PROCEEDINGS 8 INTERNATIONAL ROTAVIRUS SYMPOSIUMJune 3–4, 2008 Istanbul, Turkey. Acknowledgements...

Sabin Vaccine InstituteInternational Vaccine Advocacy

2000 Pennsylvania Avenue, NWSuite 7100

Washington, DC 20006Phone: 202-842-5025

Fax: 202-842-7689www.sabin.org

PROCEEDINGS FROM THE

8th INTERNATIONAL ROTAVIRUS SYMPOSIUM

June 3–4, 2008

Istanbul, Turkey

AcknowledgementsThe Symposium Organizing Committee wishes to thank the following organizations

for support of the 8th International Rotavirus Symposium:

Sabin Vaccine Institute

US Centers for Disease Control and Prevention

Merck Research Laboratories

GlaxoSmithKline Biologicals

PATH

Sanofi Pasteur

Norwegian Institute of Public Health

World Health Organization



Istanbul, Turkey

June 3–4, 2008

Table of Contents

Foreword . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .v

Executive Summary . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .vii

Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .ix

Keynote Address: Roger Glass, Fogarty International Center of the National Institutes of Health, US . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .1

The Emergence of Rotavirus as a Global Health Concern . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .1Developing a Strategy for Rotavirus Surveillance . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .2A Brief History of Rotavirus Vaccines . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .3Vaccine Cost and Vaccine Efficacy . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .4Mapping a Way Forward . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .4Sidebar: Rotavirus Timeline . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .5

Discovery of Rotavirus to a Vaccine in 25 years . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .6

Bovine Beginnings . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .6The Rhesus Rotavirus Vaccine . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .7Matching Safety with Efficacy . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .7

Session I: Update on Rotavirus Vaccine . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .8

Rotarix and the Key Challenges of Rotavirus Immunization . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .8RotaTeq: A Pentavalent Approach to Rotavirus Immunization . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .10World Health Organization Policies on Rotavirus Vaccines . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .11Vaccine Concerns: Interactions and Disease Transmission . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .12Sidebar: Interim Analysis of Vaccine Efficacy in South African Infants . . . . . . . . . . . . . . . . . . . . . . . . . . . . .13

Session II: Introducing New Rotavirus Vaccines . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .14

Regional Perspectives: The WHO European Region . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .14Regional Perspectives: Latin America and the Caribbean . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .14Regional Perspectives: Impact and Cost-Effectiveness in Central Asia . . . . . . . . . . . . . . . . . . . . . . . . . . . . .15Vaccine Monitoring Post-Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .16Sidebar: Keeping Track of Intussusception . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .16

Session III: Epidemiology and Burden of Rotavirus Disease . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .18

The Importance of Global Surveillance . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .18Estimating Deaths from Rotavirus . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .18Surveillance in the WHO EURO and EMRO Networks . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .19Sidebar: On the Lookout for Rotavirus Mutations . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .20

Proceedings from the 8th International Rotavirus Symposium iii

Session IV: Early Experience with Routine Use of Rotavirus Vaccines . . . . . . . . . . . . . . . . . . . .21

United States: “A Steady, Progressive Climb” . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .21Nicaragua: Responding to An Epidemic with a Vaccine . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .22European Union: Considering Disease Burden and Vaccine Costs . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .22

Session V: Policy Decision Making . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .23

Engaging the Public . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .23Confronting the Costs of Rotavirus Vaccines . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .23

The Next Steps for Rotavirus Vaccines . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .25

Vaccine as a Catalyst for Conquering Diarrheal Diseases . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .26Sidebar: Immunization Access and the Role of the GAVI Alliance . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .26Decision Making at the Country-Level . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .27

Concluding Remarks . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .29

List of Participants . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .30

iv Proceedings from the 8th International Rotavirus Symposium

Foreword

The 8th International Rotavirus Symposium was a collaborative effort of the Sabin Vaccine

Institute, PATH, the US Centers for Disease Control and Prevention, World Health

Organization and the Norwegian Institute of Public Health. The event attracted

representatives from over 67 countries who engaged the full range of scientific, social, and

economic challenges that must be overcome in order to prevent this major killer of children.

Rotavirus is the most common cause of diarrheal hospitalizations and diarrheal deaths among

children worldwide. Development of safe and effective rotavirus vaccines has been a global health

priority for many years. Two vaccines are on the market and others are in the research pipeline.

Rotavirus vaccination is now common in the US, and in several European and Latin American

countries. At the time of the conference, decision-makers in Eastern Europe, Central Asia, and the

Middle East were initiating a process to consider adding a rotavirus vaccine to their routine schedule

of childhood immunizations. Clinical trials were underway to demonstrate vaccine efficacy in low-

income countries of Africa and Asia, many of which are eligible to purchase vaccines with the

support of the GAVI Alliance.

The incredible progress toward global adoption of a rotavirus vaccination is in large part a tribute

to the focus and commitment of the scientific and policy experts from around the world who have

worked in close cooperation for many years to ensure rotavirus immunization has progressed

steadily from concept to reality.

The organizing committee would like to thank all involved for their diligent efforts and,

particularly, to our hosts in Istanbul. The practical insights coupled with the energy and enthusiasm

generated at this symposium provide a strong basis for optimism that in the near future, rotavirus

immunization will be ubiquitous and rotavirus disease will no longer rank as one of the world’s

major health problems.

Symposium Organizing Committee

Roger I. Glass, Fogarty International Center

John Wecker, Rotavirus Vaccine Program, PATH

Ciro de Quadros, Sabin Vaccine Institute

Elmira Flem, Norwegian Institute of Public Health

Cristiana Toscano, World Health Organization

Umesh Parashar, US Centers for Disease Control and Prevention

Duncan Steele, Vaccines and Immunization, PATH

Proceedings from the 8th International Rotavirus Symposium v

vi Proceedings from the 8th International Rotavirus Symposium

Executive Summary

The 8th International Rotavirus Symposiumtook place at a crucial time in the history ofrotavirus vaccines, which are intended toprovide protection from a disease that,

according to surveillance data presented by the WorldHealth Organization, kills 527,000 children each year.With two approved rotavirus vaccines in use, andtherefore two years of data on their safety and efficacynow available, participants had more information attheir command than in any previous year.

Roger Glass, Director of the Fogarty InternationalCenter at the US National Institutes of Health, openedthe meeting with a keynote address that celebrated thesize and geographic span of the meeting noting thatthe 2008 symposium attracted four times as manyparticipants as the first meeting in 1995. He then wenton to discuss how he and colleagues convinced theUnited States, a country with very few rotavirus deaths,that a vaccine could save a billion dollars a year indirect and indirect health care costs.

Glass also singled out a crucial insight in surveil-lance data, which shows that rotavirus epidemiologydiffers dramatically between high-income and low-income countries. In low-income countries, a largerproportion of rotavirus disease victims are under oneyear old, diarrheal diseases routinely involve a mix ofinfections, and the fatality rate is high.

Studies are underway in these regions to gauge thepotential efficacy and impact of rotavirus immuniza-tions, as past experience has shown that there can beimportant geographical variations in vaccine response.However, the high rate of rotavirus disease in poor coun-tries has left many eager for widespread adoption ofrotavirus immunization in the developing world.

“In the developing world, we’ve seen a very highcase fatality rate, which has motivated the entire globalprogram,” Glass said.

Glass went on to review a key development inrotavirus vaccine history: the rise and abrupt fall ofRotaShield®, the first approved vaccine for rotavirus.Within months of its introduction, some childrenvaccinated with RotaShield developed intussusception,a rare and dangerous bowel obstruction. The adverseevent prompted RotaShield’s manufacturer, Wyeth, towithdraw the vaccine from the market.

Glass and several other speakers noted that the casesof intussusception were in children vaccinated after 90

days of age. They said that since that time, all rotavirusvaccines in trials or routine use are supposed to begiven before 90 days, when babies appear to have anatural protection against intussusception.

Experts point out that the two rotavirus vaccinescurrently in use—GlaxoSmithKline Biologicals’ (GSKBio) Rotarix® and Merck’s RotaTeq®—are alwaysadministered before 90 days of age to avoid intussus-ception. Company representatives said clinical trialsconducted thus far have found the vaccines to be safeand effective.

Norman Begg of GSK said Rotarix was developedfrom the most common human rotavirus strain. Therationale for the approach, he said, was that naturalinfections with rotavirus confer excellent immunity tofurther infections. Begg said that studies show thatRotarix—when given before 90 days of age—does notincrease the risk of intussusception compared toplacebo. He stated that the vaccine produces broadprotection against many rotavirus strains, that theprotection lasts at least two years, and that the two-doseregimen can be safely administered with otherchildhood immunizations.

Max Ciarlet of Merck said the company took adifferent approach with its rotavirus vaccine. Itdeveloped RotaTeq from five human-bovine reassortantrotavirus strains. RotaTeq is administered in three dosesbecause it exhibits low replication capabilities in thehuman gastrointestinal tract, and three doses arerequired to build high and consistent immuneresponses, he said. According to data he presented,RotaTeq’s safety profile showed that RotaTeq is welltolerated and is not associated with an increase in thefrequency of serious or nonserious adverse events.

Cristiana Toscano presented the World HealthOrganization’s (WHO’s) policies on rotavirus vaccines,most notably that efficacy must be shown in at leastone low-income country in Sub-Saharan Africa orSouth Asia before WHO will recommend the use of thevaccines in these regions.

Duncan Steele, PATH’s senior advisor on diarrhealdisease, noted that trials were underway to generateefficacy data and results should be available betweenlate 2008 and 2010. He pointed out that, given the highrate of rotavirus disease in poor countries, even lessthan perfectly effective vaccines would save many livesand prove cost-effective.

Proceedings from the 8th International Rotavirus Symposium vii

Shabir Mahdi of South Africa’s University of theWitwatersrand presented interim results of an efficacytrial conducted in South Africa. He said they show that“the vaccine itself clearly offers a high degree ofprotection in South African children against severerotaviral illness during the first year of their life.”

Umesh Parashar of the US Rotavirus VaccinationProgram at the US Centers for Disease Control andPrevention presented early results from two years ofRotaTeq use in the US. Widespread monitoring ofrotavirus immunizations indicates that the rotavirusvaccine appears to be safe (when the first dose is givenbefore 90 days of age). Data on effectiveness show aslight drop in rotavirus diarrhea in the year afterRotaTeq was introduced, but a dramatic drop duringthe second year. Presentations on early experiences inNicaragua and the European Union followed. Thediscussions revealed that, despite similar rotavirusburdens, attitudes in Europe vary widely as to when,where and how to introduce a rotavirus vaccine.

Presentations on policy concerns included adiscussion of how to communicate rotavirus issues tothe public, policy makers and physicians. MathuramSantosham of the Johns Hopkins Bloomberg School ofPublic Health believes that researchers, not justadvocates, must take a lead in communicating thebenefits of rotavirus immunization.

“It’s important that we don’t assume that justbecause a study has been done in a particular region inAsia or Africa that everyone knows about it,” he said.

Santosham appealed to researchers and decisionmakers not to block rotavirus vaccines, which couldsave 2 million deaths by 2020, because of a fewinevitable cases of intussusception.

Other discussions focused on future challengesincluding the need for post-marketing surveillance, sta-ble funding for vaccine procurement, and infrastruc-ture improvements in such areas as cold-storagefacilities.

Vaccine costs and financing were also a key issue ofconcern. Deborah Atherly, senior health economist andpolicy officer at PATH, detailed a financial model thatpredicts prices will fall from a current $7.00 per dose toaround $1.25 per dose by 2020, and that if widelyadopted, the vaccine could prevent the deaths of225,000 children per year.

Roger Glass concluded that in just two years thesituation could change significantly, particularly if newrotavirus vaccines now under development come onthe market and boost competition, which would lowerprices.

“So we may well have a completely differenteconomic outlook and forecast for the vaccine finance,”he said.

viii Proceedings from the 8th International Rotavirus Symposium

The 8th International Rotavirus Symposiumbrought together scientists, clinicians, publichealth professionals, immunization leaders,vaccine industry representatives, and members

of the donor community. Dr. Ciro de Quadros, Executive Vice President of the

Sabin Vaccine Institute, welcomed participants, notingthat the large and geographically diverse groupdemonstrates that the global health community iscommitted to the fight against rotavirus disease. This, the8th International Rotavirus Symposium, he said, wouldbe a model in the history of rotavirus vaccines, and wouldhelp advance the cause of children’s health worldwide.

“We have one-third of the world present here,” hesaid “We have 67 countries. We have over 400

participants. And I think this really shows the eagernessof the world community to come to grips with rotavirusdisease.”

Dr. de Quadros highlighted the importance ofrotavirus vaccine development and deployment withthis sobering fact: worldwide, 65 children die ofrotavirus diarrhea every hour.

John Wecker, PATH’s Global Program Leader forImmunization Solutions, welcomed participants onbehalf of the organizing committee and commentedon the quality of research to be presented.

“In our work with the countries, we have come torealize the commitment that you all have to reducingmorbidity and mortality associated with diarrhealdisease, and improving a child’s survival,” he said.

Introduction

“We have one-third of the world present here. We have 67 countries. We have over 400 participants.

And I think this really shows the eagerness of the world community to come to grips

with rotavirus disease.”

Ciro de Quadros, Sabin Vaccine Institute, US

Proceedings from the 8th International Rotavirus Symposium 1

Roger Glass, who serves as director of the FogartyInternational Center at the US National Institutesof Health, delivered a sweeping and detailed

overview of how the world has arrived to the point thatit now has rotavirus on the ropes.

Glass said he has been gratified to see interest inrotavirus vaccines surge over the last ten years. Hecompared the huge turn-out in Istanbul in 2008 to aninternational rotavirus meeting in 1995 at the USCenters for Disease Control and Prevention (CDC),which he said attracted representatives from only halfa dozen countries.

Glass first became interested in rotavirus whilestudying cholera in Bangladesh in 1980. He knew, hesaid, that cholera was an important diarrheal disease.But it turned out that rotavirus was a much morecommon and frequent cause of severe diarrhea.Returning to the US, he moved to NIH to work onrotavirus and rotavirus vaccines.

“But I must say,” Glass said, “that in the back of mymind a key issue was that the control of diarrheal

disease in a place like Bangladesh, in a low-incomecountry, had to be our primary goal, because diarrheain these settings was a killer.”

The study of rotavirus began in earnest, he said, withthe 1979 WHO program for diarrheal disease control.Glass recalled that Ruth Bishop, the researcher who dis-covered rotavirus, Tom Flewett, who named rotavirus,and Albert Kapikian, who later developed the firstrotavirus vaccine, told WHO: “The world needs arotavirus vaccine.”

One issue for Glass was whether wealthycountries would be interested in a rotavirus vaccine.He said that while the disease burden of rotavirus isobvious in developing countries—120,000 deathsannually in India, 100,000 in South Asia, 230,000 inSub-Saharan Africa, and 20,000 in Latin America—Glass said the need for a rotavirus vaccine in the USwas not clear.

But he said further analysis revealed that while thenumber of deaths in the US was relatively low, rotaviruscaused many hospitalizations and clinic visits and

KEYNOTE ADDRESS Roger Glass, Fogarty International Center, US National Institutes of Health

The Emergence of Rotavirus as a Global Health Concern

Estimated Global Distribution of the >500,000

Annual Deaths Caused by Rotavirus

1 Dot = 1,000 Deaths

FIGURE 1

Parashar, 2005From Roger Glass, Fogarty International Center, National Institutes of Health, US

2 Proceedings from the 8th International Rotavirus Symposium

caused parents many days of lost work. The bottom line:Rotavirus in the US was generating $400 million inmedical costs and about $600 million in indirect costsfor a total financial burden of about $1 billion.

Developing a Strategy for Rotavirus SurveillanceIn 1995, WHO, Glass and colleagues at the US CDC,including Joe Bresee, began to think about how toconduct rotavirus surveillance. The system they arrivedat was based on simple data collection methods. Itemployed the common ELISA assay (Enzyme-LinkedImmunoSorbent Assay) for detection and allowed forrotavirus strain identification. The method is nowbeing used in more than 50 countries.

“Our first study with this protocol with the WHO

grant was in Vietnam where we studied rotavirusdiarrhea hospitalizations in six hospitals in four citiesin Vietnam,” Glass said. “We found that over half ofthe children had rotavirus as their cause ofhospitalization.”

This study led Glass and colleagues to set up theAsian Surveillance Network, which then led to theestablishment of rotavirus surveillance networksaround the world. Today, Glass said, 50 countries carryon routine rotavirus surveillance and data collection.

Surveillance has provided surprising data aboutdifferences in rotavirus epidemiology betweenindustrialized and low-income nations. In wealthiercountries, rotavirus infection is seasonal and frequentlyaffects children above one year of age. Mixed infectionsare rare and fatality is low. In low-income countries, on

BURDEN OF ROTAVIRUS IN THE US

20-40 Deaths

60-70,000 Hospitalizations

500,000 Outpatient visits

3.2 Million episodes

1:10 6

1:80

1:7

1:0.9

RISK EVENTS

Cost: $400 M medical; >$1 B total

Value of vaccine depends on direct vs. indirect costs

FIGURE 2

“In the developing world, we’ve seen a very high case fatalityrate, which has motivated the entire global program.”

Roger Glass, Fogarty International Center of the National Institutes of Health, US

From Roger Glass, Fogarty International Center of the National Institutes of Health


the other hand, rotavirus strikes all year, 80 percent ofcases are in infants, mixed infections are common, andfatality is high.

“In the developing world, we’ve seen a very high casefatality rate, which has motivated the entire globalprogram,” he said.

A Brief History of Rotavirus VaccinesAccording to Glass, the successful deployment ofrotavirus vaccines is the culmination of several decadesof research and development that included crucialsetbacks.

In 1983 and 1984, Timo Vesikari, in Finland,established the first rotavirus vaccine trial, which Glasscredits for setting the stage for all rotavirus vaccinedevelopment since. (See in-depth discussion ofrotavirus vaccine development below.) Glass saidVesikari’s work demonstrated that rotavirus vaccinesbased on bovine virus strains can work, that a poorimmune response does not necessarily predict poorefficacy, and that protection was greatest against themost severe cases of diarrhea.

About 14 years later, in 1998, Albert Kapikian, in theUS, developed the first licensed rotavirus vaccine,RotaShield, which was produced by Wyeth.

RotaShield reduced the duration of diarrhea forinfected children and prevented infections with allrotavirus serotypes. But a crucial side effect causedWyeth to withdraw the vaccine in little more than ayear. In small numbers of children, the vaccine waslinked to cases of intussusception, a dangerous andpotentially fatal obstruction of the bowel.

Worry about intussusception has affected allrotavirus vaccine development and trials since. Glasssaid evidence indicates that the intussusception riskposed by rotavirus vaccination is time and agelimited. When it occurs, it happens within two weeksof the first dose. Also, almost all cases involve childrenover 90 days old at the time of the first dose. Overall,data indicate that the risk of intussusceptionfollowing rotavirus immunization increases ten foldafter 90 days of age.

“Intussusception spares children naturally in thefirst three months of life, so that with all the new liveoral vaccines, we try to get their first doses in before 90days of age,” Glass said.

Today, there are two rotavirus vaccines—RotaTeq,from Merck, and Rotarix from GSK— licensed andwidely available in more than 100 countries. Rotavirusvaccination is now routine in the US, Australia, Austria,

Rotavirus Hospitalizations in the Asian Rotavirus Surveillance Network

China: 41%

Taiwan: 41%

Vietnam: 60%

Malaysia: 56%

Indonesia: 39%

Myanmar: 56%

Hong Kong: 29%

FIGURE 3

Bresee 2003 EIDJFrom Roger Glass, Fogarty International Center of the National Institutes of Health


Belgium, Luxembourg, Brazil, Panama, Nicaragua,Guyana, El Salvador, Venezuela, Bolivia, and parts ofMexico.

RotaTeq is licensed in 70 countries, including manyin Sub-Saharan Africa.

In the US, RotaTeq has been incorporated into theroutine immunization program. The vaccine is givenat two, four, and six months of age, with specialemphasis on administering the first dose before 90 daysof age, to avoid the naturally occurring intussusceptionpeak that occurs between 5 and 9 months of age.

Recently, Rotarix was also licensed in the US.Globally, Rotarix is licensed in more than 100countries, including Europe and Latin America wherethe vaccine has been introduced, but also includingcountries like Bangladesh and 21 countries in Sub-Saharan Africa.

The licensure in these countries is unusual, Glasssaid, because no efficacy data exists for populationsliving in low-income areas of the world.

Vaccine Cost and Vaccine EfficacySimply put, the two major considerations for a countryadopting a rotavirus vaccine focus on affordability andeffectiveness.

On the financial side of the equation, Glass saidministers of health focus more on the immediate costof an immunization, not cost-effectiveness over thelong term (which compares the cost outlays forpurchasing and administering a vaccine to thetreatment and other costs imposed by the burden ofthe targeted disease).

Rotavirus vaccines range in cost from $7.50 per doseto more than $100 per dose. But, as in the example ofthe United States, while the cost can seem prohibitive,if compared to the overall financial burden of rotavirusdisease the vaccines are likely cost-effective. The issueof cost vs. cost-effectiveness is more of a problem inmiddle and higher-income countries, Glass said,because in low-income countries, GAVI Alliance iscommitted to subsidizing vaccine costs.

Glass said that in addition to financial concerns, akey challenge is determining whether “these vaccineswork well” in the developing world.

In 1997, when RotaShield was under consideration,Wyeth requested a global recommendation from WHOfor global use of the vaccine. The WHO consensusgroup responded that researchers must demonstrateefficacy of live, oral vaccines in at least one low-incomecountry in Asia or Sub-Saharan Africa. At the time of

this symposium, clinical trials of both rotavirusvaccines had been initiated in these regions. But Glasssaid “preliminary data suggests that they may not workas well” in developing countries, and that “there maybe opportunities to improve efficacy.”

For example, past studies have shown that theimmune response to Rotarix among children inBangladesh and South Africa is only a little more thanhalf what one sees in children in Finland. Thediscrepancy is not peculiar to rotavirus vaccines but isseen with live oral vaccines in general.

“Live oral vaccines have really posed a problem inthe developing world,” Glass said.

T. Jacob John, with the Indian Academy ofPediatrics, and an attendee at the 2008 symposium wasnoted as the first to observe this phenomena duringstudies of oral polio vaccine. He found that the poliovaccine does not work as well in children in Indiacompared to children elsewhere the world. Similardifferences have been observed with oral choleravaccine and typhoid vaccine.

Glass said there are many biological factors that maybe contributing to the problem. For example, breast milkand stomach acid can neutralize the vaccine virus andlower its effective titer. In addition, maternal antibodiesmay reduce the amount of virus delivered or inhibit theimmune response. Finnish studies showed that childrenwho responded poorly to vaccines had higher levels ofmaternal antibody than did good responders.

“This observation has been repeated in other countries,and is quite consistent,” Glass said. For example, comparedto Finland, levels of maternal antibodies are four to fivetimes higher in South Africa, three times higher inBangladesh and two times higher in Mexico.

Also, a study conducted in Bangladesh showed thatbreast milk can significantly lower the amount of virusreceived by a baby during immunization. InBangladesh and South Africa, it is not uncommon forbabies to have breast milk in their mouth at the time ofimmunization, something that doesn’t happen in theUnited States where women do not breast feed inpublic as often.

Mapping a Way ForwardOne way to deal with this dilemma, Glass said, is todetermine the level of efficacy required to providesufficient protection against rotavirus. Does a vaccineneed to be 90 percent effective, or would 80 percent oreven 40 percent be worth using?

Another approach would be to provide vaccines


SIDEBAR

better suited for the biological profile ofchildren in the developing world. BothIndia and Australia are developing newvaccines based on neonatal rotavirusstrains. These are strains that reproduce inthe presence of maternal antibody. Vaccinesthat use inactivated rotavirus also couldprovide an alternative.

A major question, said Glass, is who willprovide affordable rotavirus vaccines to theworld? Today, he said, GSK and Merck aresupplying the vaccine. But vaccine manu-facturers in China, Brazil, India, Indonesia,and Germany are also potential suppliersfor developing countries.

Still, Glass said while challenges remain,overall progress on the path to widespreaduse of rotavirus vaccines is impressive.

“Rotavirus vaccines have become apriority for GAVI, for WHO, and for theGates Foundation,” he said. “We have twovaccines licensed, and we have others indevelopment. Eight countries have nationalprograms for rotavirus vaccination. So thetrain has really left the station.”

1973 Ruth Bishop and co-workers publish the discovery of humanrotavirus and its association with severe diarrhea in infants andyoung children in Melbourne, Australia

1978 Oral Rehydration Therapy (ORT) was found to be useful intreating and preventing most of the deaths due to Rotavirus.

1982 Vesikari tests bovine rotavirus vaccine in children; safe andimmunogenic.

1983 Vesikari tests bovine rotavirus vaccine in infants; safe and protective against rotavirus diarrhea.

1995 First trials in infants.

1996 Phase II trials begin, testing effectiveness in infants at fourcenters across the US.

1997 Rotavirus ELISA developed.

1997 AVANT sublicenses vaccine to GlaxoSmithKline (GSK).

1998 Rotaviruses found to cause as many as one millionhospitalizations and 500 deaths per year in the US.

1998 FDA approves RotaShield.

1998 ACIP universal recommendation of RotaShield.

1998 15 cases of intussusception in RotaShield vaccines reported tothe US Vaccine Adverse Event Reporting System (VAERS), orone in every – 12,000 vaccinated infants.

1999 CDC reports preliminary data associating RotaShield withintussusception and recommends postponing use.

1999 Wyeth temporarily suspends further distribution andadministration of RotaShield.

1999 Wyeth withdraws RotaShield from the market.

1999 US Advisory Committee on Immunization Practicesrecommends against the use of RotaShield for infants.

1999 GSK begins Phase I and Phase II studies of rotavirus vaccine inEurope, Asia and Latin America.

2001 REST Rotavirus Efficacy and Safety Trial begun, published 2006.

2003 Phase III of GSK’s Rotarix trials begin; 60,000 children in 12 Latin American countries.

2004 GSK’s Rotarix approved for licensure in Mexico.

2006 REST published, establishes safety of Merck’s RotaTeq.

2006 US FDA and Health Canada approve Merck’s RotaTeq.

2008 US FDA licenses GSK’s Rotarix.

“We have two vaccineslicensed, and we have

others in development. Eight countries have

national programs forrotavirus vaccination. So the train has really

left the station.”

Roger Glass,

Fogarty International Center of the National Institutes of Health, US

September–1999, July

July 16

October 15

July 16

October 22

August

October

ROTAVIRUS TIMELINE


Bovine BeginningsTimo Vesikari of the Vaccine Research Center ofUniversity of Tampere, Finland offered a detailedhistory of rotavirus vaccine development.

He noted that vaccine development began in 1971,when Canadian veterinary biologist C.A. Mebuspublished a description of bovine rotavirus vaccine,named RIT 4237. The highly attenuated vaccine wassafe for cattle.

In a 1982 study involving 25 children, Vesikari andcolleagues found the vaccine to be safe and to producean appropriate immune response in humans as well. Atrial in 8 to 11-month-old infants followed the nextyear. Vesikari and colleagues gave a single dose ofvaccine in January, just before the rotavirus season, andfollowed the babies throughout the season.

The bovine vaccine offered protection againstrotavirus diarrhea in these infants. Furthermore,Vesikari learned that the protection was greater formore severe diarrhea: 88% protection against severediarrhea and 50% against any rotavirus diarrhea.

“We also saw that that even some of the childrenwho did not respond serologically to the vaccineseemed to benefit from it, so the antibody response didcorrelate with protection,” Vesikari said.

In a 1983-1984 study, Vesikari collaborated withTom Flewett, one of the pioneers of rotavirus research.By studying the rotavirus strains in Finland, Vesikarishowed that the bovine vaccine offered protectionagainst several strains. The study also showed that thebovine vaccine was adversely affected by stomach acid.The simple measure of giving milk to the baby beforethe vaccination improved the immune response, byacting as a buffer against stomach acid.

“Whether the children received the bottle milk or breastmilk before vaccination did not seem to make a difference.”Vesikari said. “We’re very, very happy about that.”

Following up on the discovery of rotavirus, in 1983Ruth Bishop followed infants in Australia with andwithout a neonatal rotavirus infection. No differenceappeared between the groups in the number ofrotavirus infections during the first three years of life.But an early rotavirus infection did protect the babiesagainst rotavirus disease.

“So what we did,” Vesikari said, “was to do the samewith vaccine, and we gave the vaccine to neonates.”

As with the Australian study of natural rotavirusinfections, the bovine vaccine offered little or noprotection against rotavirus infection over the threeyears of the study. However, it provided 71% protectionagainst severe rotavirus diarrhea and 100% protectionagainst very severe disease.

“So we thought that the neonatal immunizationwas perhaps a chance, but it has not really been furtherdeveloped after this,” Vesikari said.

KEY FACTS, BOVINE ROTAVIRUS VACCINE, FINLAND 1982-1987� efficacious against severe rotavirus gastroenteritis.

� optimal efficacy at 6–12 months of age and neonatal.

� vaccination protective against severe disease.

� one dose as good as 2 doses.

� no obvious side effects (intussusception not seen).

� buffering against stomach acidity needed.

� breast-feeding did not interfere. � Oral Polio Vaccine interfered (studies in Italy

and Yugoslavia).

“The reason why the bovine rotavirus vaccine of the 1980s did not succeed was mainly that nobody was

interested. In Europe few people knew about rotavirus muchless were interested in a vaccine, they had other priorities.

The WHO’s position here was basically that a perfect vaccinewas required. A good vaccine was not enough.”

Timo Vesikari, Vaccine Research Center of University of Tampere, Finland

Discovery of Rotavirus to a Vaccine in 25 years


While the researchers saw no intussusception whenadministering bovine vaccine to older children,Vesikari said, “I think we were just lucky.” Also, thevaccine effectiveness varied from country to country.

“So the situation at the time this vaccine waswithdrawn was that it was efficacious in a country likeFinland,” Vesikari said. “It did have low efficacy inAfrica, and Latin America was somewhere in between.But the reason, really, why it did not succeed wasmainly that nobody was interested. In Europe fewpeople knew about rotavirus much less were interestedin a vaccine. They had other priorities.”

“The WHO’s position here was basically that aperfect vaccine was required,” he added. “A goodvaccine was not enough.”

The Rhesus Rotavirus VaccineSome researchers felt that the bovine vaccine was tooweak for use in low-income countries. The NIH’sAlbert Kapikian and colleagues responded bydeveloping a vaccine from a rhesus monkey rotavirus,which provoked a stronger immune response.

From rhesus rotavirus vaccine researchers developedRotaShield, which combined rhesus and human viralgenome segments. But when some vaccine recipientsdeveloped intussusception, RotaShield was withdrawnfrom the market about a year after introduction.

“It was an efficacious vaccine,” Vesikari said, “and itstill has remained so, but then we have the safety issue.

I don’t know how—how much we appreciate—thatmost of the intussusception cases were in infants whoparticipated in the catch-up program, who got the firstdose of the vaccine when they were over the age ofthree months.”

Since the withdrawal of RotaShield, intussusceptionhas been a key safety issue for all rotavirus vaccines.

Matching Safety with EfficacyIn 2001, the Rotavirus Efficacy and Safety Trial (REST)began. (The study was published in 2006). RESTshowed that Merck’s RotaTeq was safe. There were nomore cases of intussusception in vaccinated infantsthan in unvaccinated ones. In the trial, the first dose ofRotaTeq was given at 6-12 weeks. “So when this vaccineis given properly this way, it is really safe forintussusception. That’s the lesson from this trial,”Vesikari said.

A similar study of GSK’s Rotarix showed fewer casesof intussusception among vaccinated infants thanunvaccinated infants. Meanwhile, Wyeth pulled a UKbovine-human vaccine candidate because of a singlecase of intussusception in a five-month-old infant.

“The bottom line to me is that all of these vaccinescan be associated with individual cases, in the olderinfants at least, with intussusception,” he said.

The key, he said, is to avoid the mistakes of theRotaShield experience by initiating vaccination beforea child is 90 days old.

1 1

Age Distribution (0-24 months)

1 25

13

20

32 32 33

20 21

13

8

4 46

24 4

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0

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ber o

f Cas

esIntussusception in Finnish Children, 316 cases in 1980–2000

90 daysFrom Timo Vesikari, Vaccine Research Center of University of Tampere

FIGURE 4


Rotarix and the Key Challenges of Rotavirus ImmunizationFor Norman Begg, vice president of clinical develop-ment of pediatric vaccines at GSK—manufacturer ofthe Rotarix vaccine—the withdrawal of the RotaShieldvaccine made it clear there were five key challenges forany new rotavirus vaccine.

1. A vaccine must not cause an increased risk ofintussusception compared to placebo.

2. It should provide broad protection against new andemerging rotavirus strains and must cover theexisting geographic variation in rotavirus strains.

3. It should protect children against rotavirus infectionfrom infancy up to at least two years of age.

4. It should not interfere with other vaccines so that it iseasy to include in national immunization schedules.

5. It must be effective in developing countries as wellas developed countries.

“The first decision for GSK and for othermanufacturers is which strain to use, and at GSK wetook the decision to go forward with the developmentof a human strain,” Begg said. The rationale for usinga human strain rested on studies from 1991, 1996 and2000, he said, showing that natural rotavirus infectionsconfer immunity against all strains of rotavirus. Oneinfection is 87 percent effective against moderate tosevere diarrhea and two previous infections confer 100percent protection.

GSK developed a monovalent vaccine based onG1P[8], the most common circulating rotavirus strain.The vaccine is freeze-dried and diluted before oraladministration. It requires only two doses, Begg said,the first as early as six weeks, but not later than 90 days.The second dose can be given from four weeks after thefirst dose up to 26 weeks of age.

SESSION IUpdate on Rotavirus Vaccine

87

73 75

32

62

Two Previous RV infectionsOne Previous RV infection

Rational for Vaccination with Human RV Strain

Natural RV infection attenuates severity

of subsequent infections, regardless of serotype1-3

Moderate to severe diarrhea

Mild diarrhea

Asymptomatic infection

Perc

ent E

ffica

cy

100

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50

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1Velazquez et al, N Eng J Med 1996 335 1022–1028 ; 2Bernstein DI, et al. JID. 1991; 164(2); 277-83 ; 3Velazquez et al, J Infect Dis 2000 182 1602–1609

FIGURE 5

From Norman Begg, GlaxoSmithKline Biologicals


Two pivotal studies, by Guillermo Ruiz-Palacios inLatin America and Timo Vesikari in Europe assessedthe safety and efficacy of Rotarix.

� CHALLENGE 1: No intussusceptionThe Latin American study included 63,000 subjects.Intussusception was assessed during two risk periods:the first month after a dose and the first three monthsafter a dose. In the first risk period, six vaccinatedchildren suffered from intussusception, but there wereseven cases in the placebo group.

“So there was no evidence of an increased risk basedon that evaluation period.” Begg said. “And if you lookfurther out, up to 100 days, it starts to look a little bitimbalanced in favor of the vaccine. There were 16 casesin the placebo group compared to 9 in the vaccine group.I think what you certainly can conclude is that there is noincreased risk of intussusception compared to placebo.”

Similar data show that Merck’s RotaTeq is equallysafe, when the first dose is given at under 90 days.

� CHALLENGE 2: Broad protectionThe same two studies both showed broad protectionagainst the five major rotavirus strains, most importantly,the G9 strain, which is emerging in several countries.

“The overall efficacy rates were higher in Europecompared to Latin America, and I think this reflects thefact that the European study was done in highlydeveloped countries where in Latin America, they weremiddle to low income countries,” Begg said.

� CHALLENGE 3: Protection over timeThe studies showed that Rotarix protected childrenwell against severe rotavirus diarrhea throughout thefirst two years of life. “There is no significant declinein efficacy against severe and hospitalized rotavirusdiarrhea over the two year period,” Begg said.

Furthermore, the vaccine proved about 40 percenteffective against severe gastroenteritis from all causes.

“This shows you that considering the fairly broadrange of organisms that cause diarrhea, you can nonethe-

less expect substantial protection against all causes ofdiarrhea in this setting,” he said. Even one dose of Rotarixoffered significant protection.

“I must stress that this is not a label indication forthe vaccine,” Begg said. “The recommendation is thatyou have two doses. But there does seem some abilityto protect early on, which is obviously good.”

� CHALLENGE 4: Co-administration with other vaccines

“We have done studies with all the commonly usedvaccines globally,” Begg said. ”And in all those studies,high responses of rotavirus Rotarix were maintained,and no impairment of immune responses was observedto any of the co-administered vaccine antigens.”

In a separate Latin American study, 6 to 12-week-old infants were given Rotarix or a placebo along withoral poliovirus vaccine (OPV). Rotarix maintainedboth its immunogenicity and effectiveness in this studyas well. (This study was presented at the 13thInternational Congress of Infectious Diseases June 19-22, 2008, Kuala Lumpur, Malaysia.)

Begg contends that because of the flexibility of dosetiming with Rotarix, it can be included in any of thecommon schedules, the Expanded Program ofImmunization (EPI), with the classical European andUS schedules and with the Scandinavian schedule. “Sothe vaccine could be implemented in pretty much anyimmunization schedule without scheduling additionalvisits,” he said.

� CHALLENGE 5: Efficacy in low-income countries

The study in Latin America referred to above showedRotarix to be effective in 11 countries, Begg said.Ongoing studies, including the Rotarix/OPV study inLatin America, and a study in South Asia also showhigh efficacy, in the 80-100 percent range, he said.“With the completion of that study in South Africa,”Begg asserts that GSK will “have demonstrated efficacyof the vaccine in all regions of the world.”

“There is no significant decline in efficacy (of Rotarix) against severe and hospitalized

rotavirus diarrhea over the two year period.”

Norman Begg, GlaxoSmithKline Biologicals, Belgium


RotaTeq: A Pentavalent Approach to Rotavirus ImmunizationMax Ciarlet, director of the Clinical Rotavirus VaccineProgram at Merck, explained that Merck developed itsoral rotavirus vaccine, RotaTeq, as a pentavalentvaccine containing five human-bovine reassortantrotavirus strains to induce direct protection against themost common human rotavirus serotypes.

He noted that because of the lower replicationcapability of RotaTeq, it requires three doses to buildhigh and consistent immune responses, with the firstdose at 6-12 weeks and two subsequent doses at 1-2month intervals. This schedule integrates easily intopre-established immunization schedules.

Studies indicate that, like Rotarix, RotaTeq does notinterfere with or lose potency from other commonchildhood vaccines. Three phase III studies have pro-vided data on safety and efficacy of RotaTeq. Protocol006, also known as the Rotavirus Efficacy and SafetyTrial (REST), was the pivotal large-scale study. It took

place in 11 countries on three continents from 2001-2005. REST was published in 2006. More than 71,000children were enrolled in all three studies.

“One thing that was really striking, whether we lookat the results from the phase II trials or the phase IIItrials, we see that RotaTeq provides consistent highprotection against severe rotavirus gastroenteritis andgastroenteritis of any severity,” Ciarlet said. Efficacyranged from 98 percent to 100 percent for severerotavirus gastroenteritis, and almost 75 percent for anyrotavirus gastroenteritis, he said.

Since REST was so large, the trial also assessedhospitalizations, emergency room visits and doctor’soffice visits. Ciarlet said the evidence indicates thatRotaTeq reduces hospitalizations and ER visits by 95percent and office visits by 86 percent.

RotaTeq is also effective against a broad range ofrotavirus strains, including those that belong toserotype G9, he said.

“The efficacy, when we go to serotype-specific data,is very consistent and is very high,” Ciarlet said.

Phase III Studies: Protocol 006 (Rotavirus Efficacy and Safety Trial [REST]), Protocol 007, and Protocol 009

Multi-centre, 11 countries on 3 continents, from 2001 to 2005Randomised, double-blind study: RotaTeq® versus placebo controlled

Age at enrolment: 6 to 12 weeks of age, 3 oral doses provided every 4–10 weeks

United StatesPuerto Rico Jamaica Taiwan

MexicoGuatemalaCosta Rica

BelgiumItaly

Sweden

Finland

71,799 Subjects Vaccinated71,799 Subjects Vaccinated36,203 in RotaTeq® Group36,203 in RotaTeq® Group

35,596 in Placebo Group35,596 in Placebo Group

.

Germany

Vesikari et al., 2006. N Engl J Med, 354: 23-33.Vesikari et al., 2006. IJID, 25 (Suppl 1): S42-A47Dennehy et al., 2007. IJID 11 (Suppl 2): S36-S42. REST Subjects Lost to Follow-Up: 81 (0.2%) V: 97 (0.3%) P

FIGURE 6

From Max Ciarlet, Merck Vaccines, US


Furthermore, he noted that the vaccine reduced healthcare resource utilization for gastroenteritis of any kindby 59 percent.

At both 42 days and one year from the first dose,numbers of intussusception cases were similar in thevaccine group and the placebo group. A similar profileemerged for serious events, including deaths. “Themost common cause of death was SIDS,” Ciarlet said,“and the number of subjects that were discontinueddue to a serious adverse event was equal between thetwo groups.”

Ciarlet also stated that neither breastfeeding norprematurity (gestation equal to or less than 36 weeks)appeared to have any effect on vaccine efficacy orsafety.

Ciarlet said the trials were not designed to evaluatevaccine efficacy for fewer than the recommended threedoses, and the numbers of children who got only doseone or two doses were too small for statisticalsignificance. But he said that among children who gotall three doses, RotaTeq appeared to confer protectionbetween doses: 100 percent between dose one and dosetwo and 91 percent between dose two and dose three.

In Finland, Timo Vesikari followed upapproximately 21,000 trial participants for efficacy, asmeasured in rate reduction of hospitalizations and ERvisits emergency visits due to rotavirus gastroenteritis,up to the age of three and a half. These results, whichshowed high and consistent efficacy of the vaccine forup to 3 years postvaccination, were to be presented atthe 13th International Congress of Infectious ofInfectious Diseases. In addition, large-scale safetysurveillance studies continue. The US Vaccine AdverseEvent Reporting System collects information onpossible side effects. In addition, Merck has its ownongoing Phase IV safety study of intussusception,which will enrolled more than 44,000 subjects. And

there are trials being conducted in Bangladesh, Ghana,Kenya, Mali, and Vietnam that are expected to generatedata on safety, immunogenicity, and efficacy ofRotaTeq in the regions of Sub-Saharan Africa andSouth East Asia. In addition, a surveillance andeffectiveness study is ongoing in Nicaragua.

“We have almost 13 million doses distributed, andmonitoring is ongoing,” Ciarlet said. Finally, a phase IIsafety and immunogenicity study of HIV-positiveinfants in Tanzania and Zambia is about to start inearly 2009.

“We will soon show that the vaccine is efficacious upto three years post vaccination, and Merck is workingwith partners to make RotaTeq available to thosecountries that actually need it the most,” Ciarlet said.

There was a question about whether RotaTeq andRotarix can be used interchangeably, with, for example,a first dose utilizing Rotarix and the second RotaTeq.However, experts at the symposium said there is nodata on interchangeability of the vaccines, so thispractice cannot be recommended at this time.

World Health Organization Policies on Rotavirus VaccinesThe World Health Organization (WHO) StrategicAdvisory Group of Experts or SAGE has recommendeda phased introduction of rotavirus vaccine in areaswhere Phase III trials have been completed, said theWHO’s Cristiana Toscano. She said SAGE also stressesthe importance of post-marketing surveillance andcommunication strategies.

WHO recommends the inclusion of rotavirusvaccination into national immunization programs, but,again, only in regions where efficacy trials have beencompleted and, also, where infrastructure andfinancing are in place. Vaccine efficacy has been

“One thing that was really striking, whether we look at the results from the phase II trials

or the phase III trials, we see that RotaTeq provides consistenthigh protection against severe rotavirus gastroenteritis

and gastroenteritis of any severity.”

Max Ciarlet, Merck Vaccines, US


demonstrated in the US, Europe and Latin America,but new studies are expected to be completed shortly.“In 2007, WHO was not prepared to recommendglobal inclusion of rotavirus vaccines into nationalimmunization programs,” Toscano said. “Rather we’resuggesting a phased introduction.”

Based on a review of data on RotaShield, she saidWHO has recommended that the first dose of rotavirusvaccine should not be given after 12 weeks of age.Toscano said WHO advises against using rotavirusvaccines in catch-up programs because of the danger thatthe first dose may mistakenly be given to children olderthan 12 weeks of age. The entire rotavirus immunizationseries should be completed by 24 weeks for Rotarix and32 weeks for RotaTeq. This recommendation arises fromthe lack of safety data for older children.

Duncan Steele, PATH’s Senior Advisor on diarrhealdisease, noted that, due to the lack of evidence fromclinical trials, SAGE has not recommended the use ofrotavirus vaccines in the regions of the world with thehighest mortality from rotaviruses, which are low-income countries. Thus, the GAVI Alliance, aninternational coalition of public and private partners(formerly known as the Global Alliance for Vaccinesand Immunization) that subsidizes vaccine purchasesfor the world’s poorest countries, has yet to providesupport for rotavirus vaccines.

“Where the majority of the disease and mortalitiesare associated, those countries are not yet in a position

to apply for these vaccines,” Steele said. But if studiesnow underway in the developing world show that therotavirus vaccines would have even “moderate efficacy,”Steele said they are likely have an dramatic impact onlives saved and to be “cost saving.”

He said that phase III efficacy trials are currentlybeing conducted under a collaboration between theRotavirus Vaccine Program at PATH (which is apartnership including WHO, and the US CDC), andwith both Merck and GSK Bio rotavirus vaccines.

There was a question about the ethics of conductingrotavirus vaccine trials in low-income countries. Steelenoted that studies must be done in the populations thatneed the vaccines and that extrapolating results fromtrials conducted elsewhere would not be sufficient. Henoted that vaccine manufacturers, WHO and PATHfollow high ethical standards and all studies arereviewed by local ethics boards and conductedaccording to Good Clinical Practice.

Vaccine Concerns: Interactions and Disease TransmissionThere was some discussion about whether rotavirusvaccination would have any effect on the oral poliovaccine (OPV). Max Ciarlet responded that while noefficacy studies have been undertaken, OPV antigentiters were normal when the vaccine was administeredalong with RotaTeq. Merck recommends that RotaTeq

FIGURE 7. When will we know whether rotavirus vaccines will benefit children in Africa and Asia?

2008 2009 2010

Bangladesh GSK Asia effectiveness study

Vaccine,Rotarix® Malawi Malawi(Human, South Africa & South Africa & South Africa

Monovalent) AfricaInterim Final Extended

Analysis Analysis Follow-up Analysis

Bangladesh & VietnamMerck Asia

Vaccine, Final AnalysisRotaTeq®(Bovine, Ghana, Kenya,

Reassortant, & Mali Multivalent) Africa

Final Analysis

From Duncan Steele, PATH


be administered first if the vaccines arenot given together because OPV mayreplicate for up to 6 weeks.

Norman Begg added “The data showthat there is no interference and it's in thelabel of the vaccine that you can actuallyco-administer at the same visit.”

Duncan Steele noted that “The WHOposition paper clearly says that the vac-cines need to be given with OPV. We'renot talking about additional EPI visits fora new rotavirus vaccine.”

T. Jacob John, with the Indian Acad-emy of Pediatrics, wondered whetherchildren who receive the rotavirus vac-cine can transmit the rotavirus throughvirus “shedding.”

Norman Begg responded that, “As youwould expect with a live orally adminis-tered vaccine, the vaccine replicates inthe gut and there is shedding followingvaccination.”

The concern is that if virus shed froma vaccine recipient undergoes a mutationthat confers virulence, it may transmitrotavirus disease. “We are actually doinga study at GSK to look at transmission ofthe known shed virus, so we will have theanswer to that question,” Begg said.

Max Ciarlet added that researchers atMerck “have only detected shedding afterthe first dose. It is usually only one or twodays and it only happens in 9 and 12percent of the subjects.”

Duncan Steele added that thedifferences between the two vaccineswhen it comes to shedding virus mayreveal differences in the vaccines’functions, with Rotarix conferring mostof its immunity in the first dose, andRotaTeq conferring increasing immunitywith each of the three doses.

“In 2007, WHO was not prepared to recommend globalinclusion of rotavirus vaccines into national immunizationprograms. Rather we’re suggesting a phased introduction.”

Cristiana Toscano, World Health Organization

SIDEBARInterim Analysis of Vaccine Efficacy in South African Infants

Shabir Madhi of South Africa’s University of theWitwatersrand offered an interim analysis of a Rotarixtrial in South African infants.

The communities in which the study was performed areburdened with a high prevalence of HIV, 50% of children bornare born to mothers with HIV. About 5 to 6% of infants areinfected with HIV. And the unemployment rate stands at40%. In addition, Madhi said, “Only about a third of childrenactually receive appropriate oral rehydration therapy whenhaving an episode of gastroenteritis.”

The study set out to determine Rotarix efficacy againstsevere rotavirus gastroenteritis in infants up to one year ofage. Rotarix was given according to the routine EPI schedule,which included oral poliovirus vaccine. The study usedstandard definitions of gastroenteritis and severity of theepisodes was assessed by the internationally recognizedVesikari score. The presence of rotavirus was detected by acommercial ELISA assay. The pre-determined interim analysiswas performed by an independent data center.

Madhi said the results show that the vaccine efficacyagainst rotavirus gastroenteritis of any severity was 66.5percent. Against severe rotavirus gastroenteritis, the vaccineproved 82.7 percent effective according to the interim results.

“The vaccine itself clearly offers a high degree ofprotection in South African children against severe rotaviralillness during the first year of their life,” Madhi said. “Theresults I believe are extremely important in terms of informingdecision making both in South Africa as well as in othercountries in southern Africa.”

In Sub-Saharan Africa, rotavirus accounts for 25 percent ofall diarrheal deaths and 25 percent of all hospitalizations fordiarrhea, with a clear peak in dry cooler months of autumnand winter.


Regional Perspectives: The WHO European RegionThe WHO European region encompasses 53 membercountries that include nations in Western and EasternEurope, former Soviet states and the RussianFederation. It is a very diverse region with a wide rangeof economic conditions—the GNP in the richestcountry is 30 times that of its poorest country—tomatch its geographic expanse. Currently, there are 8countries eligible for GAVI assistance.

According to the WHO’s Eric Laurent, Rotarix is li-censed in 33 countries in the Eu-ropean region and Rotateq in 32.But he said thus far only threecountries—Austria, Belgium andLuxemburg—include rotavirusvaccination in their immuniza-tion schedule, though Slovakiamay soon add it.

Laurent said what is needed nowis “further research into the cost-effectiveness of universal rotavirusvaccinations, particularly in low-mortality, high-income settings.”He said there is also a need for moresurveillance, particularly in coun-tries where estimates indicate arotavirus mortality rate of greaterthan 10 per 10,000.

“We realize that many, manycountries do not have strongenough surveillance to make deci-sions about these new vaccines,”Laurent said.

He said in general, universalrotavirus vaccination should beconsidered in countries where“more than 20% of the gas-trointestinal mortality is due torotavirus, or where more than30% of the hospitalizations aredue to rotavirus.”

Laurent said countries in theregion are “pretty sensitive”

about the need to monitor for intussusception as partof vaccine introduction. And, as is the case forintroducing any new vaccine, he noted that countrieswill have to consider the impact of a rotavirusimmunization program on cold chain storagecapacity.

Regional Perspectives: Latin America and the CaribbeanLucia De Oliveira, Regional Advisor for New Vaccinesat the Pan American Health Organization (PAHO),

SESSION IIIntroducing New Rotavirus Vaccines

Countries from Latin American, Caribbean and Mexico

Introducing Rotavirus Vaccine into their Routine Schedule

ELS: Oct 2006birth cohort of 166,000

Nicaragua: Oct 2006birth cohort of 150,000

Ecuador, Oct 2007birth cohort of 294,300

Mexico: May 2007

Venezuela: Apr 2006birth cohort of 574,000

Panama: Mar 2006birth cohort of 70,000

Brazil: Mar 2006birth cohort of 3,330,000

Peru, Apr 2008priority areas

FIGURE 8

From Lucia De Oliveira, Pan American Health Organization


discussed the progress made and lessons learned inwhat has been a fairly aggressive introduction ofrotavirus vaccination in Latin America and theCaribbean (LAC).

She said the potential benefits from immunizationin the region is clear, noting that “rotavirus causes anestimated 1,500 deaths, 7,500 hospitalizations, 2 millionclinic visits, and 10 million cases of rotavirus diarrheaannually.”

In 2006, Panama became the first LAC country toadopt rotavirus vaccination and there are now eightcountries in the region that have added the vaccine totheir EPI schedule. Seven are using Rotarix, she said,and one is using RotaTeq.

“To date, no evidence of an increased risk ofintussusception or any other serious adverse events hasbeen suggested,” De Oliveira said.

She added that PAHO is seeking additional infor-mation on risks of intussusception through a collabo-rative study with Brazil and Mexico (conducted withsupport from US CDC, the US Food and Drug Admin-istration (FDA) and PATH). The results may be readyat the end of 2009.

She said challenges to rotavirus immunization in theregion have involved both supply and cost concerns.She said some countries ran out of vaccine “soon afterintroduction.” In addition, the vaccine costs countries$7.50 per dose if it is obtained through the PAHORevolving Fund for Vaccine Procurement, which helpsLatin American countries reduce immunizationsexpenses by negotiating bulk purchases frommanufacturers. But De Oliveira said at that price, therotavirus vaccine accounts for about 97% of the costof a country’s basic immunization schedule.

“Even though all Latin American countries using thevaccine have a budget line for vaccine purchase,insufficient funds continue to pose constraints forsome countries,” De Oliveira said.

Regional Perspectives: Impact and Cost-Effectiveness in Central AsiaElmira Flem of the Norwegian Institute of PublicHealth presented a case study that looked at the eco-nomic impact of rotavirus and the cost-effectiveness ofrotavirus vaccination in the Central Asian countries ofUzbekistan and Kyrgyzstan.

Economic evaluations of rotavirus vaccinationprograms have been done in most industrializedcountries, Flem said, whereas very few studies havebeen done in settings with low resources.

In general, immunizations in Uzbekistan andKyrgyzstan are free and both republics have an effectiveimmunization system with routine coverage ofvaccines that are part of the Expanded Program onImmunizations of above 90 percent. In 2003,Uzbekistan and Kyrgyzstan became the first GAVIcountries in the WHO European region to initiatehospital-based surveillance of rotavirus.

Flem said she and her colleagues were interested inestimating the costs of rotavirus disease to the healthcare system and nation and the cost-effectiveness ofroutine rotavirus vaccination as a way to help policymakers to decide if new rotavirus vaccines should beused in national immunization programs.

For each country, they identified a sample of childrenunder five-years old who had been hospitalized withacute diarrhea and collected information on healthcareand family costs associated with the illness.

“To estimate the rotavirus burden,” Flem said, “weused the country-specific data from the hospitalsurveillance to decide which fraction of diarrheahospitalizations was in fact caused by rotavirus, andthat is 30 percent in Uzbekistan and 26 percent inKyrgyzstan.”

The average total cost per child was estimated to bearound $94 in Uzbekistan, and $87 in Kyrgyzstan.

“Even though all Latin American countries using the vaccinehave a budget line for vaccine purchase, insufficient funds

continue to pose constraints for some countries.”

Lucia De Oliveira, Pan American Health Organization

SIDEBARKeeping Track of Intussusception


Age (months)

No.

of P

atie

nts

0

50

100

150

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250

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2423222120191817161514131211109876543210

FIGURE 9

From Julie Bines, University of Melbourne

Age Distribution of Intussusception in Children < 2 Years

Julie Bines with the University of Melbournelooked specifically at the need for post-vaccination monitoring of intussusception.

Why do we need to monitor for intussuscep-tion after vaccine introduction when risks havebeen assessed in clinical trials? Bines said the rea-son is that clinical trials adhere to strict protocols,while in the broader world, administration sched-ules can differ, different drugs or vaccines mightbe administered alongside the rotavirus immu-nization, and there could be a wide variety of pre-existing illnesses present in vaccine recipients.

The overall incidence of intussusceptionvaries from country to country, she said, whichcould be due to variety of factors, includingdifferences in genetics, cultures, exposures toinfections, environmental conditions, therapeutic

practices, diagnostic methods, and access tohealth care.

“Whether this will influence the safety ofvaccines when they're implemented in countrieswith varying incidence of intussusception, wedon't yet know,” Bines said. One problem, shesaid, is that the precise causes of intussusceptionare not well understood.

Also, while intussusception is rare in babiesunder three months—which is why there is arecommendations to administer rotavirus vac-cine during that time period—its severity may behigher at that age.

“So maybe intussusception, althoughuncommon, has a greater impact in the veryyoung children, and we need to be aware ofthat,” Bines said.


Based on current levels of immunization coveragein the countries and an estimated vaccine efficacy of85 percent, the rotavirus vaccination was projected toprevent 5,296 hospitalization and 463 rotavirusdeaths per year in Uzbekistan with a projected savingof nearly US $500,000. The figures for Kyrgyzstancame to more than 3,000 hospitalizations and 128death averted per year, and a savings of more than US$265,106.

Considering GAVI financial help is available to bothcountries, Flem said the rotavirus vaccine programwould meet World Bank standards for highly cost-effective interventions in both countries.

“Vaccination could be cost-effective in economicterms, and it could reduce the disease outcomes, butthe ability of the country to introduce the vaccine willbe highly dependent on the affordability of thevaccine,” Flem said.

Vaccine Monitoring Post-IntroductionSeveral speakers emphasized the importance ofmonitoring the impact of a rotavirus vaccinationprogram after introduction.

Manish Patel, a medical officer at the US CDCdiscussed how the agency worked with WHO andindividual researchers to assemble a standard approachto post-introduction monitoring. The monitoring hadthree objectives: to monitor disease trends, to assessvaccine effectiveness and to monitor rotavirus strains.

For any vaccine Patel said, researchers ask twoquestions: “Is the vaccine program modifying diseaselike it's intended to do, and can you quantify theimpact of the program?”

“The season after rotavirus introduction, you maynotice an impact in the two to six-month age group,”he said. “In the second season you might notice impactamong less than 1-year old, perhaps less than 2-yearolds. And in the third season, you should definitely seean impact in the less than 2-year old age group if thevaccine is performing as well as it's intended to perform.In regions where the disease is obviously seasonal, youshould see a blunting of the winter peaks.”

Data to evaluate vaccine program performancecomes from several sources. Standard WHO activesurveillance involves sentinel hospitals whereinvestigators monitor all children less than five whocome into the hospital setting, testing for rotavirusdisease. Other sources include clinics, passive labsurveillance and mortality data.

Patel cited data from Nicaragua (which uses RotaTeq)showing some of the predicted blunting of rotaviruspeaks after vaccine introduction. Data from El Salvador(Rotarix) indicated a drop in incidence of rotavirusdisease in the first season after vaccine introduction, buta more marked reduction in the second season.

Assessing the impact of vaccination on rotavirusstrains is a hot topic, Patel said. While some data doshow a change in the mixture of rotavirus strains aftervaccine introduction, it’s not clear if the vaccinationprogram is the cause.


The Importance of Global SurveillanceMarc-Alain Widdowson with the Division of ViralDiseases at the US CDC discussed the importance ofhaving a global network focused on conductingsurveillance of rotavirus disease.

“The important thing about having a network ofsites is you standardize data collection, you cancompare and contrast and combine data and you havea much stronger voice in terms of advocacy,” he said.

Widdowson said there are now >50 countries whoare either conducting “rotavirus surveillance or havedone rotavirus surveillance in the past.” They areworking within five different networks, one in theAmericas (coordinated through PAHO), one in Africa(the WHO AFRO network), one in the EasternMediterranean (the WHO EMRO network), one inSoutheast Asia and Western Pacific regions (WHOSEARO/WPRO network) and one in the Europe (theWHO EURO network).

Global surveillance uses the WHO generic protocolfor hospital-based data collection. The same protocol isused in, for example, the Asian Network, with 19countries, and the African network with 10 countries.Data are published in traditional journals as well as onthe CDC web site.

“We’ve got a couple other supplements in the worksnow trying to get much of this surveillance data out inthe open,” Widdowson said.

He noted that the data derived from this networkroutinely provides valuable insights into the nature ofthe disease in different regions. For example, he saidthat the surveillance has revealed that children inpoorer countries get rotavirus infections earlier than

children in wealthier countries. Widdowson said thesurveillance also has detected a change in straindiversity in Korea where there was a “quite rapid risein G3 genotypes over one year.”

He said the regular flow of illuminating informationis key to “keeping people motivated and interested” andfighting what he called “surveillance fatigue.”

Widdowson also noted how the data can point tothe limits of hospital-based surveillance to actuallycapturing the true burden of disease in a country orregion. For example, in rural Kenya between 2005 and2006, 22% of children admitted to the hospital hadrotavirus. However, because they receive rehydrationtherapy, only 2% of hospital deaths are in children whoare “rotavirus positive.”

“Most of the deaths from rotavirus are notoccurring in the hospital and this is a real challenge forhospital-based surveillance,” he said.

Estimating Deaths from RotavirusAccording to Tony Burton of the WHO, WHO hasissued an estimate which asserts that in 2004, 527,000children under five died of rotavirus disease. Deathswere found to be highest in Africa, India, and SouthAsia. The estimate relied on a model starting with alldeaths of children under five, and then factoring in first:

� the percent of deaths caused by diarrhea and then,

� the percent of diarrhea deaths believed to be due to rotavirus.

Several issues may influence the accuracy of theestimate. According to Burton, there are those who

SESSION IIIEpidemiology and Burden of Rotavirus Disease

“Most of the deaths from rotavirus are not occurring in the hospital and this is a real challenge

for hospital-based surveillance.”

Marc-Alain Widdowson, Centers for Disease Control and Prevention, US


could argue that the estimate is too low becauselaboratories may be missing about 30% of all infectionswhile there were elements of the study design—such asthe decision to collect data during a period when therewas a high rate of diarrhea caused by something otherthan rotavirus—that could mask the actual percentageof rotavirus-induced mortality.

Meanwhile, he showed that one might also argue theopposite, that the estimate was too high, because it wasconducted in the winter, when rotavirus levels areelevated, and that the study population was not arepresentative sample of a whole country.

The next challenge, according to Burton’s presenta-tion, is to develop a model for assessing the impact ofvaccination.

Surveillance in the WHO EURO and EMRO NetworksDavid Mercer, with the WHO Regional Office for Europe,said WHO plans to support rotavirus surveillance,integrating the WHO generic protocol into existing

surveillance, with top priority given to GAVI-eligiblecountries. The most important data to be collected, hesaid, includes disease burden, strain prevalence, andpublic and health-care worker awareness of rotavirusdisease. Finally, the laboratory component of surveillancemust be strengthened, with the applications of bothinternal and external quality controls.

Nadia Teleb with the WHO Rotavirus SurveillanceNetwork in the Eastern Mediterranean Region(WHO/EMRO), presented data showing that diarrheadiseases, including rotavirus, cause almost two-thirdsof hospitalizations due to acute gastroenteritis in theEastern Mediterranean Region.

All children under five-years-old in the region whoare hospitalized at a sentinel hospital for treatment ofsuspected rotavirus gastroenteritis are enrolled in thesurveillance system, she said. An enzyme immunoassay(EIA) of stool is used to prove the presence of rotavirusand genotyping of subset of the positive specimens aresystematically performed.

In addition to availing local data on disease burdenand genotype prevalence, the main strength of this

100 to 500 deaths per 100,000

50 to 100 deaths per 100,000

10 to 50 deaths per 100,000

<10 deaths per 100,000

The boundaries and names shown and the designations used on this map do not imply the expression of any opinion whatsoever on the part of the World Health Organization concerning the legal status of any country, territory, city or area or of its authorities, or concerning the delimitation of its frontiers or boundaries. Dotted lines on maps represent approximate border lines for which there may not yet be full agreement. ©WHO 2008. All rights reserved

Rotavirus Mortality Rate per 100,000 Population Less than 5 Years of Age: 2004

FIGURE 10

From Tony Burton, World Health Organization


surveillance network, Teleb said, is building thenetwork as part of national programmes which ensuresnational ownership of data and, hence, using the databy the Ministries of Health, for decision making onrotavirus vaccine introduction.

But as has been noted elsewhere, Teleb said that theinfluence of hospital surveillance on government policy

in some countries is complicated by the fact that deathsfrom rotavirus in hospitals “is almost nil,” even in “veryhigh burden countries.”

“We need stronger advocacy in order to convincesome decision makers that these mortality results fromhospitals do not mean that there is no mortality fromrotavirus diseases,” Teleb said.

Jim Gray, who works with EuroRotaNetStrain Surveillance at the UK Centre forInfections, is interested not just in

documenting circulating rotavirus strains beforeand after vaccination but also in detecting newlyemerging strains.

These strains may result from anaccumulation of mutations, he said, and canoccur in such a way as to prevent the binding ofthe antibody stimulated by the vaccine. This is notjust a theoretical concern, he said, but has beendocumented, for example in a strain in Taiwan inthe 1990s that underwent such a mutation andthen circulated around the world.

“The rate of mutation with the rotavirus geneis relatively high because the RNA replication iserror-prone,” Gray said.

Another potential genetic event to monitor, hesaid, is antigenic shift, which can occur when asingle human cell is infected by more than onerotavirus strain.

“These reassortments of human strains,although they’re interesting, are unlikely to haveany major public health importance becausethey’re carrying antigens that are alreadycirculating in the human population,” Gray said.

But dual infections can also occur with animaland human strains.

“Animal strains replicate very poorly in thehuman host and they transmit very rarelybetween humans,” Gray said, but added that thepotential exists for a mixed infection to create anew, virulent strain, with the replicativeadvantage of the human strain and the novelantigens of the animal strain.

Yet strain diversity does not by itself bode illfor rotavirus vaccines, he said. In practice, thevaccines spur an immune response against manystrains, including potential reassortants.

Meanwhile, Gray is looking beyond childhoodinfections to study rotavirus infections in adults asa way to develop a more detailed understanding ofthe disease.

“Because we don’t restrict our database to 5-year-old or under, we’re seeing the interestingphenomenon here of adults having a symptomaticrotavirus infection, probably parents being infectedby their children and grandparents by theirgrandchildren,” he said. “So we’re beginning tosee the whole picture of the epidemiology ofrotavirus and the multiple times that we getinfected and disease throughout life.”

SIDEBAROn the Lookout for Rotavirus Mutations

“We need stronger advocacy in order to convince some decision makers that these mortality results

from hospitals do not mean that there is no mortality from rotavirus diseases,” Teleb said.


United States: “A Steady, Progressive Climb”Umesh Parashar with the US CDC discussed his country’sexperience with rotavirus vaccination. As of 2008,RotaTeq had been available for about two years. Rotarixwas licensed in 2008 and was under consideration forwider use in childhood immunization programs.

At the time of the conference, US health officials werestill collecting comprehensive data on rotavirus vaccineadoption, but preliminary information was availablethrough CDC’s Immunization Information Systems(IIS), which monitors vaccine administration at sixSentinel sites nationally. According to IIS, through 2007,about 60 percent children 3 months old at the sentinelsites were getting the vaccines, Parashar said.

“It’s been a steady progressive climb, but we are stillnot where we would like to be,” Parashar said.

Thus far, Parashar said that according to information

gathered by CDC’s Vaccine Adverse Events ReportingSystem (VAERS), along with a study by Merck, therehave been 226 cases of intussusception since the vaccinewas introduced. Of those, 65 have occurred after the firstdose, 100 after the second, and 61 after the third.

Parashar said that when one compares the reports ofintussusception involving RotaTeq to the earlier vaccine,RotaShield, key differences emerged. First, “almost all ofthe cases” with RotaShield occurred “immediately aftervaccination,” he said, while reports associated withRotaTeq were “much more spread out and you have quitea few reports occurring further out from vaccination.”

“This really gives us confidence that you’re nottalking about a risk anywhere like what was seen withRotaShield vaccine,” Parashar said.

In addition, an analysis conducted with data from theVaccine Safety Datalink (VSD), which studied 165,000vaccinations administered in a managed care setting,documented five reports of intussusception, which was

SESSION IVEarly Experience with Routine Use of Rotavirus Vaccines

Sentinel Site

First dose rotavirus vaccination coverage among children aged

3 months in IIS Sentinel Sites, by quarter and site

% V

acci

nate

d

Q 4 2007Q 3 2007

Q 2 2007

Q 1 2007

Q 4 2006

Q 3 2006

0

20

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OregonMontanaMinnesotaMichiganDCArizona

FIGURE 11

From Umesh Parashar Centers for Disease Control and Prevention


slightly less than what was expected. An analysis of130,000 first doses found no reports of intussusceptionwere in the first week of vaccination, Parashar said.

In terms of the effect on the burden of disease,Parashar said that in 2008, surveillance systems showeda marked reduction in severe diarrhea from all causes,and almost no rotavirus diarrhea.

“So there are remarkable changes, which we see fromeach of these systems showing substantial declines inrotavirus this year.” Parashar said. “I think we feelconfident saying that the changes you are seeing this yearare unlike what we have seen in all the data we have frombefore and the trends are beyond natural variation.”

A study of the attitudes toward rotavirus vaccinesamong physicians across the country showed pediatri-cians to be very aware of rotavirus disease and to supportvaccination. Family physicians, however, were signifi-cantly less likely to promote rotavirus vaccination.

“Family medicine physicians deal with patientsacross all ages, so they have to digest manyrecommendations for many, many interventions andgenerally their uptake of vaccines are slower thanpediatricians,” Parashar said.

Nicaragua: Responding to an Epidemic with a VaccineNicaragua, with 140,000 births per year and a percapita annual income of less than $1,000, is dividedbetween the well-developed Pacific side and the under-developed Atlantic side.

After cholera was eliminated in 2000, Nicaragua beganto track rotavirus disease, which shows the seasonalityseen elsewhere in the world. In Nicaragua, rotaviruspeaks from January to April, during dry season.

According to Juan Jose Amador with PATH,RotaTeq was introduced in Nicaragua in October 2006in the wake of a rotavirus epidemic that hit the countrythe previous year. As in the US only a slight drop inrotavirus deaths occurred in 2007. But the proportionof rotavirus-positive tests was significantly lower inMay to November of 2007 than in the previous three

months.From 2007 to early 2008, about 86 percent of

children under one year of age were getting the firstdose of the vaccine. At the same time, deaths in thatage group from acute diarrheal diseases appear to begoing down, dropping from 97.5 per 10,000 in 2000 to2005 to 77.9 in 2007, a 20% reduction.

Amador said the vaccine has been well accepted bythe medical and scientific community in Nicaraguaand has exhibited a good “safety profile and minimalsecondary effects.”

European Union: Considering Disease Burden and Vaccine CostsAccording to Pierre Van Damme with the Center forthe Evaluation of Vaccination at Belgium’s Universityof Antwerp, as of March 2007, five EU countries hadmade a decision regarding rotavirus vaccination.

He said Belgium and Luxemburg will integraterotavirus vaccine into the national immunizationschedule at low net cost to families, with a more than80% reimbursement by National Health Insurance.Austria will integrate the vaccine, but has not decidedon cost. Germany and France will not integrate thevaccine. Issues driving country considerations includeoverall rotavirus burden and an economic assessmentof the rotavirus vaccination program.

Scientific societies in Germany, France, Spain, Italy andBelgium have moved forward with recommendations tointroduce rotavirus vaccines.

“Despite similar burden of disease, countries differin their attitude towards rotavirus vaccineintroduction,” Van Damme said. “We know there is alack of awareness of potential disease severity andoverall burden of disease in many countries.”Furthermore, he said countries are realizing that theoverall burden of rotavirus disease must be considered,not just mortality.

Van Damme said the official recommendation forthe use of the current vaccine remains: “two doses forone vaccine, three doses for the other vaccine.”

“There are remarkable changes, which we see from each of these systems showing substantial declines

(post-immunization) in rotavirus this year.”

Umesh Parashar, Centers for Disease Control and Prevention, US


Engaging the Public According to Lulu Bravo, an infectious disease expert atthe University of the Philippines, - “for many countriesof both the developed and developing world, a vaccinewill be the most cost-effective way to stop rotavirus.”

Advocacy and elevating public awareness are seenas key elements to encouraging widespread adoptionof rotavirus vaccines, particular in countries withlimited resources. Bravo described how healthauthorities in her country engaged in a multifacetedeffort to educate the public about the dangers posed byrotavirus and the benefits of prevention.

Rotavirus has been a known problem in thePhilippines for 25 years, affecting children under five,and especially from six to eleven months. In 2007rotavirus caused 38% of hospitalizations for diarrheain the Philippines.

In 2000, the Philippine Foundation for Vaccinationwas launched, the first organization of its kind in Asia,aiming to reduce childhood morbidity and mortality.

In 2005, Bravo said a group of gastroenterologists,infectious disease physicians, pediatricians andepidemiologists formed ROTAPhil to improvecommunication about rotavirus disease in the Philippines.ROTAPhil organized a program consisting of pamphlets,media ads, press kits, “meet-the-expert” booths atconventions and other communication strategies.

“Most of all I think we had to partner with media,”Bravo said.

ROTAPhil also partnered with physicians’ societiesto educate physicians about the burden of rotavirusinfections. Family physicians were another target ofrotavirus education.

“We have heard lots of reasons in the last two daysto support rotavirus vaccination, but the best reasonof all is to say that every child has the right to goodhealth,” Bravo said.

Mathuram Santosham of the Johns HopkinsBloomberg School of Public Health said researchersneed to understand that many of the people in a posi-tion to make a decision about rotavirus vaccinationknow very little about the disease.

“I want to point out that for a decision maker,rotavirus means very little,” Santosham said. “If youcan go to a decision maker and say I can reduce yourdiarrhea mortality, that means something.”

Researchers also must focus on the things mostimportant to Ministers of Health: how much thevaccine is going to cost and how many lives will it save.

Clear WHO recommendations are also important,Santosham said.

“If we go out and give ambiguous messages tocountries we will never get these vaccines intocountries,” he said.

In addition, Santosham said it is important toacknowledge how immunizations are delivered in realworld settings. For example, he said it is likely that insome countries, rotavirus vaccines would beadministered outside the ideal time-frame forminimizing risk of intussusception.

Overall, he said the process for encouraging adoptionof rotavirus vaccines must “include all stakeholders(and) be aware that research without appropriateinclusion of stakeholders may delay introduction.”

Confronting the Costs of Rotavirus VaccinesDeborah Atherly, a health economist with the PATHRotavirus program, focused on cost concerns andfinancing strategies for deploying rotavirus immunizationswhere they are needed most.

PATH has completed and submitted for publicationan analysis on the cost-effectiveness and impact ofintroducing rotavirus vaccines in all GAVI-eligible

SESSION VPolicy Decision Making

“We have heard lots of reasons in the last two days to support rotavirus vaccination, but the best reason of

all is to say that every child has the right to good health.”

Lulu Bravo, University of the Philippines, Philippines


countries, which collectively represent nearly 85% ofthe rotavirus mortality burden. Atherly views theanalysis as providing a platform for discussion ofmarket issues: supply, demand and affordability.

She said it will be the first vaccine analysis tocombine a cost-effectiveness assessment with demandforecasting and price assumptions to estimate bothcost-effectiveness and impact over time.

The PATH model shows rotavirus vaccine pricesdropping (they are currently about US $7 per dose) as newmanufacturers enter the market around 2012. By 2020, themodel predicts, rotavirus vaccine will reach a stable $1.25per dose. And as costs drop, the study predicts the numberof children vaccinated per year will rise, reaching some 60million children in 72 countries by 2025.

“Under a range of assumptions, we can consider thevaccine cost-effective, especially in the low incomesetting, and it has a potential to avert over 225,000deaths per year by 2020 or 2 million deaths over time,”Atherly said. “As suppliers increase [around 2012], you

actually start to create more of a robust market, orsupply side market for vaccines”

Atherly said the analysis reveals that as prices go down,the vaccine becomes more cost-effective. Economistsanalyze the cost-effectiveness of vaccines or other healthinterventions by looking at what they call “disabilityadjusted life years or DALYS.” Essentially, a DALYmeasures a year of life lost to either death or disabilitycaused by a particular disease of condition. Atherly saidfor rotavirus vaccination, the cost per DALY saved couldfall from nearly $450 in 2008 to below $50 around 2020.

“As the countries with high mortality rates come onboard, those cost-effectiveness ratios obviouslyimprove quite dramatically,” she said.

While the study took the perspective of GAVI as thekey donor, Atherly said, “I think we can also look at thisfrom a more generic donor perspective, that is, GAVImay not be here forever, and we need to look at otherpossibilities for funding and funding resources forrotavirus beyond say 2015.”

0.0

0.5

1.0

1.5

2.0

2.5

3.0

3.5

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ual D

eath

s Av

erte

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Chi

ldre

n Va

ccin

ated

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

Year

Deaths averted per 1,000 children vaccinated—baseline

Deaths averted per 1,000 children vaccinated—accelerated

Deaths averted per 1,000 children vaccinated—delayed

Annual deaths averted—baseline

Annual deaths averted—accelerated

Annual deaths averted—delayed

Deaths Averted per 1,000 Vaccinated and Deaths Averted by Year: 2007–2025

FIGURE 11

From Deborah Atherly, PATH


Future issues and challenges for rotavirus vaccinationinclude evolving needs for disease surveillance and thelikelihood that new vaccines will be arriving on themarket.

PATH’s Duncan Steele said that as routine surveil-lance demands are shifted to countries and ministriesof health, there will be a need for enhanced surveillancein sentinel sites, with particular emphasis on the analy-sis of strain diversity.

“The research studies that we are doing at themoment, which are going to generate really importantinformation for Africa and Asia, are, in some ways, onlythe tip of the iceberg of what is coming,” Steele said.

Also, the WHO Strategic Advisory Group of Expertshas recommended conducting post-marketing surveil-lance of vaccine impact and safety. These studies areespecially important, Steele said, in developing countries.

“We are not going to see clean data like [thepreliminary results from the US] in developingcountries, because they don’t have the same reportingsystems and surveillance systems,” he said.

Meanwhile, as demand rises there are expectationsthat new rotavirus vaccine candidates will be comingfrom manufacturers in Brazil, China, India, Australiaand Indonesia.

Steele noted that “[GSK and Merck] are not capableof supplying the numbers of doses, the millions ofdoses that will be needed once countries in the poorerresource areas start to introduce rotavirus vaccine.”

Recommendations emerging from a WHO meetingthat focused on vaccine candidates now in the productpipeline cited the need for internationally standardizedquality assurance programs for the safety, theproduction and the conduct of efficacy trials of liveattenuated vaccines, and also called for the continueddevelopment of non-living, inactivated rotavirusvaccines. Several approaches to non-living rotavirusvaccines are now under consideration by researchgroups in the US and Japan, amongst others.

Also, Steele said PATH’s Advancing RotavirusVaccine Development initiative is working withmanufacturers in India and China throughout the fullvaccine development cycle, to ensure that theseinternational acceptable standards are achieved.

The challenges rotavirus vaccines present to thehealth care and immunization infrastructure systemsare also a key concern, he said. For example, the vac-cines now available will challenge each country’s systemof refrigerated storage—known as “cold chain.” Steelesaid the Rotarix vaccine and associated supplies require

VACCINE NAME COMPANY STRAIN(S)

NIH Bovine-human UK Butantan, Brazil Bovine (G6) +reassortant rotavirus Wuhan & Chengdu, China G1,G2,G3,G4,P[8]

SSI, Shanta, Biologicals E, Bharat, India + designerreassortants

Australian neonatal RV3 MCRI / Biofarma , Australia / Indonesia G3, P[6]

Indian neonatal 116E US - Indian consortium — G9, P[11](bovine-human PATH, USA and Bharat Biotech Ltd, Indiareassortant)

Rhesus-human RRV-TV BIOVIRx / USA (IMF) US Rhesus (G3) +tetravalent rotavirus IDT / Germany VP7 (G1,G2,G4)

Lamb rotavirus — LLR Lanzhou Biologicals / Xinkexian G10,P[12] +lamb human reassortant LLR+ Biological Technology, China G1,G2,G3,G4vaccine

FIGURE 12. Other Candidate Live Oral Rotavirus Vaccines

From Duncan Steele, PATH

SESSION VIThe Next Steps for Rotavirus Vaccines


more storage space than do the traditional child-hood vaccines including DPT, polio or measlesvaccines. In particular, he pointed out that the cur-rent formulation of Rotarix immunizations, withthe buffer and connector - take up to ten times asmuch space in a refrigerator as the vaccine itself.

“There has to be an effort in formulation andin repackaging these vaccines if we want to rollthem out into huge countries in Africa or Asia,”Steele said.

Immunization Access and theRole of the GAVI AllianceRanjana Kumar of the GAVI Alliance offered anoverview and update of an internationalorganization that is expected to play a central rolein helping the world’s poorest countriesimplement widespread rotavirus immunization.

GAVI is a global public-private partnershipestablished in 2000 with the mission of savingchildren’s lives, and protecting people’s health byincreasing access to immunization in poor coun-tries.

Currently GAVI works with 72 of the world’spoorest countries, those with less than $1000 percapita income as of the year 2003. Foundingmembers included The World Bank, WHO, andUNICEF. The Bill & Melinda Gates Foundationjump-started GAVI with a large grant.

“GAVI has committed about $2.6 billiondollars for new vaccines and the rest, which isHealth System and Immunization ServiceSupport, comes to about $800 million,” Kumarsaid.

Kumar explained that GAVI funding pays mostof the cost of vaccines, but eligible countriesremain responsible for part of the cost. Forexample, haemophilus influenzae type B or Hibvaccine may cost approximately US $3.00 perdose. The country pays only US $0.30, and GAVIpays the remainder. A second vaccine costs thecountry even less.

“Policy makers need to be convinced that it’sreally cost-effective, it’s affordable, and it willindeed save lives,” Kumar said.

GAVI also seeks funding from a variety ofsources. The International Finance Facility forImmunization (IFFIm) raises $4 billion in capitalmarkets to provide funding for GAVI-supported

SIDEBARVaccine as a Catalyst for ConqueringDiarrheal Diseases

John Wecker, director of the PATH Rotavirus VaccineProgram, endeavored to take the audience “beyond theworld of rotavirus disease and beyond rotavirus

vaccines into the broader world of diarrheal disease.”Moreover, Wecker said “we have to remember that

mortality due to rotavirus disease only accounts for about 31percent of all diarrheal disease deaths.”

“We have the other 69 percent that we have to deal with,if we’re serious about reducing under five mortality,” he said.

Wecker pointed out that more proven interventions areavailable to prevent and treat diarrhea than any other majorchild killer. He said oral rehydration has reduced mortality—

saving the lives of more than 40million children—and has furtherpotential if it can be delivered tothe children who need it most.Zinc can control both acute andpersistent diarrhea, he said, andis approved by WHO and theWorld Health Assembly. Also,Wecker observed that exclusivelybreastfeeding babies for the firstfive months reduces the risk ofdiarrhea death by seven times.

But despite the availableapproaches and interventions, Wecker said diarrhea stillaccounts for 17 percent of deaths in children under five yearsold. And since 1995, he said, the use of oral rehydration hasdropped in countries where it’s most needed, especiallycountries of Sub-Saharan Africa.

Wecker said rotavirus vaccine introduction can provide anopportunity to improve treatments for all diarrheal diseasesby prompting far-reaching changes in national healthsystems. For example, he said that when Nicaraguaintroduced rotavirus vaccine, it simultaneously worked toretrain health-care workers nationwide, increase access tooral rehydration and, with a donation from UNICEF, introducezinc therapy for diarrhea.

A study of perceptions, Wecker said, found that diarrheahas dropped off the map of globally important diseases, whileAIDS, malaria and TB remain prominent. “Diarrheal diseaseranked actually last in terms of its current priority for donors,for funders on the global health agenda.” Wecker said.

“Take your data and get out there and let the policymakers know what you’re doing,” Wecker said.

“Credible research results can help pushdonors and policymakers to take action,he said, but researchresults must reachpolicymakers to have an effect.”

John Wecker, PATH, US


immunization activities. In addition, GAVI hopes touse its Advance Market Commitment program (AMC)to entice more companies to develop new vaccines byassuring them a future market for their products. ButKumar said ultimately, “it’s really up to the countriesto decide which of the vaccines they want according totheir own priorities.”

Kumar noted a WHO analysis that has provided a“consensus assessment” for which diseases deserve thehighest priority. Malaria and pneumococcal disease areconsidered the “highest priority,” while rotavirus is in agroup of ten diseases, which include seasonal influenza,cervical cancer and Japanese Encephalitis, classified as“high priority.”

Decision Making at the Country-Level Shahin Huseynov of the WHO initiated a paneldiscussion of government health officials from theWHO EURO region—all of whom represented formerSoviet states—by asking whether rotavirus vaccine wasa priority in their country.

Sabirjon Abdukarimov, Deputy Minister of Healthfor Kyrgyzstan, said “We need to convince our politicalactors to be committed, and of the economic efficiency,first of all, and the social importance of this issue.” Hesaid rotavirus disease may account for 40-60 percentof all diarrheal disease in Kyrgyzstan.

In Georgia, other vaccines still to be introduced willhave first priority, but cost-effectiveness research onrotavirus vaccine will be conducted, said PaataImnadze, of the National Center for Disease Control.He said one factor that could influence vaccineadoption is the impending privatization of thecountry’s health care system.

Ludmila Chernyshova from the Ukraine said it isdifficult to determine when rotavirus vaccine may beintroduced. Anti-vaccine lobbying has been strong inUkraine, especially after a recent death due to measlesvaccine. On the other hand, rotavirus research isongoing, as is communication about rotavirus to thepublic. Rotarix is currently being registered in Ukraine.

Armenia’s Gayane Sahakyan said the country hashad several outbreaks of gastroenteritis, half of which

WHO Disease Prioritization

(Nov. 2007)

Medium Priority

Consensus Assessment of Relative Importance (n=27)

High Priority

Highest Priority

Malaria .160Pneumococcal .102Influenza (seasonal) .076Meningococcal ACWY .068Cervical Cancer (HPV) .066Cholera .066Rabies .066Japanese Encephalitis .065Yellow Fever .064Rotavirus .055Typhoid Fever .054Dengue .043Meninqococcal B .031Rubella .021Varicella .017Hepatitis A .016Hepatitis E .016Mumps .015

FIGURE 13

From Ranjana Kumar, GAVI Alliance


were caused by rotavirus. She said Armenia’s Ministryof Health is interested in rotavirus vaccination, butbecause Armenia has no sentinel epidemiologicalsurveillance, there is no concrete data on the disease.Infrastructure is also a concern. For example, there isinadequate cold storage at treatment facilities.

Dilorom Tursunova of Uzbekistan said there hasbeen research on rotavirus in the country, and sentinelsurveillance is in place, as are training programs forfamily physicians.

“Naturally, after listening to the two days of thissymposium, we think that the research we areconducting is of course not enough,” Tursunova said.“And we would like to conduct more research, tocontinue, and to convince our government of thenecessity of introducing a rotavirus vaccine.”

Nadia Teleb of the World Health Organization askedhealth officials from countries in WHO’s EasternMediterranean Region (EMRO) to discuss how they goabout evaluating a new vaccine.

Ali Moghaddam of Libya said vaccines are evaluatedby a national advisory committee of pediatricians. Butbecause surveillance is not good, making evidence-based decisions remains difficult, he said. In addition,Moghaddam said, Libya is struggling to prioritize: “Is itthe rotavirus first or is it pneumococcal or is it chickenpox or is it human papillomavirus?”

Libyan mothers are overwhelmingly in favor ofvaccinations, he said, and some even travel outside thecountry for vaccinations.

In Iran, an expert committee convenes every two

years to consider how to budget for bothcommunicable and non-communicable diseases, saidIran’s Abdoul Reza Esteghamati. Research in Iranshows about 55% of children hospitalized forgastroenteritis test positive for rotavirus. As a result,Esteghamati said Iran has decided to introducerotavirus vaccine in the next two years, probably withfunding from the Ministry of Health. But rotavirusmust take second place to introducing vaccine againstHib, Esteghamati said, as Hib occurs at a surprisinglyhigh rate in Iran.

WHO recommendations can be influential,Esteghamati said, but affordability is also important.One approach Iran is considering is to reduce costs byproducing more vaccines domestically.

Ataya Medasate noted that Sudan, with a totalpopulation of 7 million, has separated into NorthSudan and South Sudan, each of which have differenthealth systems. Decision making on vaccines in NorthSudan begins with data collection, moves on to apresentation to a joint forum between the Ministry ofHealth and the Pediatric Association, and finally to theFederal Ministers of Health and Finance.

“If you have a strong recommendation from WHO,that is enough for the Federal Administer of Health,but sometimes, we face problems with the PediatricAssociation,” Medasate said. “They are very insistentto have local data regarding the burden of disease inthe country.”

Sudan plans to apply for GAVI funding for rotavirusvaccination in 2010.


Concluding Remarks

Roger Glass of the Fogarty International Center observed that the

presentations at the conference offered a clear sense of rapid progress. He

said they showed that in just the last three years, many countries have begun

data collection, surveillance procedures and made a general movement

toward introduction of rotavirus vaccines.

“Where will we be now in two years? What will be different in two years

from where we are today? That’s the question I’d like to pose,” he said. “In

two years, we will know how well these vaccines work in the poorest, low-

income countries of world. We’ll have definitive data to know whether these

will be the lifesavers that we’re all expecting or whether we have to think of

other iterations to accomplish our goal.”

“In two years,” he added, “we should have data, literally, on millions of

children about the safety of this vaccine, so we might, potentially, be able to

put the intussusception issue to rest. In two years, we’ll have new issues and

new knowledge on pricing. We’ll have new vaccines on the horizon. We’ll

have some competition in countries. We’ll have experience with the vaccines,

so we may well have a completely different economic outlook and forecast

for the vaccine finance.”

Almost all of these insights, he said, will come “from people in this room”

who would be departing from the conference “invigorated” by a wealth of

new data, contacts and networks.” Glass said for people like him who have

devoted a large part of their careers to the study of rotavirus disease, the

groundswell of global interest on display in Istanbul is “absolutely inspiring.”


SpeakersSabirjon AbdukarimovMinistry of Health, Kyrgyzstan

Juan Jose AmadorPATH, Nicaragua

Deborah AtherlyPATH,United States

Norman BeggGlaxoSmithKline, Belgium

Zulfiqar Bhutta Aga Kahn University, Pakistan

Julie BinesRoyal Children’s Hospital,Australia

Lulu BravoUniversity of the Philippines,Philippines

Anthony BurtonWorld Health Organization,Switzerland

Liudmyla ChernyshovaUkraine

Max CiarletMerck, United States

Lucia De OliveiraPan American HealthOrganization, United States

Ciro de QuadrosSabin Vaccine Institute, United States

Abdoul Reza EsteghamatiMinistry of Health, Iran

Elmira FlemNorwegian Institute of PublicHealth, Uzbekistan

Roger GlassFogarty Center, National Instituteof Health, United States

Jim GrayHealth Protection Agency,United Kingdom

Shahin HuseynovWorld Health Organization,Azerbaijan

Paata ImnadzeNational Center for DiseaseControl, Georgia

Ranjana KumarGAVI Alliance, Switzerland

Eric LaurentWorld Health Organization

Shabir MadhiUniversity of Witwatersrand,South Africa

Ataya MedasateSudan

David MercerWorld Health OrganizationDenmark

Ali MoghaddamLibya

Umesh ParasharCenters for Disease Control & Prevention, United States

Manish PatelCenters for Disease Control & Prevention, United States

Gayane SahakyanMinistry of Health, Armenia

Mathuram SantoshamJohns Hopkins BloombergSchool of Public Health, United States

Duncan SteelePATH, United States

Nadia TelebWorld Health Organization,Egypt

Cristina ToscanoWorld Health Organization, Switzerland

Dilorom TursunovaMinistry of Health, Uzbekistan

Timo VesikariUniversity of Tampere, Finland

John R. WeckerPATH, United States

Marc Alain WiddowsonCenters for Disease Control & Prevention, United States

Pierre Van DammeUniversity of Antwerp, Belgium

Preben AavitslandNorway

Karashash AbauovaKazakhstan

Abudhyr AbdulhafeezLibya

Almaz Tadesse AbebeEthiopia

Patric R. AbelleKenya

Camilo J. AcostaUnited States

Ibrahim Adib

Jan AgostiUnited States

Salwa Fouad Ahmed

Necmi AksarayTurkey

Olga AleksinskayaRussia

Rafila AlexandruRomania

Germen AlfredGreece

Sadık Emre AlhanTurkey

Kunwar AliEgypt

Syed Muhammed AliciaPakistan

Kunwar AliciaPakistan

Sanchez Fauquier AliciaSpain

Malika Almansouri

Gulnar AlshinbayevaKazakhstan

Fuat AltayTurkey

Mustafa AltındişTurkey

Pinaki AminUnited Kingdom

Natalia AndronovaRussia

Chouikha AnissaTurkey

Tülay AnlaşTurkey

Oğuz Alp AnselTurkey

Nilgün ArazTurkey

Rashmi AroraTurkey

Ahmet ArvasTurkey

Tigran AvagyanArmenia

Esperanza AvilaBrazil

Özgür AydınTurkey

Adem AydınTurkey

Simten AydınTurkey

Birsen AykutoğluTurkey

Mamadou BaCote D’Lvoire

Elena BaburaRussia

Mustafa BakırTurkey

Rajiv Bansal

Jameela Bassa

Nyambath BatmunkhKorea

Ayşe Seza BaykanTurkey

Todorka BelevaBulgaria

Robin J. BiellikSwitzerland

Muminjon BobojonovTajikistan

Hans Ludwig BockSingapore

Syedah Maria BokhariPakistan

Irving Charles BoudvilleSingapore

Gürkan BozanTurkey

Van Brackel

Alain BrecxBelgium

Javier BuesaSpain

Kateryna BulavinovaUkraine

Beyhan Göksan BulgurluTurkey

Diana Carolina CaceresColombia

Emel CandaşTorunTurkey

Florence CarayonFrance

Ana CarvalhoUnited States

Enrique CasanuevaArgentina

Evelyne CaulinFrance

Noureddine ChaoukiMorocco

Leticia Chapuis

Ivdity ChikovaniGeorgia

Ergin ÇiftçiTurkey

Candan ÇırayTurkey

Romulo ColindresBrazil

Marina ConynNetherlands

Jailson Barros CorreiaBrazil

Margaret CorteseUnited States

Cisterna CristinaSpain

Celso CunhaPortugal

Nigel CunliffeUnited Kingdom

Tim DallmanUnited Kingdom

Norbert De ClercqBelgium

Serge DebrusBelgium

DeğerliTurkey

Mohammed DeknaMadagascar

Yulia DeminaRussia

Özge Demir LemanTurkey

Tsvetelina Dimitrova

Ener Çağrı DinleyiciTurkey

Quesmane Madiagne DiopSenegal

Chantal Claire DondeFrance

Elena Donosa

Dana DraganRomania

Shamsidin DzhabirovTajikistan

Osama EdwardEgypt

Hanaa El KaraksyEgypt

Ali El MkadmiLibya

Hanan El MohammadyEgypt

El Tayeb Ahmed El SayedSudan

Jilan ElGarfEgypt

Hale ErelTurkey

Tuba ErenerTurkey

Margareta ErikssonSweden

Abdoulreza EsteghamatiIran

Sherief FamTurkey

Zhao Yin FangChina

Shahid FarooquiPakistan

Elena FenskeRussia

Elena FilipRomania

Rodrigo Vergara FisherChile

Rassen Fosse

Leonard FriedlandUnited States

Ludmila FunsoRussia

Kateryna GamazinaUkraine

Philip Garnier

Britta GartnerGermany

Nina GatchevaBulgaria

Zipporah GatheruKenya

Jon GentschUnited States

Tovetelina GeonovaBulgaria

Domintak Geraldine

Stela GheorghitaMoldova

Molnar Gheza

�smail Göçmen

Gülbin GökçayTurkey

Hayri GözlüklügillerTurkey

Maria Lourdes GuerreroMexico

Ayşe GüneyTurkey

Chundrbhan Gupt DomahMalawi

Duygu GürTurkey

Emel Gür

Ricardo GurgelBrazil

Nuran GürsesTurkey

Vijdan GüvenTurkey

Ghazaros HakobyanArmenia

Shahid HameedPakistan

Khaoula HarkatUnited Arab Emirates

HarputoğluTurkey

Hashim Eldar HashimovAzerbaijan

Margaret HaughFrance

Janie HayesUnited States

Waqar HussainPakistan

Hyat Hyat Han

Demet IlıkkanTurkey

Özdemir �lterTurkey

Mehmet �lterTurkey

Vladimir IlyukhinRussia

Fodha ImeneTunisia

Syed Muhammad Inkisar AliEgypt

Nurhan �pekTurkey

Claudia IstratePortugal

Miren Iturriza

Khahial Javed

Alvarez JavierSpain

Khalid JawaidPakistan

Baoming JiangUnited States

Kari JohansenSweden

Karina JunussovaEstonia

Rivojiddin JurayevUzbekistan

Participants


Murat KaçarTurkey

Rahat KadyrovaKyrgyzstan

Joldosh KalilovKyrgyzstan

Rose KamenwaKenya

Hüseyin Kandemir

Şenay KaraarslanTurkey

Matthew KasperIndonesia

Kaliya KasymbekovaKyrgyzstan

Nezihe KavaşTurkey

Bilge KayıranTurkey

Kaya KayranTurkey

Zarif KazakovUzbekistan

Peter Nicholas KazembeMalawi

Kulnur KembabanovaKazakhstan

Melike KeserTurkey

Nurdan KeskinTurkey

Bakhtier KhashimovUzbekistan

Manana KhochavaGeorgia

Lyutsia KimUzbekistan

Sue KingSouth Africa

Carl KirkwoodAustralia

John KlenaUnited States

Dirk Knieps

Jean KokoSenegal

Majlinda KotaAlbenia

Triveni KrishnaIndia

Annelies KronemanNetherlands

Ainagul KuatbayevaKazakhstan

Olga KubarRussia

Canan KüçükTurkey

Nuri Zafer KurugölTurkey

Hülya KutluTurkey

Necdet KuyucuTurkey

Rabih Kyriakos

Renat LatipovUzbekistan

Luan Thi LeVietnam

Yang LiChina

Alexandre LinharesBrazil

Erlin ListiyaningsihIndonesia

Ben LopmanUnited Kingdom

Prakash LuchoomanMorocco

Anton LuchytskyUnited States

Stanislava LukovnikovaRussia

Virginia García Luque

Karianne Lyche

Bassem Mahmoud

Issa MakumbiUganda

Vladimir MalyshevRussia

Sajid MaqboolPakistan

Abdel Massih

Jelle MatthijnssensBelgium

Leena MaunulaFinland

Ayoub MbonyintwariBurundi

Linda Mcgehee

�lhan Hatip MehmetTurkey

Aisha MehnazPakistan

Iqbal MemonPakistan

Ibrahim Abdel MesihEgypt

Christine MiddletonUnited States

Sofie Elisabeth MidgleyDenmark

Radmila MirzayevaSwitzerland

Ciza MisigaroBurundi

Zoznitsa MladenovaBulgaria

Hilal MocanTurkey

Ali MokadamyLibya

Ida Berenice MolinaHonduras

Osman MonsourUnited States

Khitam MuhsenAzerbaijan

Kyialbek MukashovKyrgyzstan

Nazifa MursalovaAzerbaijan

Charles MwansamboMalawi

Meyer Nadia

Osamu NakagomiJapan

Tony NaoumChina

Willy Karim NdjaliBurundi

Tony NelsonHong Kong

Christopher Nelson

Mohamed El Amin NibarutaBurundi

De Clercq NorbertBelgium

Anita NordbyNorway

Badru K. NtabumkaBurundi

Zuridin NurmatovKyrgyzstan

Emel Öcal

Marc OdicFrance

Zeki ÖdünçTurkey

Özgür OkumuşTurkey

Selim ÖncelTurkey

Hester C. O’NeillSouth Africa

Valerie OriolFrance

Kunle Oyelana

Alper ÖzçelikTurkey

Rengin ÖzçiçekTurkey

Anıl Özkan

Y. Jak ÖzsarfatiTurkey

Nediha Öztürk

Serdar Öztürk

Niky PageMadagascar

Nicola PageSouth Africa

Latha ParvataneniUnited Kingdom

Robert PawinskiMorocco

Daniel Cooper PayneUnited States

Maria Cristina PedreiraNicaragua

Salinas PedroSpain

Ina PeenzeSouth Africa

Ender PehlivanoğluTurkey

Irene PerezColombia

Gemma PhilipsUnited Kingdom

Christopher PittsUnited Kingdom

Mateja Poljsak-Prijatelj

Julian PoppleUnited Kingdom

David PradoGuatemala

Sai D PrasadIndia

Nikoloz PruidzeGeorgia

Gayle PulleCanada

Romena Qazi

Feiyu QuChina

Farida QureshiPakistan

Silke Raab-PlessGermany

Maria Lucia RaczBrazil

Sajjad RafiquePakistan

Rehab RagabEgypt

Noeline RavelomananaMadagascar

Hany RiadTurkey

Malin RinderSweden

John RoordNetherlands

Leonard RuizUnited States

Guillermo Ruiz-PalaciosMexico

Zerrin SabuncuTurkey

Gülcan SağnakTurkey

Panayota SakuliasSouth Africa

Nuran Salman Turkey

Sema SaltıkTurkey

Olga SamodovaRussia

Claudine SanaFrance

Synne SandbuNorway

Hardeep Sandhu

Carlos Santiso

Fikriye SarıkayalarTurkey

Mehmet SatarTurkey

Luyanda SeheriSouth Africa

Muhammet Abdullah Selçuk

Tolga ŞentürkTurkey

Imdad ShahPakistan

Gayane ShakyanArmeniaBrian ShawUnited States

Salma SheikhPakistan

Asif Kaleem SheikhPakistan

Mae ShiehItaly

Sunheang ShinSouth Korea

Meredith ShireyDenmark

Sanat ShoumarovUzbekistan

Müjgan Sıdal

Evan SimpsonUnited States

Boriana SlanchevaBulgaria

Philip SlatisSweden

Thomas SnellingAustralia

Eduardo Soares

Ayper Somer

Samba Ousmane SowMali

Kemal SoydanTurkey

Ömer Alper SözüdüzTurkey

Constantin SpinuMoldova

Andrej Steyer

Necdet SungurtekinTurkey

Gyorgy SzucsKuwait

Milagritos Tapia

Derrough TarikFrance

Ozan TaşpınarTurkey

Jacqueline TateUnited States

Olga TcheremenskaiaItaly

Van Effelterre ThierryBelgium

Georges ThiryFrance

Sohail Thobani Pakistan

Ali TırtırTurkey

Elvira ToialievaKyrgyzstan

Aslı Toros SağlamTurkey

Anh Nhi TranSweden

Reda TrusieneLithuania

Özden TürelTurkey

Mehmet TürkoğluTurkey

Tomris TürmenTURKEY

Laziz Nadirovich TuychievUzbekistan

Remzi UğraşTurkey

Betül UlukolTurkey

Elmira UtegenovaKazakhstan

Selçuk UyluçgilTurkey

Hasan UzpakTurkey

Erdem UzunoğluTurkey

Kirsti VainioNorway

Albie Van DijkSouth Africa

Barend Van Loo

Raul Velazquez

Carlos VernePeru

Naozer VirjiPakistan

James WassilUnited States

Fred WereKenya

Pushpa WijesingheSirilanka

Oma WimalaretneSirilanka

Janice WoolfordGuyana

Fang Tzy WuTaiwan

Songül YalçınTurkey

Lütfiye Oya YalmanTurkey

GüneşYarımayTurkey

Olcay YasaTurkey

Erdal YaşarTurkey

Anıl YeşildalTurkey

Şükran YıldızTurkey

Osman Yılmaz

Pınar YılmazbaşTurkey

Tuncay YılmazerTurkey

Garcia YolandaSpain

Oya YücelTurkey

Demina Yuliya

Refiye ZaferTurkey

Khalequzzaman ZamanBangladesh

Hugo Zepeda

AcknowledgementsThe Symposium Organizing Committee wishes to thank the following organizations

for support of the 8th International Rotavirus Symposium:

Sabin Vaccine Institute

US Centers for Disease Control and Prevention

Merck Research Laboratories

GlaxoSmithKline Biologicals

PATH

Sanofi Pasteur

Norwegian Institute of Public Health

World Health Organization

Sabin Vaccine InstituteInternational Vaccine Advocacy

2000 Pennsylvania Avenue, NWSuite 7100

Washington, DC 20006Phone: 202-842-5025

Fax: 202-842-7689www.sabin.org



June 3–4, 2008

Istanbul, Turkey

PROCEEDINGS 8 INTERNATIONAL ROTAVIRUS SYMPOSIUMJune 3–4, 2008 Istanbul, Turkey. Acknowledgements...

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Transcript of PROCEEDINGS 8 INTERNATIONAL ROTAVIRUS SYMPOSIUMJune 3–4, 2008 Istanbul, Turkey. Acknowledgements...