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9th International Rotavirus Symposium
Johannesburg, South Africa
The 9th International Rotavirus Symposium, held in Johannesburg, South Africa in August 2010, capped a period of dramatic progress in the fight against rotavirus, the most common cause of severe childhood diarrheal disease. Since the 8th Symposium, held in 2008 in Istanbul, several major milestones had been reached:
• Two effective vaccines were licensed in more than 100 countries, and 24 countries incorporated them into mass immunization programs, leading to major reductions of rotavirus disease in several countries.
• The World Health Organization (WHO) recommended universal use of rotavirus vaccines.
• The GAVI Alliance committed to funding introduction of rotavirus vaccination at a cost of as little as 15 to 30 cents per series for GAVIeligible low-income countries.
• New vaccine candidates under development offer the hope of cheaper and perhaps more effective vaccination within several years.
At the Johannesburg symposium, researchers and health officials presented new data on rotavirus disease and rotavirus vaccines, with special attention paid to reports from
Africa and Asia. The participants discussed the significance of the latest surveillance data and the challenge of adding rotavirus vaccines to national immunization schedules, particularly in the poorest countries of the world where rotavirus takes its greatest toll but where vaccine costs are a barrier to adoption.
«There is a serious and growing need to increase access to affordable rotavirus vaccine in the developing world, where 85 percent of rotavirus deaths occur. This need is most severe in impoverished communities where access to medical care for rotavirus is often out of reach,» said Ciro de Quadros, executive vice president of the Sabin Vaccine Institute. «The symposium conveners, as well as the hundreds of attendees, are committed to ensuring that universal access to rotavirus vaccine becomes a reality.»
We are grateful to the physicians, epidemiologists, researchers, public health workers, industry officials, policymakers, donors, economists and health instructors who made the 9th International Rotavirus Symposium possible, and who continue to have a major impact on the health of the world's most vulnerable children.
Executive Summary
Rotavirus is one of the most common childhood diseases, striking nearly every child in the world before the age of 5. In the industrialized world it causes hundreds of thousands of hospitalizations each year because of severe diarrhea and dehydration. The disease is much more severe in countries with high malnutrition and low access to medical care.
Rotavirus kills an estimated 500,000 children each year under five years of age and causes millions of hospital visits. It is responsible for about 40 percent of all diarrhea l diseases serious enough to require hospitalizations in young children. The worst burden of rotavirus is in Africa, Asia, and Latin America.
The virus was identified by Ruth Bishop in 1973. The first international symposium on rotavirus was held in 1985 and involved 50 participants.
«When we started there was an unknown virus, now it's recognized and it has gotten global priorities,» said Roger Glass, director of the Fogarty International Center at the U. S. National Institutes of Health.
Some 400 people from 65 countries took part in the 9th International Rotavirus Symposium in Johannesburg in August 2010. The meeting was convened by the Sabin Vaccine Institute, the University of Witwatersrand, the global health organization PATH, and the U. S. Centers for Disease Control and Prevention (CDC).
Participants discussed the disease's epidemiology and the performance of vaccines in preventing serious rotavirus infections. There was a particular focus on the impact of the disease in Africa and Asia, regions where rotavirus is an especially deadly killer but where vaccine introduction has been slow. For example, almost half of all rotavirus deaths occur in sub-Saharan Africa, yet at the time of the symposium, South Africa was the only African nation to have introduced rotavirus vaccination.
Participants analyzed vaccine studies involving 12,000 children that have been conducted in Ghana, Kenya, Malawi, Mali, Bangladesh and Vietnam, which offer evidence of the power of rotavirus vaccines to reduce deaths and hospitalizations in Africa and South Asia.
Getting Past the Paradox to Consider Major Impact on Deaths, Severe Disease
During the discussions, a potentially distracting paradox arose that seems to be central to current considerations of rotavirus vaccination. The vaccines appear to be less efficacious at preventing severe rotavirus disease in the poorest countries; the poorer the vaccinated population, in fact, the lower its efficacy to the vaccine.
Yet despite this fact, the benefits of the vaccine appear highest in the poorest countries. When the vaccine was tested in Malawi and South Africa, for example, the vaccine was clearly more efficacious in middle-income South Africa. Yet the number of severe and fatal cases of rotavirus infection prevented by the vaccine was higher in Malawi.
This paradox was explained by Mary Agocs of the World Health Organization: «Although vaccine efficacy may be lowest in (the poorest fourth) of countries,» she said, «more children are severely impacted in these countries, so the vaccine would have a larger impact in terms of numbers of children.»
In other words, rotavirus is such a big problem in these areas that the efficacy of existing rotavirus vaccines is sufficient to have a dramatic impact on deaths and severe disease. In fact, one of the take-home messages at the conference was that rotavirus vaccine advocates should focus on reductions in deaths and severe disease as the best measures of the value of rotavirus immunization.
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The Two Vaccines Currently Available: Rotarix and RotaTeq
At the time of the conference, 24 countries had begun mass immunization campaigns using one of the two globally licensed rotavirus vaccines, Rotarix and RotaTeq, both of which are administered orally.
From a technical perspective, the vaccines are characterized by the number of rotavirus strains they contain and by variants of two protein complexes that are described as G or P types.
Rotarix, made by GlaxoSmithKline Biologicals, is a monovalent G1P [8] vaccine that originally was isolated from an infant at the Children's Hospital of Cincinnati. RotaTeq, made by
Merck & Co., Inc., is a pentavalent vaccine derived from bovine and human rotaviruses and contains human rotavirus serotypes G1, G2, G3, G4, and P1A [8]. Rotarix is given in two doses, RotaTeq in three, and both can be administered in regular routine immunization schedules.
The Rotarix and RotaTeq vaccines were licensed beginning in 2004 and 2006 respectively. In 2007, WHO recommended the vaccines for regions of the world where efficacy data suggested a high public health impact. In December 2009, WHO recommended that all children be vaccinated against rotavirus.
Impact of Rotavirus Vaccination
In the United States, the introduction of rotavirus vaccines has dramatically reduced serious rotavirus infections. In 2008, after the introduction of RotaTeq, health care resource utilization for rotavirus disease was reduced by almost 90%. Thus, preventing some 50,000 hospital stays there each year.
In Latin America, the vaccine has had a major impact on deaths due to rotavirus — reducing diarrhea-related infant mortality by 30-40%.
Preliminary data from South Africa — which in 2008 became the only African country to begin nationwide rotavirus vaccination — indicates cases of severe rotavirus disease have fallen dramatically as well.
In many countries, the vaccine is having an even larger impact than expected, perhaps because rotavir us was under-diagnosed in the past, or because of herd immunity. There's a lot about the activity of the vaccine and the virus that is not yet understood, said Glass.
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«We really don't know whether the glass is half empty or half full, and how then should we proceed and what can we do,» he said.
One of the unknowns, he said, is the degree of herd immunity one can expect from use of the vaccines in resource-poor countries.
«It may be that by reducing the amount of rotavirus in the environment, we will have a reduced force of infection, and will have less severe disease,» Glass said.
«It might be that the vaccine will push disease to an older age so that those small children, the ones at the greatest risk of death, will not die from rotavirus.»
There were also many issues of concern raised at the meeting, ranging from disappointment at the efficacy rates of the vaccines in some countries, to lingering questions about safety. Both vaccines have proven extremely safe, but some data have suggested possible, though rare, links to bowel obstruction or intussusception, the adverse event that caused Wyeth's RotaShield vaccine to be withdrawn.
Most speakers agreed that rotavirus vaccines would be valuable to poor countries, but there was some uncertainty about which countries would be able to pay for it.
Some of the key research findings discussed at the symposium included the following:
• Rotavirus is the leading cause of diarrheal hospitalizations in children, accounting for about 40% on
average. In Africa and Asia, rotavirus vaccines have shown a potential to prevent more than 20% of all diarrhea-related hospitalizations in children.
• In Mexico, rotavirus vaccination has prevented more than 600 deaths a year, with 41% fewer diarrhea-related deaths in infants. Similar results appeared after use of the vaccine in Brazil.
• The lower the socioeconomic status of a population, the lower the efficacy of rotavirus vaccines — yet, due to the high burden of disease, the more serious disease the vaccines prevent.
• New, less expensive rotavirus vaccines produced in Brazil, Indonesia, India and China may be available within five years.
• After millions of doses have been given, rotavirus vaccines continue to have an excellent safety record. Contradictory data show that intussusceptions might or might not be a rare side effect (so if it occurs it is uncommon), but the risk is tiny compared to the benefits of both vaccines.
• Investigations in March 2010 by the U. S. Food and Drug Administration (FDA), Merck and GSK found traces of a porcine circovirus in both rotavirus vaccines, but it was determined that the contamination had no effects of any kind on children who received the vaccines.
• Though they are live virus vaccines, there is no indication that Rotarix or RotaTeq harm HIVpositive children.
The Future of Vaccines
In addition to reviewing data from epidemiological studies of rotavirus and rotavirus vaccination, the symposium members discussed future prospects for expanding rotavirus vaccination. One participant said his goal was to have 60 countries using rotavirus vaccine before the 10th symposium (24 currently use it).
Reaching that goal, participants said, will require stimulation of both supply and demand.
The two global vaccines currently on the market cost as much as $200 per child in the industrial world, and as little as $15 in Latin America. This price is still too high for many countries to afford, however, and participants said it was likely that many countries would be unable to purchase rotavirus vaccines until a new, third generation of vaccines, produced in developing countries, are ready.
Currently, manufacturers in India, China, Vietnam, and Brazil have developed experimental vaccines and are at relatively advanced stages in the clinical process. But the fate of any such product depends both on its eventual safety and efficacy record, and on clear demand for the product.
GAVI is offering the GSK and Merck vaccines at 15 to 30 cents per series for five years to the poorest countries. But while their initial contributions are fairly modest, these developing countries must demonstrate that they
are interested in becoming markets for rotavirus vaccine. Expanded markets could lead GSK and Merck to expand vaccine production and will also incentivize developingworld manufacturers.
Some speakers at the symposium stressed the need for newer vaccines, including injectable killed-virus or subunit vaccines that may not require the large clinical trials of the type done to evaluate RotaTeq and Rotarix (which are both live, oral vaccines).
«I think we realize that we should not put all the eggs in one basket,» said the CDC's Baoming Jiang, who is working on an injectable vaccine.
But others stressed that it was crucial to introduce existing vaccines as quickly as possible, despite their potential imperfections. «We can't wait until we get 100% efficacy,» said Kathleen Neuzil of PATH. «We really need to introduce these vaccines now, with the impact that they can have, while simultaneously working for better vaccines.»
«We can't wait until we get 100% efficacy. We really need to introduce these vaccines now, with the impact that they can have, while simultaneously working for better vaccines.»
— Kathleen Neuzil, PATH
Next Steps for Rotavirus Vaccine
To introduce a roundtable discussion on vaccine introduction, John Wecker, Program Leader of PATH's Vaccine Access and Delivery program, challenged participants at the conference to come up with simple messages about rotavirus vaccines that can be effectively conveyed to decision-makers. Will this intervention save lives? Is this a good use of my money? Is this a decision I should take?
A number of issues were raised about how to make the case for rotavirus vaccines. The following are highlights from the discussion:
• Rotavirus vaccines save lives. There is strong evidence from surveillance in countries that have introduced rotavirus immunizations, particularly Mexico, that the vaccines reduce mortality and the effect is almost immediate. And while there is not a lot of data from Africa, the evidence available indicates a potential to prevent many deaths.
• Rotavirus vaccines reduce hospitalizations. The vaccines appear capable of reducing hospitable admissions for diarrhea by 50%.
• Know your audience. Messages should be tailored to the situation in a particular country or region. For example, the focus in Africa should be on the ability of the vaccines to prevent death, not on pure efficacy against infections. However, in other countries, such as South Korea, where there are not a lot of deaths from rotavirus, the main benefit is the ability of the vaccines to prevent hospitalizations.
• Intussusception risks can confuse. Discussing the data on intussusception risk is difficult because some scientists would say there is no risk, others might indicate a minor risk. As one participant noted, «When you go in front of the decision-makers, they've got all of our experts there, each one is saying something different. That kills the program. We've got to figure out a way of doing this better as scientists.»
• Put risks in context. Rotavirus vaccine risks should be discussed in relation to other vaccines. As Tony Nelson noted, «no vaccine is 100% safe. Rotavirus is no different than oral polio or flu vaccine.»
• Stress benefits beyond rotavirus. There is potentially a strong argument to make for the vaccine's ability to reduce all causes of diarrhea by 25%.
• Don't let waning immunity be a cause for delay. Waning immunity in the second year of life may not be
significant because 80% of diarrhea deaths occur in the first year of life.
• Be an advocate for all rotavirus health interventions, not just vaccines. Advocacy for vaccines should occur in tandem with advocacy for wider use of oral rehydration and zinc supplementation to treat diarrheal diseases. This approach frames the discussion of rotavirus vaccines as part of a suite of interventions, which is likely to get a more receptive audience within Health Ministries suspicious that vaccine advocates may have ties with industry.
• Cost considerations require evidence of value. Price remains a barrier so government officials need to be convinced of the value of the vaccines and have options for funding their introduction.
• New vaccines in pipeline could cause confusion. Wecker noted that one complicating factor in seeking rapid expansion of rotavirus immunization is the potential for new rotavirus vaccines to be available as early as 2013 that could be cheaper than existing products. He wondered, «Do we wait until that happens, or do we move on what we know today in terms of the effectiveness, the safety of these vaccines, and the number of children we know are dying out there?» Wecker pointed out that there is a «chicken and egg» dilemma in that the best way to drive prices down is byboosting demand, but if countries wait to see if the price is going to fall, that decision alone could keep prices relatively high.
• Focus on the link to Millennium Development Goals. Rotavirus vaccines should be put forward as a way for Health Ministers to achieve the childhood mortality reductions set forth in the UN Millennium Development Goal (MDG) 4.
• Use past vaccine successes to make case for rotavirus. An EPI manager from Ghana said that when talking about new vaccines, advocates can make a strong case by pointing to the success of existing immunizations. For example, Ghana started its measles control program in 2002 and since 2003, no child in Ghana has died of measles.
• Build a broad advocacy coalition. It is critical to assemble a diverse group of stakeholders to endorse vaccine introduction. In almost every country, successful adoption of a new vaccine involved alliances with pediatric associations.
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Evidence for Adoption
In his concluding remarks, Duncan Steele summarized the findings discussed at the symposium. He noted that in seven African and Asian countries where 12,500 children were enrolled in rotavirus vaccine trials, the vaccines prevented about 23% of all serious diarrheal illnesses. In Malawi and South Africa, it prevented 30% of all diarrhea-related hospitalizations.
Rotarix prevented three serious bouts of gastroenteritis per 100 children in an African setting. In all countries into which it has been introduced so far, the vaccine has done better than expected at reducing disease. There has been a herd effect on illnesses in older children who do not receive the vaccine. Particularly striking was the reduction in deaths seen after introduction in Mexico. If the vaccine proved 60% efficacious, on average, in preventing deaths, it could prevent 1.5 million deaths by 2025 if it was introduced across the world.
«The efficacy data from these seven countries with both vaccines in 12,500 kids is that the vaccines are going to make a significant impact when we roll them out.»
«If we look at experiences in the slightly more developed countries, like Rotarix in El Salvador, there has been adramatic decline in serious disease, with a 79% decline in hospitalized rotavirus diarrhea in children under 5 years old at seven hospitals in that country.»
In Mexico, there was a 41% reduction in infant deaths caused by diarrheal disease after introduction of Rotarix.
«We can keep talking about the vaccines, or we can start using them, and if we start using them we will prevent a significant burden in terms of diarrheal mortality due to rotavirus and diarrheal hospitalizations. It's really a time for a call for action.»
«We can keep talking about the vaccines, or we can start using them, and if we start using them we will prevent a significant burden in terms of diarrheal mortality due to rotavirus and diarrheal hospitalizations. It's really a time for a call for action.»
— Duncan Steele, PATH
Call to Action
We the Participants of the 9th International Rotavirus
Symposium agree to:
1) Continue to support immunization as a common public good worldwide, an economic necessity and a vital political priority;
2) To encourage increased vaccine research and expanded surveillance for vaccine-preventable diseases;
3) Encourage the joint collaboration ofnational governments, bilateral and multilateral agencies, the GAVI Alliance, and the manufacturers of vaccines to facilitate and accelerate the introduction of rotavirus vaccines worldwide;
4) To advocate for and raise awareness among public and policy makers of the burden of rotavirusrelated diarrheal disease and the value of vaccination;
5) To call upon political leaders and decision-makers from developing countries to increase financial support to their national immunization programs; and finally
6) To call upon political leaders and decision-makers from developed countries and global immunization partners to scale-up financial support to the GAVI Alliance.
От редакции.
Полную версию информационного бюллетеня о IX Международном симпозиуме по ротавирусной инфекции можно посмотреть на сайте — http://www.sabin.org/ news-resources/publication/9th-international-rotavirus-symposium-proceedings
