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“We Were Quite Lucky”
But GSK found two reasons not to stop. First, the company determined that tests were unlikely to reveal a risk for intussusception, since its candidate vaccine was quite different from Wyeth’s. Most significantly, GSK’s vaccine was based on a human strain, while Wyeth’s was a rhesus monkey rotavirus genetically engineered to carry surface proteins representing the human virus. GSK speculated that the nonhuman nature of the vaccine virus could be the source of the intussusception problem. “We started looking into the literature to try to figure out if there was any possible link between natural infection [with human rotavirus] and intussusception,” says De Vos. “There was absolutely no evidence [of such a link].” That news helped convince upper management to carry on with the development.

The other advantage of GSK’s vaccine was that it was much simpler than Wyeth’s vaccine, because it targeted just one strain of rotavirus. Strains are defined by the chemical nature of key proteins that make up the outer shell of a virus. When a virus of a particular strain enters the human body, the immune system recognizes it and launches an antibody response. Four strains account for as much as 96 percent of rotavirus infections around the world. Wyeth’s vaccine incorporated all four of those strains, which gave it a wider coverage of rotavirus as a whole than did GSK’s vaccine, but which also came with safety drawbacks. Each incorporated strain requires an additional dose of virus during vaccine preparation, so that injection of a vaccine with four strains subjects a child to four times the amount of virus. It also makes potential safety problems more difficult to track down, because vaccine preparation is more complicated.

None of these matters was strongly considered when GSK first licensed its vaccine, because Wyeth’s vaccine had already been approved and seemed well on its way to becoming a success. “We were quite lucky,” says De Vos. But GSK’s decision to target just one serotype with its vaccine was not without good reason. The single strain of rotavirus the company was targeting caused 75 percent of infections worldwide. And though Rotarix targeted only one set of surface proteins, clinical trials showed that the vaccine also conferred protection against other important strains. “This is a well-known phenomenon with viruses,” says De Vos.

While GSK forged ahead with its preparation, it kept a close eye on events outside its walls. In February 2000, the World Health Organization (WHO) called a meeting to discuss the progress of rotavirus vaccines, including RotaShield, for developing countries. To the surprise of many, some health ministers at the meeting, upon consideration of evidence from Wyeth’s clinical trials and the postmarketing studies, were disinclined to use RotaShield in their countries. De Vos believes the problem may have stemmed from the fact that a vaccine often elicits stronger immune responses from children in developed countries than in developing countries, possibly because of differences in nutrition. Wyeth conducted most of its clinical studies in the United States and Finland. Because of that, the health ministers from the developing world had no reliable information to approve the use of RotaShield in their own countries.

The WHO meeting was a further blow to RotaShield, but it represented an opportunity for GSK. WHO officials met with GSK soon after to ask the company to develop Rotarix for both developed and developing countries in parallel. “They did not want what happened with Wyeth’s vaccine – where there was no data for the developing world – to happen again,” says Deborah Myers, director of external and government affairs and public partnerships at GSK Biologicals. Such an expansion represented a much larger market than the United States and Europe, but it also would require expanded clinical trials and higher cost, and thus greater financial risk. The WHO’s wish for a two-track vaccine launch also flew in the face of what De Vos calls “classical” vaccine development, where companies introduce a novel vaccine in developed countries at high prices, then sell the vaccine to underdeveloped countries at a reduced cost.

Introducing a vaccine simultaneously to developed and developing markets required GSK to adjust its thinking, but an outside development helped make the economics of bringing vaccines to poor countries more feasible. Nongovernmental organizations (NGOs) were becoming an increasingly potent economic force in the developing world. The Bill and Melinda Gates Foundation, for one, was beginning to make major contributions, especially to the Global Alliance for Vaccines and Immunizations (GAVI), a private-public sector partnership launched in 2000 to promote the widespread use of vaccines. That influx of money represented a boost to the existing NGOs and other buyers of vaccines in developing countries, such as government immunization programs and various countries’ private sectors. (By December 2004, GAVI had disbursed over $532 million for vaccines, supplies, and support.) In 2003, GAVI announced that rotavirus was one of its two vaccine priorities, and seeded its Rotavirus Vaccine Program with $30 million.

Emboldened by the new buying power of NGOs, GSK completed phase II and phase III clinical trials to prove the vaccine’s efficacy in Finland and several developing countries, including Brazil, Mexico, and Venezuela. Those trials were completely funded by GSK. The results were announced in October 2004. Rotarix was 85 percent effective in preventing severe rotavirus-induced diarrhea in Finland, and 86 percent effective in the Latin American countries. GSK is doing additional trials in South Africa and Bangladesh with support from the WHO, CDC, and other agencies to determine Rotarix’s efficacy in these impoverished countries.

The positive results in Latin America gave Rotarix an apparently bright future in the developing world, but one more course adjustment was forthcoming. In a public meeting in September 2001, the National Vaccine Advisory Committee discussed the sample size that would be required to eliminate the possibility of a risk of intussusception. After the meeting and some internal discussion, GSK management decided to turn the entire classical vaccine development paradigm on its head, dropping its plan to do parallel introductions in the United States and developing countries, and focus solely on the latter. The company wouldn’t elaborate on what was said at the FDA meeting, but GSK still plans to do a U.S. introduction after it proceeds in developing countries and Europe, which it hopes will approve a Rotarix license by early 2006. GSK also hopes that clinical trials in developing countries will eventually help convince the FDA of the vaccine’s safety.

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