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The Vaccine That Almost Wasn’t

GlaxoSmithKline’s Rotarix
June 1, 2005

In the fall of 1998, rotavirus, a leading cause of severe childhood diarrhea, seemed ready to go the way of measles and rubella, viral diseases largely defeated by the administration of childhood vaccines. Wyeth had just had its RotaShield vaccine approved by the U.S. Food and Drug Administration (FDA), and it was poised to begin hastening the virus’s decline.

Rotavirus is a worldwide affliction: almost every child is exposed to it by age five. Every year in the United States, 50,000 people (mostly children) are hospitalized with rotavirus-induced diarrhea and dehydration, and between 20 and 40 die. In poor countries the picture is much more grim. Of two million deaths attributable to diarrhea worldwide each year, over half a million are caused by rotavirus. A successful rotavirus vaccine would make an enormous impact on world health.

In line behind Wyeth were SmithKline Beecham (now GlaxoSmithKline, or GSK) and Merck. Both companies had vaccine programs of their own and were eager to fight it out with Wyeth for the rights to a massive worldwide market. But a seemingly minor development in Wyeth’s clinical trials portended trying times ahead. Five cases of intussusception occurred among the 10,000 recipients of the vaccine during clinical trials in the United States and Finland. Intussusception is a treatable but potentially fatal intestinal condition in which one section of the bowel slides into the next, like a collapsible telescope. The cases did not stop the FDA from approving the vaccine, but the potential side effect was noted in the vaccine’s packaging insert.

For the next nine months, Wyeth’s investment seemed to be paying off handsomely. At $38 a dose, with a three-dose regimen, RotaShield joined the U.S. schedule for routine childhood immunizations for 1999, and about one million infants received the vaccine. But by May 1999, 10 cases of intussusception were reported to the Vaccine Adverse Event Reporting System, which is jointly sponsored by the FDA and the U.S. Centers for Disease Control and Prevention (CDC). CDC officials looked into the matter, and an analysis turned up Wyeth’s worst fear: rare cases of intussusception, estimated to be one in every 2,500 children vaccinated. (About a year later the best estimate was one in 10,000.) A rare enough side effect – but in a country where only 20 to 40 people will die each year from complications of rotavirus infection, the CDC deemed it an unacceptable risk. In July 1999, Wyeth suspended distribution of the vaccine. In October, a CDC advisory committee withdrew its recommendation that RotaShield be included in vaccination programs.

The finding prompted a crisis at GSK, which had a long-standing interest in a rotavirus vaccine, as well as a tradition of selling products to developing countries. The company had attempted to develop a rotavirus vaccine in the 1980s based on a bovine strain of rotavirus, but disappointing results prompted management to shift its R&D emphasis to an investment in a hepatitis E program. But Wyeth’s apparent success with RotaShield led to renewed interest, and in 1997, GSK entered into an agreement with Avant Immunotherapeutics that secured the rights to market a vaccine initially developed by Richard Ward at the Cincinnati Children’s Hospital Medical Center, based on a sample of a weakened human virus isolated from a Cincinnati child.

Like Wyeth, GSK had intended to introduce its vaccine (which would eventually be named Rotarix) to the U.S. market. But the intussusception problem represented a big hurdle. Rare side effects are extremely difficult to detect; to ensure that cases of intussusception either were not occurring or were mere coincidence, GSK would be required to conduct very large clinical trials. Before RotaShield, vaccine development did not routinely look for such rare side effects. Still, GSK had already invested millions in the rotavirus vaccine, and its managers did not want to give up so quickly, especially in light of the worldwide market for a vaccine.

When the CDC withdrew its recommendation for RotaShield in October 1999, GSK knew it was staring at a suddenly inflated cost for its own upcoming clinical trials. The company had already initiated discussions with the FDA about applying for approval, and it was finalizing the small-scale, phase I clinical trials intended to demonstrate the vaccine’s safety. Those trials were far too small to show rare side effects like intussusception. If ever there was a time to cut its losses, this was it – before the launch of costly, large-scale clinical trials. “We could have stopped easily,” says Beatrice De Vos, director of worldwide medical affairs at GSK Biologicals, the Belgium-based subsidiary of GSK that handles Rotarix.

“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.

Getting to Market
In July 2004, Rotarix was approved for use in Mexico, where one in 50 children is hospitalized for rotavirus infection, and GSK introduced the vaccine to private markets in the country in January 2005. It began by supplying the vaccines to pediatricians. Though the company won’t reveal sales figures, they are “in line” with expectations, says Pierrick Rollet, director of life cycle management. The company also expects the Mexican government to decide soon to include the vaccine in its general vaccine protocol. After Mexico, GSK plans to introduce the vaccine to other countries in Latin America as well as Asia this year and next. In the meantime, it is already licensed in the Dominican Republic and Kuwait, and GSK is in the process of obtaining licenses for it in 25 other countries, according to Myers.

In pursuit of opening up the widest possible market for Rotarix, the company is doing a complex dance with international agencies and national health authorities. GSK’s chief goal is to get GAVI to approve Rotarix for funding. But to do that, GSK must first get the blessing of the WHO, because that is a prerequisite for UNICEF to buy the vaccine, and UNICEF is the procurement organization for GAVI. Once GAVI approves the vaccine, individual countries can make a request to receive funding for vaccine purchase. Even then, the vaccine must be approved for use by each country. If the process sounds complicated, that’s because it is. “This is the first vaccine [not previously approved for use in developed countries] that GAVI will be considering for eligibility of funding. They’re trying to decide what the process is. We’re waiting for instructions on how to proceed,” says Myers.

While it waits on those commitments, GSK plans to introduce the vaccine to private markets. Regardless of the outcome of negotiations with GAVI and others, GSK is deeply committed to Rotarix. “We can’t afford to back out now. I think the bulk of the investment is done,” says De Vos. Indeed, GSK recently completed a 450-million-euro (about $550 million) manufacturing facility in Belgium that primarily produces Rotarix.

GSK is not alone in its quest. Merck continued developing its rotavirus vaccine when RotaShield was withdrawn from the U.S. market in July 1999. Based on a bovine rotavirus that, like RotaShield, is engineered to include surface proteins from predominant human rotavirus strains, Merck’s vaccine has done well in trials in the United States and Finland. Merck hopes to introduce it to the United States and Europe in this year or next.

The ultimate success of Rotarix remains to be seen, but Myers sees it as a model for GSK’s future and the future of the vaccine industry. The launch has also taught GSK lessons about how best to bring a vaccine to market in the developing world. For starters, Myers believes there was insufficient public education in preparation for the vaccine’s introduction. “Most mothers understand that their children have diarrhea, but they don’t know about rotavirus and the impact that the virus can have on the health of their child,” she says. In hindsight, GSK also would have started the prequalification process with the WHO sooner – before seeking licenses in individual countries – to prevent a holdup after licenses were granted.

An Emerging Model for Pharma
GSK has more than 25 products in its pipeline, a third of which are for diseases that are serious problems in the developing world, says Myers. One is a malaria vaccine, which completed phase II proof-of-concept trials in Mozambique in October 2004. The company is doing trials to see how well it works when administered with other vaccines to children younger than one, who are most susceptible. GSK hopes to enter the critical phase III trials at the end of 2006 or beginning of 2007, which if successful would put the vaccine in the developing world in 2009 at the earliest. The company can’t say for sure what the strategy for introducing the malaria vaccine will be, however, because it is developing the vaccine with partners.

Still, Myers expects the Rotarix experience to be repeated at GSK: “We’ve made it clear that this strategy is not just a one-off.” That could be good news for poor countries. The traditional model of developing a drug or vaccine and recouping costs in the developed world before introducing it farther afield leaves most of the world’s population in peril. Myers expects other companies to follow GSK’s lead in introducing vaccines and drugs quickly to neglected areas. “It’s something that’s going to be needed, and we need to figure out the issues and hurdles that need to be overcome in order to get vaccines as quickly as possible to the people that need them,” she says.

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