017

 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 2017. 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
                                                    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                                        Estimated deaths
 Country                      averted through 2025            Country                 averted through 2025
 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
                                                Annex 9: Timeline of Components
                                 Required to Assure Accelerated Introduction of Rotavirus Vaccines
                                                           PRE-PROJECT                                                                         INVESTMENT CASE PROJECT

                                                                                                                          Investment 1                                                      Investment 2
                                           2003           2004         2005             2006             2007            2008      2009               2010          2011         2012           2013       2014     2015

GAVI investment decisions      (♦)
                                       ♦                                                         ♦                                             ♦
Latin America                                               Surveillance
                                       Clinical trials*
                                                                   Logistics support
                                                                                                     Post-marketing activities
                                                                                                Demonstration project




Eastern Europe                                                     Surveillance
                                       Clinical trials*
                                                                                                     Logistics support
                                                                                                                   Post-marketing activities
                                                                                                     Demonstration project




Asia                                   Surveillance
                                                                           Clinical trials **
                                                                                                                   Logistics support
                                                                                                                                                   Post-marketing activities
                                                                                                     Effectiveness study




Africa                                                      Surveillance
                                                                           Clinical trials **
                                                                                                                                                   Logistics support
                                                                                                                                                                Post-marketing activities




Global
                     Investment case                               Development                                                   Refinement
           Demand/supply monitoring                         Forecast                        Estimation                           Refinement        Ongoing monitoring
          Policy development/support
         Project management & admin.


                                           2003           2004         2005             2006             2007            2008       2009              2010          2011         2012          2013        2014     2015

                                       * 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
                                                   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 post-
   marketing 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 cost-
effectiveness 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 GAVI-
eligible 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
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
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 2006.

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
•   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 post-
marketing 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 post-
marketing 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
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 post-
introduction. 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 disease-
burden 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
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 risk-
benefit 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 2007-2010 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
                                                   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 cm3 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 cm3 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
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 squeeze-
dropper 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 cm3 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
                            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
                                                                                                                                   3
                                                                                                                      Polio: 2.5 cm /dose (10-dose vial)*
                                                                                                                                      3
                                                                                                                      Measles: 1.5 cm /dose (20-dose vial)*

                                                                                                                      Rotarix® :
                                                                                                                      - Contents include vaccine, diluent,
                                                                                                                                                      3
                                                                                                                      applicator, connector: 111.6 cm /dose
                                                                                                                                              3
                                                                                                                      - Vaccine only: 11.4 cm /dose

                                                                                                                      *Source: WHO. Guidelines on the
                                                                                                                      international packaging and shipping of
                                                                                                                      vaccines. 2002; WHO/V&B/01.05.



Vaccine store at rural hospital, Mozambique
• 1 pack polio vaccine (upper shelf) = 100 doses (16   District vaccine store, Brazil
  packs visible = 1600 doses)                          • 1 pack Rotarix® = 25 doses, including diluent (25
• 1 pack measles vaccine = 500 doses                     packs visible = 625 doses in standard refrigerator)
  (5 packs visible = 2500 doses)
• Storage also includes doses of DPT and other EPI     Note: Despite current Rotarix® packaging that includes
  vaccines.                                            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
                                                   Annex 12
             Harmonization of Economic Analysis Models for the
           Rotavirus and Pneumococcal Vaccine Investment Cases


   The models used to gauge rotavirus and pneumococcal vaccine cost-effectiveness are
   highly similar in major assumptions and methods. Each economic team used an external
   expert panel to review and revise key assumptions, and both panels concluded the overall
   results were generally comparable. A discussion follows of each model’s approach.



Comparability of models

The models shared common sources of data for:
• Birth cohorts (UN Population Division).
• DTP3 coverage rates (WHO ICE-T).
• Discount rates for costs and benefits (3% per annum).
• Vaccine wastage rates (10%).
• Disability weights for calculating DALYs (Disability Adjusted Life Years).

The central assumptions driving cost-effectiveness in both models were vaccine cost, estimated
disease burden, and vaccine efficacy. Overall comparability between models depends on
comparable assumptions for these aspects of the models. These critical assumptions are
comparable across models, and reflect the current state of knowledge for rotavirus and
pneumococcal diseases and vaccines.
• Vaccine cost. The pneumococcal vaccine model incorporates a steady state assumption for
  vaccine cost per dose, while the rotavirus vaccine model incorporates a price erosion
  projection over time. The pneumococcal team is currently incorporating a price erosion
  projection into PCV’s economic model.
• Disease burden. Both models accounted for inpatient and outpatient, fatal and non-fatal
  disease, using best empiric estimates and expert panel validation.
• Vaccine efficacy. Both models used high quality, Phase 3 clinical trial data as the basis for
  their vaccine efficacy estimates. The rotavirus model explicitly modeled delays in
  immunization and a resultant blunted vaccine efficacy compared with on-time immunization.
  The pneumococcal model accounted for this by incorporating vaccine efficacy estimates from
  a clinical trial in which delayed immunization occurred routinely (median, five and ten weeks
  delay for first and third doses), but did not otherwise model immunization delays explicitly.
  The pneumococcal model incorporated both direct vaccine effect and indirect protection via



Annex 12
Accelerating the Introduction of Rotavirus Vaccines into GAVI-Eligible Countries      Page A12-1
   herd immunity, extrapolating from the U.S. experience. As is appropriate to the current state
   of knowledge, the rotavirus vaccine model did not incorporate indirect effects.

In a second tier are assumptions to which results from these economic models are robust but
which differ between models. Because the models are robust to them, they have little potential to
influence comparability, but perceived differences may influence face validity. Such assumptions
include perspective and currency.
• Perspective. The rotavirus model primarily used a healthcare system perspective, while the
  pneumococcal model employed a societal perspective. The incorporation of transportation
  costs and caregiver productivity costs (i.e., societal costs) into the pneumococcal vaccine
  model had minimal effects on net costs. Net costs and cost-effectiveness remain comparable
  between models.
• Currency. The bulk of net costs in both models are derived from vaccine-related costs. These
  costs are comparable across both models, despite being presented in international dollars
  versus U.S. dollars. Why? Vaccine will be traded on the international market where the PPP
  weight is 1. On that market, one international dollar equals one U.S. dollar. Cost offsets due to
  averted disease-related costs will differ according to the currency (ID versus USD) used.
  However, both models are robust to disease-related cost assumptions.

There are other minor differences in the models, included in the summary table below. These
minor differences do not influence comparability. As an example, while methods to estimate
vaccine administration costs differed between models, the RV per-dose estimate of USD 0.50
and the PCV model per-dose estimate (weighted average) of ID 0.47 differ trivially.


Overall comparability and implications for interpretation

Despite some differences between the two models, both research teams feel that the results are
generally comparable. Each model includes additional sensitivity analyses and scenarios that
address key uncertainties and provide a range of estimates of impacts and cost-effectiveness that
are likely to capture the actual outcomes. Although the point estimates for the two analyses
differ, the ranges of estimates for the two vaccines are very similar. Both vaccines should be
considered equally cost-effective and both would meet the standard of “very cost-effective”
suggested by the World Health Organization.




Annex 12
Accelerating the Introduction of Rotavirus Vaccines into GAVI-Eligible Countries         Page A12-2
Methods used in rotavirus vaccine and pneumococcal vaccine economic
analyses

                        Rotavirus                    Pneumococcal                  Comments

 Perspective            Primary perspective is       Primary perspective is        Societal costs, including
                        health care system;          societal; Secondary is        household indirect and
                        Secondary is societal        health care system            direct costs have a
                                                                                   minimal impact on cost-
                                                                                   effectiveness results.

 Expert panel           Yes                          Yes                           Same in both models.

 Discounting            3% costs and benefits        3% costs and benefits         Same in both models.

 Costs:

 • Direct medical       Source: WHO-CHOICE           Source: WHO-CHOICE            Same in both models.
   costs

 • Vaccine              Literature review            Source: 8 Financial           Vaccination administration
   administration                                    Sustainability Plans          costs account for a small
   costs                                                                           fraction of the intervention
                                                                                   costs. The independent
                                                                                   estimates were very
                                                                                   similar.

 • Currency             2002 USD                     2000 International D          The difference in base
                                                     (PPP-adjusted US dollars)     year does not significantly
                                                                                   impact values. The
                                                                                   majority of the net cost is
                                                                                   driven by the purchase
                                                                                   price of the vaccine. Since
                                                                                   the vaccine would be an
                                                                                   internationally purchased
                                                                                   good, the USD and
                                                                                   International dollar price
                                                                                   would be essentially
                                                                                   equivalent.

 • DALYs                Formula: based on life       Formula: based on life        Same in both models.
                        expectancy at age 1 for      expectancy at age 1 for
                        fatal events; standard       fatal events; standard
                        disability weights for       disability weights for non-
                        non-fatal cases; age-        fatal cases; age-weighted
                        weighted and                 and discounted at 3%
                        discounted at 3%




Annex 12
Accelerating the Introduction of Rotavirus Vaccines into GAVI-Eligible Countries                     Page A12-3
                        Rotavirus                    Pneumococcal                  Comments

 Vaccine
 program:

 • Doses                2                            3                             Intrinsic difference.

 • Wastage rate         10%                          10%                           Same in both models.

 • Coverage             Base case coverage is        DTP3 for steady state         Actual coverage levels do
                        from WHO estimates of        based on WHO ICE-T            not impact cost-
                        DTP3 coverage.               estimates for 2003            effectiveness. Base case
                        Accounts for delays in                                     in the pneumo model
                        dose 1 and 2, as well                                      would be comparable to
                        as reduced coverage in                                     the ‘on-time’ scenario in
                        those at high risk of                                      the rota model.
                        mortality. Additional
                        scenarios for on-time
                        vaccination, delayed
                        vaccination and
                        theoretical best-
                        achievable DTP3.

 • Vaccine              85% against severe           Based on Gambian trial        Both models use the best
   efficacy             disease resulting in         result of 7.4 deaths          available clinical and
                        hospitalization or           averted per 1000 children     epidemiological data to
                        mortality; 70% for other     (16% of all deaths) against   estimate the burden and
                        rotavirus illness; if only   all-cause mortality,          health benefit relevant for
                        one dose received,           adjusted at country-level     each vaccine. Differences
                        efficacy is ½ two-dose       as described above.           in methods are based on
                        efficacy.                                                  differences in disease
                                                     Additional assumptions in     dynamics and information
                                                     pneumo analysis:              availability.
                                                     • VE against non-fatal
                                                       hospitalized
                                                       pneumonia 35%
                                                     • VE against non-fatal
                                                       meningitis 22%
                                                     • VE against non-fatal,
                                                       outpatient pneumonia
                                                       7%
                                                     Herd immunity effects:
                                                     • Clinical pneumonia:
                                                       Non-vaccinated infants
                                                       received ¼ the
                                                       protection afforded
                                                       vaccinated infants
                                                     • IPD: Non-vaccinated
                                                       children receive ½ the
                                                       protection afforded
                                                       vaccinated infants




Annex 12
Accelerating the Introduction of Rotavirus Vaccines into GAVI-Eligible Countries                     Page A12-4
This comparison was written by the developers of the cost-effectiveness models:

Rotavirus vaccine
• Richard Rheingans, PhD
  Assistant Professor
  Hubert Department of Global Health
  Rollins School of Public Health, Emory University

Pneumococcal vaccine
• Tracy Lieu, MD MPH
  Professor
  Department of Ambulatory Care and Prevention, Harvard Medical School and
  Harvard Pilgrim Health Care

• Anushua Sinha, MD MPH
  Assistant Professor
  Department of Preventive Medicine and Community Health New Jersey Medical School




Annex 12
Accelerating the Introduction of Rotavirus Vaccines into GAVI-Eligible Countries   Page A12-5

				
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