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Vaccines enter battle against an intestinal virus

New vaccines prevent potentially deadly diarrheal disease in infants

Almost all infants, everywhere in the world, have been infected with rotavirus by age five. This common pathogen can cause a range of symptoms, from mild gastrointestinal discomfort to the diarrheal disease known as acute gastroenteritis that can lead to serious dehydration. And although even the most severe cases of the disease can usually be treated easily with replenishment of fluids or electrolytes, rotavirus kills 600,000 children each year, the vast majority in developing countries where access to healthcare services is limited. This single virus accounts for about 5% of all childhood deaths worldwide.

Yet as organizations such as the Program for Appropriate Technology in Health (PATH), a Seattle-based non-profit organization, meet with policymakers in developing countries to discuss rotavirus, they find many have never even heard of it. These meetings are the first step in preparing governments for the introduction of two new vaccines that may help prevent the tragic consequences of this viral infection.

Despite setbacks with an earlier rotavirus vaccine, which was abruptly revoked over safety concerns, continued efforts by vaccine manufacturers GlaxoSmithKline (GSK) and Merck culminated earlier this year in landmark clinical trials showing that both company's rotavirus vaccines were highly effective in preventing severe gastroenteritis in infants, and were not associated with similar safety issues.

"Given the challenges and the enormous resource requirements, it is just amazing that we actually have two new products," says Umesh Parashar, a medical epidemiologist at the US Centers for Disease Control and Prevention (CDC). His enthusiasm for these vaccines is tempered by only one thing. Neither have been tested in efficacy trials in Africa or Asia, so it's unclear if they will be as effective at preventing severe disease in these populations as the already completed Phase III trials indicated in infants from the US, Europe, and Latin America. "That's the biggest scientific question that remains," says Parashar.

Evidence suggests that immune responses induced by orally administered vaccines are reduced in these populations. Trials in developing countries demonstrated the need for additional doses of oral polio vaccine to stimulate equivalent immunity, and both cholera vaccine and earlier versions of rotavirus vaccine performed less favorably in these settings. So it is essential that the new rotavirus vaccines are tested there before rotavirus vaccination programs can be implemented around the world.

GSK has already started two trials in Malawi and South Africa and Merck plans to initiate trials by the end of the year at yet to be identified sites in Africa and Asia, all of which are being conducted in cooperation with PATH. Although data from these studies isn't expected until 2009, organizations like the Global Alliance for Vaccines and Immunizations (GAVI), PATH, the World Health Organization (WHO), and the CDC are already actively engaged in accelerating the testing and introduction of rotavirus vaccines in countries where the most deaths from severe gastroenteritis occur.

The culprit

Many serotypes of rotavirus are currently in circulation around the globe, but luckily for vaccine developers more than 80% of rotavirus-related disease is caused by just four of these serotypes. Rotavirus is transmitted orally and once inside the body, it can trigger the diarrhea and vomiting that together account for the often rapid and severe dehydration. In developing countries, where prompt access to healthcare services is limited, approximately 1 in 200 children who are infected with rotavirus will die.

The personal toll associated with such a pervasive virus spurred researchers into developing vaccines that would completely prevent infection. However they soon changed course when studies of natural infection showed that children who are repeatedly infected with the virus develop some level of natural immunity that, although not able to prevent subsequent re-infection, can reduce the risk of developing severe disease. After a second infection it becomes unlikely that an infant will ever experience severe gastroenteritis. "Efforts were then focused on developing a vaccine to mimic this effect," says Parashar.

Several vaccine candidates were developed based on different animal strains of rotavirus. One developed by Wyeth called Rotashield was based on a monkey virus engineered to express proteins from the human rotavirus strain. After clinical trials showed this vaccine to be effective it received approval and licensure from the US Food and Drug Administration (FDA). But just nine months later physicians in the US were advised by the CDC to immediately suspend use of the vaccine after a small number of unexpected cases of intussusception occurred in infants who received Rotashield. Intussusception is a serious bowel obstruction that happens when part of the small intestine folds over itself like a collapsing telescope. If left untreated it can sometimes be fatal.

Further analysis showed that most cases of intussusception occurred within two weeks of infants receiving their first vaccination, suggesting Rotashield was the cause. A study by the CDC calculated that the intussusception risk for vaccinated infants was between 1 in 4500 and 1 in 9500. "That level of risk was not considered acceptable in the US," says Parashar, where only 20 deaths each year are attributable to rotavirus infection. Wyeth soon withdrew Rotashield from the market and stopped manufacturing the vaccine.

This ignited debate among scientists and bioethicists over whether or not the vaccine could still provide benefit in developing countries where the death toll is much higher. In an article bioethicist Charles Weijer of Dalhousie University, Canada said it was "imperialistic to transfer this standard of care to a country in which 1 in 200 children die of rotavirus infection."

Weijer calculated that even in a worst-case scenario, the intussusception associated with Rotashield would have caused 2000-3000 deaths per year, which is far fewer than the 600,000 deaths caused by rotavirus-induced severe gastroenteritis.

"One of the challenges with this vaccine was that it hadn't already been tested in Africa and Asia," says Parashar. Not knowing if the vaccine was even effective in these developing-country settings made it difficult for policymakers to overlook the possible adverse effects. But if Rotashield had been tested simultaneously in developing countries there may have been greater enthusiasm for the vaccine preventing rotavirus-related death, and possibly even a movement to seek independent licensure.

Small risk, huge trials

Soon after Rotashield's withdrawal Merck was preparing to take their lead rotavirus vaccine candidate into large-scale efficacy trials. Suddenly the trial plans changed dramatically. To rule out the possibility of intussusception the Phase III trials would need to include 60,000-100,000 infants. Both financially and organizationally this was no small matter. However the company chose to move forward and began a placebo-controlled trial with their rotavirus vaccine, Rotateq, in more than 69,000 infants in 11 industrialized countries. GSK was faced with a similar situation with their vaccine, known as Rotarix, and they too pushed ahead with a trial involving 63,000 children in Finland and 11 countries in Latin America.

These trials are the largest industry-sponsored vaccine trials ever conducted and both showed that the vaccines were highly effective. Rotateq prevented 74% of any rotavirus-related gastroenteritis and 98% of severe cases. The vaccine also reduced the number of hospital visits for gastroenteritis by 86%. Immunization with Rotarix prevented 85% of severe gastroenteritis cases and associated hospitalizations and was 100% effective at reducing the most severe cases of the disease. Just as importantly, neither live-attenuated vaccine was associated with an increased risk of intussusception. "It was likely a Rotashield-specific issue," says Mark Feinberg of Merck.

A few months after the final data was released, Merck received approval to license and market Rotateq in the US and GSK received licensure for Rotarix from the European Commission. Rotarix is also licensed in Mexico, Brazil, Philippines, and Singapore.

These vaccines were developed without a good animal model and, even after large studies proved their efficacy, researchers have yet to identify exactly what immune response is responsible for protection. This gives hope to AIDS vaccine researchers who are working under similar constraints. Paul Offit of the Children's Hospital of Philadelphia in the US and one of the co-discoverers of Rotateq says that in comparison "rotavirus vaccines were much easier to make," yet it still took a quarter of a century of research and development.

Rolling out vaccines

Before the WHO will recommend rotavirus vaccination for infants in developing countries, where infants are at the greatest risk of developing life-threatening gastroenteritis, the vaccines must be tested in these populations. Despite the experiences of Wyeth with Rotashield, neither manufacturer chose to run efficacy trials with their second-generation vaccines in both developed and developing countries simultaneously. According to Feinberg, Merck decided their large efficacy trial would only be conducted in countries where they were confident all possible cases of intussusception could be detected and treated quickly. "Now that we know the vaccine is highly efficacious and well tolerated we want to move forward as quickly as possible in resource-poor countries," he says.

This is happening with the help of PATH, whose goal is to reduce the delay between initial licensure of vaccines and availability in developing countries. The first step is talking with policymakers in the 72 poorest countries and educating them about the disease and the vaccines. "If we go to countries right now and say we want to talk about rotavirus, they say 'What's that?'" says John Wecker of PATH. These countries know they have a diarrheal disease but are unaware that rotavirus is the cause. "We want to provide a solid evidence base for developing-country governments, and we have a long way to go," he adds.

In the future PATH will also have to explain the characteristics that differentiate Rotateq from Rotarix, mainly serotype coverage and dosing schedule, so that representatives from developing countries can choose which vaccine to include in their immunization programs.

But in the end their decisions may be mainly driven by price. PATH is now holding consultations with the manufacturers on pricing. In the US, Merck's vaccine costs $180 for the three-dose course, making it one of the highest-priced childhood immunizations. Wecker is confident that financial subsidies provided by GAVI will help reduce the cost burden in developing countries.