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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.


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