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PROCEEDINGS FROM THE
8th INTERNATIONAL ROTAVIRUS SYMPOSIUM
Sabin Vaccine Institute
International Vaccine Advocacy
2000 Pennsylvania Avenue, NW
Suite 7100
Washington, DC 20006
Phone: 202-842-5025 June 3–4, 2008
Fax: 202-842-7689
www.sabin.org
Istanbul, Turkey
Acknowledgements
The 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 OrganizationPROCEEDINGS FROM THE
th
8 INTERNATIONAL
ROTAVIRUS SYMPOSIUM
Istanbul, Turkey
June 3–4, 2008Table 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 . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .1
Developing a Strategy for Rotavirus Surveillance . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .2
A Brief History of Rotavirus Vaccines . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .3
Vaccine Cost and Vaccine Efficacy . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .4
Mapping a Way Forward . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .4
Sidebar: Rotavirus Timeline . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .5
Discovery of Rotavirus to a Vaccine in 25 years . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .6
Bovine Beginnings . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .6
The Rhesus Rotavirus Vaccine . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .7
Matching Safety with Efficacy . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .7
Session I: Update on Rotavirus Vaccine . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .8
Rotarix and the Key Challenges of Rotavirus Immunization . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .8
RotaTeq: A Pentavalent Approach to Rotavirus Immunization . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .10
World Health Organization Policies on Rotavirus Vaccines . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .11
Vaccine Concerns: Interactions and Disease Transmission . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .12
Sidebar: Interim Analysis of Vaccine Efficacy in South African Infants . . . . . . . . . . . . . . . . . . . . . . . . . . . . .13
Session II: Introducing New Rotavirus Vaccines . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .14
Regional Perspectives: The WHO European Region . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .14
Regional Perspectives: Latin America and the Caribbean . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .14
Regional Perspectives: Impact and Cost-Effectiveness in Central Asia . . . . . . . . . . . . . . . . . . . . . . . . . . . . .15
Vaccine Monitoring Post-Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .16
Sidebar: Keeping Track of Intussusception . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .16
Session III: Epidemiology and Burden of Rotavirus Disease . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .18
The Importance of Global Surveillance . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .18
Estimating Deaths from Rotavirus . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .18
Surveillance in the WHO EURO and EMRO Networks . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .19
Sidebar: On the Lookout for Rotavirus Mutations . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .20
Proceedings from the 8th International Rotavirus Symposium iiiSession IV: Early Experience with Routine Use of Rotavirus Vaccines . . . . . . . . . . . . . . . . . . . .21 United States: “A Steady, Progressive Climb” . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .21 Nicaragua: Responding to An Epidemic with a Vaccine . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .22 European Union: Considering Disease Burden and Vaccine Costs . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .22 Session V: Policy Decision Making . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .23 Engaging the Public . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .23 Confronting the Costs of Rotavirus Vaccines . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .23 The Next Steps for Rotavirus Vaccines . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .25 Vaccine as a Catalyst for Conquering Diarrheal Diseases . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .26 Sidebar: Immunization Access and the Role of the GAVI Alliance . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .26 Decision Making at the Country-Level . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .27 Concluding Remarks . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .29 List of Participants . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .30 iv Proceedings from the 8th International Rotavirus Symposium
Foreword
he 8th International Rotavirus Symposium was a collaborative effort of the Sabin Vaccine
T 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 vExecutive Summary
he 8th International Rotavirus Symposium days of age. They said that since that time, all rotavirus
T took place at a crucial time in the history of
rotavirus vaccines, which are intended to
provide protection from a disease that,
according to surveillance data presented by the World
Health Organization, kills 527,000 children each year.
vaccines in trials or routine use are supposed to be
given before 90 days, when babies appear to have a
natural protection against intussusception.
Experts point out that the two rotavirus vaccines
currently in use—GlaxoSmithKline Biologicals’ (GSK
With two approved rotavirus vaccines in use, and Bio) Rotarix® and Merck’s RotaTeq®—are always
therefore two years of data on their safety and efficacy administered before 90 days of age to avoid intussus-
now available, participants had more information at ception. Company representatives said clinical trials
their command than in any previous year. conducted thus far have found the vaccines to be safe
Roger Glass, Director of the Fogarty International and effective.
Center at the US National Institutes of Health, opened Norman Begg of GSK said Rotarix was developed
the meeting with a keynote address that celebrated the from the most common human rotavirus strain. The
size and geographic span of the meeting noting that rationale for the approach, he said, was that natural
the 2008 symposium attracted four times as many infections with rotavirus confer excellent immunity to
participants as the first meeting in 1995. He then went further infections. Begg said that studies show that
on to discuss how he and colleagues convinced the Rotarix—when given before 90 days of age—does not
United States, a country with very few rotavirus deaths, increase the risk of intussusception compared to
that a vaccine could save a billion dollars a year in placebo. He stated that the vaccine produces broad
direct and indirect health care costs. protection against many rotavirus strains, that the
Glass also singled out a crucial insight in surveil- protection lasts at least two years, and that the two-dose
lance data, which shows that rotavirus epidemiology regimen can be safely administered with other
differs dramatically between high-income and low- childhood immunizations.
income countries. In low-income countries, a larger Max Ciarlet of Merck said the company took a
proportion of rotavirus disease victims are under one different approach with its rotavirus vaccine. It
year old, diarrheal diseases routinely involve a mix of developed RotaTeq from five human-bovine reassortant
infections, and the fatality rate is high. rotavirus strains. RotaTeq is administered in three doses
Studies are underway in these regions to gauge the because it exhibits low replication capabilities in the
potential efficacy and impact of rotavirus immuniza- human gastrointestinal tract, and three doses are
tions, as past experience has shown that there can be required to build high and consistent immune
important geographical variations in vaccine response. responses, he said. According to data he presented,
However, the high rate of rotavirus disease in poor coun- RotaTeq’s safety profile showed that RotaTeq is well
tries has left many eager for widespread adoption of tolerated and is not associated with an increase in the
rotavirus immunization in the developing world. frequency of serious or nonserious adverse events.
“In the developing world, we’ve seen a very high Cristiana Toscano presented the World Health
case fatality rate, which has motivated the entire global Organization’s (WHO’s) policies on rotavirus vaccines,
program,” Glass said. most notably that efficacy must be shown in at least
Glass went on to review a key development in one low-income country in Sub-Saharan Africa or
rotavirus vaccine history: the rise and abrupt fall of South Asia before WHO will recommend the use of the
RotaShield®, the first approved vaccine for rotavirus. vaccines in these regions.
Within months of its introduction, some children Duncan Steele, PATH’s senior advisor on diarrheal
vaccinated with RotaShield developed intussusception, disease, noted that trials were underway to generate
a rare and dangerous bowel obstruction. The adverse efficacy data and results should be available between
event prompted RotaShield’s manufacturer, Wyeth, to late 2008 and 2010. He pointed out that, given the high
withdraw the vaccine from the market. rate of rotavirus disease in poor countries, even less
Glass and several other speakers noted that the cases than perfectly effective vaccines would save many lives
of intussusception were in children vaccinated after 90 and prove cost-effective.
vi Proceedings from the 8th International Rotavirus SymposiumShabir Mahdi of South Africa’s University of the “It’s important that we don’t assume that just
Witwatersrand presented interim results of an efficacy because a study has been done in a particular region in
trial conducted in South Africa. He said they show that Asia or Africa that everyone knows about it,” he said.
“the vaccine itself clearly offers a high degree of Santosham appealed to researchers and decision
protection in South African children against severe makers not to block rotavirus vaccines, which could
rotaviral illness during the first year of their life.” save 2 million deaths by 2020, because of a few
Umesh Parashar of the US Rotavirus Vaccination inevitable cases of intussusception.
Program at the US Centers for Disease Control and Other discussions focused on future challenges
Prevention presented early results from two years of including the need for post-marketing surveillance, sta-
RotaTeq use in the US. Widespread monitoring of ble funding for vaccine procurement, and infrastruc-
rotavirus immunizations indicates that the rotavirus ture improvements in such areas as cold-storage
vaccine appears to be safe (when the first dose is given facilities.
before 90 days of age). Data on effectiveness show a Vaccine costs and financing were also a key issue of
slight drop in rotavirus diarrhea in the year after concern. Deborah Atherly, senior health economist and
RotaTeq was introduced, but a dramatic drop during policy officer at PATH, detailed a financial model that
the second year. Presentations on early experiences in predicts prices will fall from a current $7.00 per dose to
Nicaragua and the European Union followed. The around $1.25 per dose by 2020, and that if widely
discussions revealed that, despite similar rotavirus adopted, the vaccine could prevent the deaths of
burdens, attitudes in Europe vary widely as to when, 225,000 children per year.
where and how to introduce a rotavirus vaccine. Roger Glass concluded that in just two years the
Presentations on policy concerns included a situation could change significantly, particularly if new
discussion of how to communicate rotavirus issues to rotavirus vaccines now under development come on
the public, policy makers and physicians. Mathuram the market and boost competition, which would lower
Santosham of the Johns Hopkins Bloomberg School of prices.
Public Health believes that researchers, not just “So we may well have a completely different
advocates, must take a lead in communicating the economic outlook and forecast for the vaccine finance,”
benefits of rotavirus immunization. he said.
Proceedings from the 8th International Rotavirus Symposium viiIntroduction
he 8th International Rotavirus Symposium participants. And I think this really shows the eagerness
T brought together scientists, clinicians, public
health professionals, immunization leaders,
vaccine industry representatives, and members
of the donor community.
Dr. Ciro de Quadros, Executive Vice President of the
of the world community to come to grips with rotavirus
disease.”
Dr. de Quadros highlighted the importance of
rotavirus vaccine development and deployment with
this sobering fact: worldwide, 65 children die of
Sabin Vaccine Institute, welcomed participants, noting rotavirus diarrhea every hour.
that the large and geographically diverse group John Wecker, PATH’s Global Program Leader for
demonstrates that the global health community is Immunization Solutions, welcomed participants on
committed to the fight against rotavirus disease. This, the behalf of the organizing committee and commented
8th International Rotavirus Symposium, he said, would on the quality of research to be presented.
be a model in the history of rotavirus vaccines, and would “In our work with the countries, we have come to
help advance the cause of children’s health worldwide. realize the commitment that you all have to reducing
“We have one-third of the world present here,” he morbidity and mortality associated with diarrheal
said “We have 67 countries. We have over 400 disease, and improving a child’s survival,” he said.
“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
viii Proceedings from the 8th International Rotavirus SymposiumKEYNOTE ADDRESS
Roger Glass, Fogarty International Center, US National Institutes of Health
The Emergence of Rotavirus as a Global Health Concern
oger Glass, who serves as director of the Fogarty disease in a place like Bangladesh, in a low-income
R International Center at the US National Institutes
of Health, delivered a sweeping and detailed
overview of how the world has arrived to the point that
country, had to be our primary goal, because diarrhea
in these settings was a killer.”
The study of rotavirus began in earnest, he said, with
it now has rotavirus on the ropes. the 1979 WHO program for diarrheal disease control.
Glass said he has been gratified to see interest in Glass recalled that Ruth Bishop, the researcher who dis-
rotavirus vaccines surge over the last ten years. He covered rotavirus, Tom Flewett, who named rotavirus,
compared the huge turn-out in Istanbul in 2008 to an and Albert Kapikian, who later developed the first
international rotavirus meeting in 1995 at the US rotavirus vaccine, told WHO: “The world needs a
Centers for Disease Control and Prevention (CDC), rotavirus vaccine.”
which he said attracted representatives from only half One issue for Glass was whether wealthy
a dozen countries. countries would be interested in a rotavirus vaccine.
Glass first became interested in rotavirus while He said that while the disease burden of rotavirus is
studying cholera in Bangladesh in 1980. He knew, he obvious in developing countries—120,000 deaths
said, that cholera was an important diarrheal disease. annually in India, 100,000 in South Asia, 230,000 in
But it turned out that rotavirus was a much more Sub-Saharan Africa, and 20,000 in Latin America—
common and frequent cause of severe diarrhea. Glass said the need for a rotavirus vaccine in the US
Returning to the US, he moved to NIH to work on was not clear.
rotavirus and rotavirus vaccines. But he said further analysis revealed that while the
“But I must say,” Glass said, “that in the back of my number of deaths in the US was relatively low, rotavirus
mind a key issue was that the control of diarrheal caused many hospitalizations and clinic visits and
FIGURE 1
Estimated Global Distribution of the >500,000
Annual Deaths Caused by Rotavirus
1 Dot = 1,000 Deaths
Parashar, 2005
From Roger Glass, Fogarty International Center, National Institutes of Health, US
Proceedings from the 8th International Rotavirus Symposium 1“In the developing world, we’ve seen a very high case fatality
rate, which has motivated the entire global program.”
Roger Glass, Fogarty International Center of the National Institutes of Health, US
caused parents many days of lost work. The bottom line: grant was in Vietnam where we studied rotavirus
Rotavirus in the US was generating $400 million in diarrhea hospitalizations in six hospitals in four cities
medical costs and about $600 million in indirect costs in Vietnam,” Glass said. “We found that over half of
for a total financial burden of about $1 billion. the children had rotavirus as their cause of
hospitalization.”
Developing a Strategy This study led Glass and colleagues to set up the
for Rotavirus Surveillance Asian Surveillance Network, which then led to the
In 1995, WHO, Glass and colleagues at the US CDC, establishment of rotavirus surveillance networks
including Joe Bresee, began to think about how to around the world. Today, Glass said, 50 countries carry
conduct rotavirus surveillance. The system they arrived on routine rotavirus surveillance and data collection.
at was based on simple data collection methods. It Surveillance has provided surprising data about
employed the common ELISA assay (Enzyme-Linked differences in rotavirus epidemiology between
ImmunoSorbent Assay) for detection and allowed for industrialized and low-income nations. In wealthier
rotavirus strain identification. The method is now countries, rotavirus infection is seasonal and frequently
being used in more than 50 countries. affects children above one year of age. Mixed infections
“Our first study with this protocol with the WHO are rare and fatality is low. In low-income countries, on
FIGURE 2
BURDEN OF ROTAVIRUS IN THE US
RISK EVENTS
1:10 6 20-40 Deaths
1:80 60-70,000 Hospitalizations
1:7 500,000 Outpatient visits
1:0.9
3.2 Million episodes
Cost: $400 M medical; >$1 B total
Value of vaccine depends on direct vs. indirect costs
From Roger Glass, Fogarty International Center of the National Institutes of Health
2 Proceedings from the 8th International Rotavirus SymposiumFIGURE 3
Rotavirus Hospitalizations
in the Asian Rotavirus Surveillance Network
China: 41%
Taiwan: 41%
Hong Kong: 29%
Vietnam: 60%
Myanmar: 56%
Malaysia: 56%
Indonesia: 39%
Bresee 2003 EIDJ
From Roger Glass, Fogarty International Center of the National Institutes of Health
the other hand, rotavirus strikes all year, 80 percent of RotaShield reduced the duration of diarrhea for
cases are in infants, mixed infections are common, and infected children and prevented infections with all
fatality is high. rotavirus serotypes. But a crucial side effect caused
“In the developing world, we’ve seen a very high case Wyeth to withdraw the vaccine in little more than a
fatality rate, which has motivated the entire global year. In small numbers of children, the vaccine was
program,” he said. linked to cases of intussusception, a dangerous and
potentially fatal obstruction of the bowel.
A Brief History of Rotavirus Vaccines Worry about intussusception has affected all
According to Glass, the successful deployment of rotavirus vaccine development and trials since. Glass
rotavirus vaccines is the culmination of several decades said evidence indicates that the intussusception risk
of research and development that included crucial posed by rotavirus vaccination is time and age
setbacks. limited. When it occurs, it happens within two weeks
In 1983 and 1984, Timo Vesikari, in Finland, of the first dose. Also, almost all cases involve children
established the first rotavirus vaccine trial, which Glass over 90 days old at the time of the first dose. Overall,
credits for setting the stage for all rotavirus vaccine data indicate that the risk of intussusception
development since. (See in-depth discussion of following rotavirus immunization increases ten fold
rotavirus vaccine development below.) Glass said after 90 days of age.
Vesikari’s work demonstrated that rotavirus vaccines “Intussusception spares children naturally in the
based on bovine virus strains can work, that a poor first three months of life, so that with all the new live
immune response does not necessarily predict poor oral vaccines, we try to get their first doses in before 90
efficacy, and that protection was greatest against the days of age,” Glass said.
most severe cases of diarrhea. Today, there are two rotavirus vaccines—RotaTeq,
About 14 years later, in 1998, Albert Kapikian, in the from Merck, and Rotarix from GSK— licensed and
US, developed the first licensed rotavirus vaccine, widely available in more than 100 countries. Rotavirus
RotaShield, which was produced by Wyeth. vaccination is now routine in the US, Australia, Austria,
Proceedings from the 8th International Rotavirus Symposium 3Belgium, Luxembourg, Brazil, Panama, Nicaragua, this symposium, clinical trials of both rotavirus
Guyana, El Salvador, Venezuela, Bolivia, and parts of vaccines had been initiated in these regions. But Glass
Mexico. said “preliminary data suggests that they may not work
RotaTeq is licensed in 70 countries, including many as well” in developing countries, and that “there may
in Sub-Saharan Africa. be opportunities to improve efficacy.”
In the US, RotaTeq has been incorporated into the For example, past studies have shown that the
routine immunization program. The vaccine is given immune response to Rotarix among children in
at two, four, and six months of age, with special Bangladesh and South Africa is only a little more than
emphasis on administering the first dose before 90 days half what one sees in children in Finland. The
of age, to avoid the naturally occurring intussusception discrepancy is not peculiar to rotavirus vaccines but is
peak that occurs between 5 and 9 months of age. seen with live oral vaccines in general.
Recently, Rotarix was also licensed in the US. “Live oral vaccines have really posed a problem in
Globally, Rotarix is licensed in more than 100 the developing world,” Glass said.
countries, including Europe and Latin America where T. Jacob John, with the Indian Academy of
the vaccine has been introduced, but also including Pediatrics, and an attendee at the 2008 symposium was
countries like Bangladesh and 21 countries in Sub- noted as the first to observe this phenomena during
Saharan Africa. studies of oral polio vaccine. He found that the polio
The licensure in these countries is unusual, Glass vaccine does not work as well in children in India
said, because no efficacy data exists for populations compared to children elsewhere the world. Similar
living in low-income areas of the world. differences have been observed with oral cholera
vaccine and typhoid vaccine.
Vaccine Cost and Vaccine Efficacy Glass said there are many biological factors that may
Simply put, the two major considerations for a country be contributing to the problem. For example, breast milk
adopting a rotavirus vaccine focus on affordability and and stomach acid can neutralize the vaccine virus and
effectiveness. lower its effective titer. In addition, maternal antibodies
On the financial side of the equation, Glass said may reduce the amount of virus delivered or inhibit the
ministers of health focus more on the immediate cost immune response. Finnish studies showed that children
of an immunization, not cost-effectiveness over the who responded poorly to vaccines had higher levels of
long term (which compares the cost outlays for maternal antibody than did good responders.
purchasing and administering a vaccine to the “This observation has been repeated in other countries,
treatment and other costs imposed by the burden of and is quite consistent,” Glass said. For example, compared
the targeted disease). to Finland, levels of maternal antibodies are four to five
Rotavirus vaccines range in cost from $7.50 per dose times higher in South Africa, three times higher in
to more than $100 per dose. But, as in the example of Bangladesh and two times higher in Mexico.
the United States, while the cost can seem prohibitive, Also, a study conducted in Bangladesh showed that
if compared to the overall financial burden of rotavirus breast milk can significantly lower the amount of virus
disease the vaccines are likely cost-effective. The issue received by a baby during immunization. In
of cost vs. cost-effectiveness is more of a problem in Bangladesh and South Africa, it is not uncommon for
middle and higher-income countries, Glass said, babies to have breast milk in their mouth at the time of
because in low-income countries, GAVI Alliance is immunization, something that doesn’t happen in the
committed to subsidizing vaccine costs. United States where women do not breast feed in
Glass said that in addition to financial concerns, a public as often.
key challenge is determining whether “these vaccines
work well” in the developing world. Mapping a Way Forward
In 1997, when RotaShield was under consideration, One way to deal with this dilemma, Glass said, is to
Wyeth requested a global recommendation from WHO determine the level of efficacy required to provide
for global use of the vaccine. The WHO consensus sufficient protection against rotavirus. Does a vaccine
group responded that researchers must demonstrate need to be 90 percent effective, or would 80 percent or
efficacy of live, oral vaccines in at least one low-income even 40 percent be worth using?
country in Asia or Sub-Saharan Africa. At the time of Another approach would be to provide vaccines
4 Proceedings from the 8th International Rotavirus SymposiumSIDEBAR
ROTAVIRUS TIMELINE
better suited for the biological profile of
1973 Ruth Bishop and co-workers publish the discovery of human
children in the developing world. Both
rotavirus and its association with severe diarrhea in infants and
India and Australia are developing new young children in Melbourne, Australia
vaccines based on neonatal rotavirus
strains. These are strains that reproduce in 1978 Oral Rehydration Therapy (ORT) was found to be useful in
treating and preventing most of the deaths due to Rotavirus.
the presence of maternal antibody. Vaccines
that use inactivated rotavirus also could 1982 Vesikari tests bovine rotavirus vaccine in children; safe and
provide an alternative. immunogenic.
A major question, said Glass, is who will
1983 Vesikari tests bovine rotavirus vaccine in infants; safe
provide affordable rotavirus vaccines to the and protective against rotavirus diarrhea.
world? Today, he said, GSK and Merck are
supplying the vaccine. But vaccine manu- 1995 First trials in infants.
facturers in China, Brazil, India, Indonesia, 1996 Phase II trials begin, testing effectiveness in infants at four
and Germany are also potential suppliers centers across the US.
for developing countries.
Still, Glass said while challenges remain, 1997 Rotavirus ELISA developed.
overall progress on the path to widespread 1997 AVANT sublicenses vaccine to GlaxoSmithKline (GSK).
use of rotavirus vaccines is impressive.
“Rotavirus vaccines have become a 1998 Rotaviruses found to cause as many as one million
August hospitalizations and 500 deaths per year in the US.
priority for GAVI, for WHO, and for the
Gates Foundation,” he said. “We have two 1998 FDA approves RotaShield.
vaccines licensed, and we have others in October
development. Eight countries have national 1998 ACIP universal recommendation of RotaShield.
programs for rotavirus vaccination. So the September
train has really left the station.” –1999, July
1998 15 cases of intussusception in RotaShield vaccines reported to
July 16 the US Vaccine Adverse Event Reporting System (VAERS), or
one in every – 12,000 vaccinated infants.
1999 CDC reports preliminary data associating RotaShield with
“We have two vaccines July 16 intussusception and recommends postponing use.
licensed, and we have 1999 Wyeth temporarily suspends further distribution and
October 15 administration of RotaShield.
others in development.
1999 Wyeth withdraws RotaShield from the market.
Eight countries have October 22
national programs for 1999 US Advisory Committee on Immunization Practices
recommends against the use of RotaShield for infants.
rotavirus vaccination.
1999 GSK begins Phase I and Phase II studies of rotavirus vaccine in
So the train has really Europe, Asia and Latin America.
left the station.” 2001 REST Rotavirus Efficacy and Safety Trial begun, published 2006.
2003 Phase III of GSK’s Rotarix trials begin; 60,000 children
Roger Glass, in 12 Latin American countries.
Fogarty International Center
of the National Institutes of Health, US 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.
Proceedings from the 8th International Rotavirus Symposium 5Discovery of Rotavirus to a Vaccine in 25 years
Bovine Beginnings “Whether the children received the bottle milk or breast
milk before vaccination did not seem to make a difference.”
Timo Vesikari of the Vaccine Research Center of Vesikari said. “We’re very, very happy about that.”
University of Tampere, Finland offered a detailed Following up on the discovery of rotavirus, in 1983
history of rotavirus vaccine development. Ruth Bishop followed infants in Australia with and
He noted that vaccine development began in 1971, without a neonatal rotavirus infection. No difference
when Canadian veterinary biologist C.A. Mebus appeared between the groups in the number of
published a description of bovine rotavirus vaccine, rotavirus infections during the first three years of life.
named RIT 4237. The highly attenuated vaccine was But an early rotavirus infection did protect the babies
safe for cattle. against rotavirus disease.
In a 1982 study involving 25 children, Vesikari and “So what we did,” Vesikari said, “was to do the same
colleagues found the vaccine to be safe and to produce with vaccine, and we gave the vaccine to neonates.”
an appropriate immune response in humans as well. A As with the Australian study of natural rotavirus
trial in 8 to 11-month-old infants followed the next infections, the bovine vaccine offered little or no
year. Vesikari and colleagues gave a single dose of protection against rotavirus infection over the three
vaccine in January, just before the rotavirus season, and years of the study. However, it provided 71% protection
followed the babies throughout the season. against severe rotavirus diarrhea and 100% protection
The bovine vaccine offered protection against against very severe disease.
rotavirus diarrhea in these infants. Furthermore, “So we thought that the neonatal immunization
Vesikari learned that the protection was greater for was perhaps a chance, but it has not really been further
more severe diarrhea: 88% protection against severe developed after this,” Vesikari said.
diarrhea and 50% against any rotavirus diarrhea.
“We also saw that that even some of the children
who did not respond serologically to the vaccine KEY FACTS, BOVINE ROTAVIRUS VACCINE,
seemed to benefit from it, so the antibody response did FINLAND 1982-1987
correlate with protection,” Vesikari said. efficacious against severe rotavirus gastroenteritis.
In a 1983-1984 study, Vesikari collaborated with optimal efficacy at 6–12 months of age and neonatal.
Tom Flewett, one of the pioneers of rotavirus research. vaccination protective against severe disease.
By studying the rotavirus strains in Finland, Vesikari one dose as good as 2 doses.
showed that the bovine vaccine offered protection
no obvious side effects (intussusception not seen).
against several strains. The study also showed that the
buffering against stomach acidity needed.
bovine vaccine was adversely affected by stomach acid.
The simple measure of giving milk to the baby before breast-feeding did not interfere.
the vaccination improved the immune response, by Oral Polio Vaccine interfered (studies in Italy
and Yugoslavia).
acting as a buffer against stomach acid.
“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 much
less were interested in a vaccine, they had other priorities.
The WHO’s position here was basically that a perfect vaccine
was required. A good vaccine was not enough.”
Timo Vesikari, Vaccine Research Center of University of Tampere, Finland
6 Proceedings from the 8th International Rotavirus SymposiumFIGURE 4
Intussusception in Finnish Children, 316 cases in 1980–2000
Age Distribution (0-24 months)
35
32 32 33
30
25
Number of Cases
20 20 21
20
15 13 13
10 8
5 6
5 4 4 4 4 3 3
1 2 2 1 1 2 2 2
0
0 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24
Age (months)
90 days
From Timo Vesikari, Vaccine Research Center of University of Tampere
While the researchers saw no intussusception when I don’t know how—how much we appreciate—that
administering bovine vaccine to older children, most of the intussusception cases were in infants who
Vesikari said, “I think we were just lucky.” Also, the participated in the catch-up program, who got the first
vaccine effectiveness varied from country to country. dose of the vaccine when they were over the age of
“So the situation at the time this vaccine was three months.”
withdrawn was that it was efficacious in a country like Since the withdrawal of RotaShield, intussusception
Finland,” Vesikari said. “It did have low efficacy in has been a key safety issue for all rotavirus vaccines.
Africa, and Latin America was somewhere in between.
But the reason, really, why it did not succeed was Matching Safety with Efficacy
mainly that nobody was interested. In Europe few In 2001, the Rotavirus Efficacy and Safety Trial (REST)
people knew about rotavirus much less were interested began. (The study was published in 2006). REST
in a vaccine. They had other priorities.” showed that Merck’s RotaTeq was safe. There were no
“The WHO’s position here was basically that a more cases of intussusception in vaccinated infants
perfect vaccine was required,” he added. “A good than in unvaccinated ones. In the trial, the first dose of
vaccine was not enough.” RotaTeq was given at 6-12 weeks. “So when this vaccine
is given properly this way, it is really safe for
The Rhesus Rotavirus Vaccine intussusception. That’s the lesson from this trial,”
Some researchers felt that the bovine vaccine was too Vesikari said.
weak for use in low-income countries. The NIH’s A similar study of GSK’s Rotarix showed fewer cases
Albert Kapikian and colleagues responded by of intussusception among vaccinated infants than
developing a vaccine from a rhesus monkey rotavirus, unvaccinated infants. Meanwhile, Wyeth pulled a UK
which provoked a stronger immune response. bovine-human vaccine candidate because of a single
From rhesus rotavirus vaccine researchers developed case of intussusception in a five-month-old infant.
RotaShield, which combined rhesus and human viral “The bottom line to me is that all of these vaccines
genome segments. But when some vaccine recipients can be associated with individual cases, in the older
developed intussusception, RotaShield was withdrawn infants at least, with intussusception,” he said.
from the market about a year after introduction. The key, he said, is to avoid the mistakes of the
“It was an efficacious vaccine,” Vesikari said, “and it RotaShield experience by initiating vaccination before
still has remained so, but then we have the safety issue. a child is 90 days old.
Proceedings from the 8th International Rotavirus Symposium 7SESSION I
Update on Rotavirus Vaccine
Rotarix and the Key Challenges 5. It must be effective in developing countries as well
as developed countries.
of Rotavirus Immunization
“The first decision for GSK and for other
For Norman Begg, vice president of clinical develop-
manufacturers is which strain to use, and at GSK we
ment of pediatric vaccines at GSK—manufacturer of
took the decision to go forward with the development
the Rotarix vaccine—the withdrawal of the RotaShield
of a human strain,” Begg said. The rationale for using
vaccine made it clear there were five key challenges for
a human strain rested on studies from 1991, 1996 and
any new rotavirus vaccine.
2000, he said, showing that natural rotavirus infections
1. A vaccine must not cause an increased risk of confer immunity against all strains of rotavirus. One
intussusception compared to placebo. infection is 87 percent effective against moderate to
severe diarrhea and two previous infections confer 100
2. It should provide broad protection against new and percent protection.
emerging rotavirus strains and must cover the GSK developed a monovalent vaccine based on
existing geographic variation in rotavirus strains. G1P[8], the most common circulating rotavirus strain.
3. It should protect children against rotavirus infection The vaccine is freeze-dried and diluted before oral
from infancy up to at least two years of age. administration. It requires only two doses, Begg said,
the first as early as six weeks, but not later than 90 days.
4. It should not interfere with other vaccines so that it is The second dose can be given from four weeks after the
easy to include in national immunization schedules. first dose up to 26 weeks of age.
FIGURE 5
Rational for Vaccination with Human RV Strain
Natural RV infection attenuates severity
of subsequent infections, regardless of serotype1-3
100
100
90 87
80 75 Moderate
73 to severe diarrhea
Percent Efficacy
70
62
Mild diarrhea
60
50 Asymptomatic
infection
40 32
30
20
10
0
One Previous RV infection Two Previous RV infections
1
Velazquez 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
From Norman Begg, GlaxoSmithKline Biologicals
8 Proceedings from the 8th International Rotavirus Symposium“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
Two pivotal studies, by Guillermo Ruiz-Palacios in less expect substantial protection against all causes of
Latin America and Timo Vesikari in Europe assessed diarrhea in this setting,” he said. Even one dose of Rotarix
the safety and efficacy of Rotarix. offered significant protection.
“I must stress that this is not a label indication for
CHALLENGE 1: No intussusception the vaccine,” Begg said. “The recommendation is that
you have two doses. But there does seem some ability
The Latin American study included 63,000 subjects.
to protect early on, which is obviously good.”
Intussusception was assessed during two risk periods:
the first month after a dose and the first three months
after a dose. In the first risk period, six vaccinated CHALLENGE 4: Co-administration
children suffered from intussusception, but there were with other vaccines
seven cases in the placebo group. “We have done studies with all the commonly used
“So there was no evidence of an increased risk based vaccines globally,” Begg said. ”And in all those studies,
on that evaluation period.” Begg said. “And if you look high responses of rotavirus Rotarix were maintained,
further out, up to 100 days, it starts to look a little bit and no impairment of immune responses was observed
imbalanced in favor of the vaccine. There were 16 cases to any of the co-administered vaccine antigens.”
in the placebo group compared to 9 in the vaccine group. In a separate Latin American study, 6 to 12-week-
I think what you certainly can conclude is that there is no old infants were given Rotarix or a placebo along with
increased risk of intussusception compared to placebo.” oral poliovirus vaccine (OPV). Rotarix maintained
Similar data show that Merck’s RotaTeq is equally both its immunogenicity and effectiveness in this study
safe, when the first dose is given at under 90 days. as well. (This study was presented at the 13th
International Congress of Infectious Diseases June 19-
CHALLENGE 2: Broad protection 22, 2008, Kuala Lumpur, Malaysia.)
The same two studies both showed broad protection Begg contends that because of the flexibility of dose
against the five major rotavirus strains, most importantly, timing with Rotarix, it can be included in any of the
the G9 strain, which is emerging in several countries. common schedules, the Expanded Program of
“The overall efficacy rates were higher in Europe Immunization (EPI), with the classical European and
compared to Latin America, and I think this reflects the US schedules and with the Scandinavian schedule. “So
fact that the European study was done in highly the vaccine could be implemented in pretty much any
developed countries where in Latin America, they were immunization schedule without scheduling additional
middle to low income countries,” Begg said. visits,” he said.
CHALLENGE 3: Protection over time CHALLENGE 5: Efficacy in low-income
countries
The studies showed that Rotarix protected children
well against severe rotavirus diarrhea throughout the The study in Latin America referred to above showed
first two years of life. “There is no significant decline Rotarix to be effective in 11 countries, Begg said.
in efficacy against severe and hospitalized rotavirus Ongoing studies, including the Rotarix/OPV study in
diarrhea over the two year period,” Begg said. Latin America, and a study in South Asia also show
Furthermore, the vaccine proved about 40 percent high efficacy, in the 80-100 percent range, he said.
effective against severe gastroenteritis from all causes. “With the completion of that study in South Africa,”
“This shows you that considering the fairly broad Begg asserts that GSK will “have demonstrated efficacy
range of organisms that cause diarrhea, you can nonethe- of the vaccine in all regions of the world.”
Proceedings from the 8th International Rotavirus Symposium 9RotaTeq: A Pentavalent Approach place in 11 countries on three continents from 2001-
2005. REST was published in 2006. More than 71,000
to Rotavirus Immunization children were enrolled in all three studies.
Max Ciarlet, director of the Clinical Rotavirus Vaccine “One thing that was really striking, whether we look
Program at Merck, explained that Merck developed its at the results from the phase II trials or the phase III
oral rotavirus vaccine, RotaTeq, as a pentavalent trials, we see that RotaTeq provides consistent high
vaccine containing five human-bovine reassortant protection against severe rotavirus gastroenteritis and
rotavirus strains to induce direct protection against the gastroenteritis of any severity,” Ciarlet said. Efficacy
most common human rotavirus serotypes. ranged from 98 percent to 100 percent for severe
He noted that because of the lower replication rotavirus gastroenteritis, and almost 75 percent for any
capability of RotaTeq, it requires three doses to build rotavirus gastroenteritis, he said.
high and consistent immune responses, with the first Since REST was so large, the trial also assessed
dose at 6-12 weeks and two subsequent doses at 1-2 hospitalizations, emergency room visits and doctor’s
month intervals. This schedule integrates easily into office visits. Ciarlet said the evidence indicates that
pre-established immunization schedules. RotaTeq reduces hospitalizations and ER visits by 95
Studies indicate that, like Rotarix, RotaTeq does not percent and office visits by 86 percent.
interfere with or lose potency from other common RotaTeq is also effective against a broad range of
childhood vaccines. Three phase III studies have pro- rotavirus strains, including those that belong to
vided data on safety and efficacy of RotaTeq. Protocol serotype G9, he said.
006, also known as the Rotavirus Efficacy and Safety “The efficacy, when we go to serotype-specific data,
Trial (REST), was the pivotal large-scale study. It took is very consistent and is very high,” Ciarlet said.
FIGURE 6
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 2005
Randomised, double-blind study: RotaTeq® versus placebo controlled
Age at enrolment: 6 to 12 weeks of age, 3 oral doses provided every 4–10 weeks
Finland
Sweden
Germany
Belgium
Italy
United States
Puerto Rico
Jamaica Taiwan
Mexico
Guatemala
.
Costa Rica
71,799 Subjects Vaccinated
36,203 in RotaTeq® Group
35,596 in Placebo Group
Vesikari et al., 2006. N Engl J Med, 354: 23-33.
Vesikari et al., 2006. IJID, 25 (Suppl 1): S42-A47
Dennehy et al., 2007. IJID 11 (Suppl 2): S36-S42. REST Subjects Lost to Follow-Up: 81 (0.2%) V: 97 (0.3%) P
From Max Ciarlet, Merck Vaccines, US
10 Proceedings from the 8th International Rotavirus Symposium“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 consistent
high protection against severe rotavirus gastroenteritis
and gastroenteritis of any severity.”
Max Ciarlet, Merck Vaccines, US
Furthermore, he noted that the vaccine reduced health there are trials being conducted in Bangladesh, Ghana,
care resource utilization for gastroenteritis of any kind Kenya, Mali, and Vietnam that are expected to generate
by 59 percent. data on safety, immunogenicity, and efficacy of
At both 42 days and one year from the first dose, RotaTeq in the regions of Sub-Saharan Africa and
numbers of intussusception cases were similar in the South East Asia. In addition, a surveillance and
vaccine group and the placebo group. A similar profile effectiveness study is ongoing in Nicaragua.
emerged for serious events, including deaths. “The “We have almost 13 million doses distributed, and
most common cause of death was SIDS,” Ciarlet said, monitoring is ongoing,” Ciarlet said. Finally, a phase II
“and the number of subjects that were discontinued safety and immunogenicity study of HIV-positive
due to a serious adverse event was equal between the infants in Tanzania and Zambia is about to start in
two groups.” early 2009.
Ciarlet also stated that neither breastfeeding nor “We will soon show that the vaccine is efficacious up
prematurity (gestation equal to or less than 36 weeks) to three years post vaccination, and Merck is working
appeared to have any effect on vaccine efficacy or with partners to make RotaTeq available to those
safety. countries that actually need it the most,” Ciarlet said.
Ciarlet said the trials were not designed to evaluate There was a question about whether RotaTeq and
vaccine efficacy for fewer than the recommended three Rotarix can be used interchangeably, with, for example,
doses, and the numbers of children who got only dose a first dose utilizing Rotarix and the second RotaTeq.
one or two doses were too small for statistical However, experts at the symposium said there is no
significance. But he said that among children who got data on interchangeability of the vaccines, so this
all three doses, RotaTeq appeared to confer protection practice cannot be recommended at this time.
between doses: 100 percent between dose one and dose
two and 91 percent between dose two and dose three.
In Finland, Timo Vesikari followed up
World Health Organization Policies
approximately 21,000 trial participants for efficacy, as on Rotavirus Vaccines
measured in rate reduction of hospitalizations and ER
The World Health Organization (WHO) Strategic
visits emergency visits due to rotavirus gastroenteritis,
Advisory Group of Experts or SAGE has recommended
up to the age of three and a half. These results, which
a phased introduction of rotavirus vaccine in areas
showed high and consistent efficacy of the vaccine for
where Phase III trials have been completed, said the
up to 3 years postvaccination, were to be presented at
WHO’s Cristiana Toscano. She said SAGE also stresses
the 13th International Congress of Infectious of
the importance of post-marketing surveillance and
Infectious Diseases. In addition, large-scale safety
communication strategies.
surveillance studies continue. The US Vaccine Adverse
WHO recommends the inclusion of rotavirus
Event Reporting System collects information on
vaccination into national immunization programs, but,
possible side effects. In addition, Merck has its own
again, only in regions where efficacy trials have been
ongoing Phase IV safety study of intussusception,
completed and, also, where infrastructure and
which will enrolled more than 44,000 subjects. And
financing are in place. Vaccine efficacy has been
Proceedings from the 8th International Rotavirus Symposium 11demonstrated in the US, Europe and Latin America, to apply for these vaccines,” Steele said. But if studies
but new studies are expected to be completed shortly. now underway in the developing world show that the
“In 2007, WHO was not prepared to recommend rotavirus vaccines would have even “moderate efficacy,”
global inclusion of rotavirus vaccines into national Steele said they are likely have an dramatic impact on
immunization programs,” Toscano said. “Rather we’re lives saved and to be “cost saving.”
suggesting a phased introduction.” He said that phase III efficacy trials are currently
Based on a review of data on RotaShield, she said being conducted under a collaboration between the
WHO has recommended that the first dose of rotavirus Rotavirus Vaccine Program at PATH (which is a
vaccine should not be given after 12 weeks of age. partnership including WHO, and the US CDC), and
Toscano said WHO advises against using rotavirus with both Merck and GSK Bio rotavirus vaccines.
vaccines in catch-up programs because of the danger that There was a question about the ethics of conducting
the first dose may mistakenly be given to children older rotavirus vaccine trials in low-income countries. Steele
than 12 weeks of age. The entire rotavirus immunization noted that studies must be done in the populations that
series should be completed by 24 weeks for Rotarix and need the vaccines and that extrapolating results from
32 weeks for RotaTeq. This recommendation arises from trials conducted elsewhere would not be sufficient. He
the lack of safety data for older children. noted that vaccine manufacturers, WHO and PATH
Duncan Steele, PATH’s Senior Advisor on diarrheal follow high ethical standards and all studies are
disease, noted that, due to the lack of evidence from reviewed by local ethics boards and conducted
clinical trials, SAGE has not recommended the use of according to Good Clinical Practice.
rotavirus vaccines in the regions of the world with the
highest mortality from rotaviruses, which are low- Vaccine Concerns: Interactions
income countries. Thus, the GAVI Alliance, an and Disease Transmission
international coalition of public and private partners
(formerly known as the Global Alliance for Vaccines There was some discussion about whether rotavirus
and Immunization) that subsidizes vaccine purchases vaccination would have any effect on the oral polio
for the world’s poorest countries, has yet to provide vaccine (OPV). Max Ciarlet responded that while no
support for rotavirus vaccines. efficacy studies have been undertaken, OPV antigen
“Where the majority of the disease and mortalities titers were normal when the vaccine was administered
are associated, those countries are not yet in a position along 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) Africa
Interim Final Extended
Analysis Analysis Follow-up Analysis
Bangladesh & Vietnam
Merck Asia
Vaccine, Final Analysis
RotaTeq®
(Bovine, Ghana, Kenya,
Reassortant, & Mali
Multivalent) Africa
Final Analysis
From Duncan Steele, PATH
12 Proceedings from the 8th International Rotavirus Symposium“In 2007, WHO was not prepared to recommend global
inclusion of rotavirus vaccines into national immunization
programs. Rather we’re suggesting a phased introduction.”
Cristiana Toscano, World Health Organization
be administered first if the vaccines are
SIDEBAR not given together because OPV may
replicate for up to 6 weeks.
Interim Analysis of Vaccine Efficacy Norman Begg added “The data show
in South African Infants that there is no interference and it's in the
label of the vaccine that you can actually
habir Madhi of South Africa’s University of the co-administer at the same visit.”
S Witwatersrand offered an interim analysis of a Rotarix
trial in South African infants.
The communities in which the study was performed are
Duncan Steele noted that “The WHO
position paper clearly says that the vac-
cines need to be given with OPV. We're
burdened with a high prevalence of HIV, 50% of children born not talking about additional EPI visits for
are born to mothers with HIV. About 5 to 6% of infants are a new rotavirus vaccine.”
infected with HIV. And the unemployment rate stands at T. Jacob John, with the Indian Acad-
40%. In addition, Madhi said, “Only about a third of children emy of Pediatrics, wondered whether
actually receive appropriate oral rehydration therapy when children who receive the rotavirus vac-
having an episode of gastroenteritis.” cine can transmit the rotavirus through
The study set out to determine Rotarix efficacy against virus “shedding.”
severe rotavirus gastroenteritis in infants up to one year of Norman Begg responded that, “As you
age. Rotarix was given according to the routine EPI schedule, would expect with a live orally adminis-
which included oral poliovirus vaccine. The study used
tered vaccine, the vaccine replicates in
the gut and there is shedding following
standard definitions of gastroenteritis and severity of the
vaccination.”
episodes was assessed by the internationally recognized
The concern is that if virus shed from
Vesikari score. The presence of rotavirus was detected by a
a vaccine recipient undergoes a mutation
commercial ELISA assay. The pre-determined interim analysis
that confers virulence, it may transmit
was performed by an independent data center.
rotavirus disease. “We are actually doing
Madhi said the results show that the vaccine efficacy
a study at GSK to look at transmission of
against rotavirus gastroenteritis of any severity was 66.5
the known shed virus, so we will have the
percent. Against severe rotavirus gastroenteritis, the vaccine
answer to that question,” Begg said.
proved 82.7 percent effective according to the interim results.
Max Ciarlet added that researchers at
“The vaccine itself clearly offers a high degree of Merck “have only detected shedding after
protection in South African children against severe rotaviral the first dose. It is usually only one or two
illness during the first year of their life,” Madhi said. “The days and it only happens in 9 and 12
results I believe are extremely important in terms of informing percent of the subjects.”
decision making both in South Africa as well as in other Duncan Steele added that the
countries in southern Africa.” differences between the two vaccines
In Sub-Saharan Africa, rotavirus accounts for 25 percent of when it comes to shedding virus may
all diarrheal deaths and 25 percent of all hospitalizations for reveal differences in the vaccines’
diarrhea, with a clear peak in dry cooler months of autumn functions, with Rotarix conferring most
and winter. of its immunity in the first dose, and
RotaTeq conferring increasing immunity
with each of the three doses.
Proceedings from the 8th International Rotavirus Symposium 13You can also read
