FOCUS | March 10, 2006

Infant diarrhea may not appear to some as an important cause of morbidity and mortality. Yet rotavirus, the most common cause of severe diarrhea in children, is responsible for about 55,000 hospitalizations of infants and young children each year in the United States. In developing countries, more than 500,000 children die each year as a result of the infection.

A vaccine against rotavirus, RotaShield, was approved by the Food and Drug Administration in 1998, but later withdrawn because children who received it were at increased risk of intussusception, in which one piece of bowel prolapses on another. The condition can cause bowel perforation, infection, and death. The withdrawal of the vaccine prompted an international debate about its risks and benefits, with some believing the balance was tolerable in developing countries, where the risk of death was considerably higher than in the United States. In 1999, the Advisory Committee on Immunization Practices of the Centers for Disease Control and Prevention (CDC) withdrew its recommendation of RotaShield, and Wyeth, the manufacturer, withdrew the product from the market.

Take Two Against Infant Diarrhea
When RotaShield was withdrawn in 1999, there was concern that the pharmaceutical industry would shy away from investing in a new rotavirus vaccine. The two major hurdles were the size of clinical trials that would be required to demonstrate safety and the postmarketing surveillance requirements. Fortunately, at least two major pharmaceutical companies, Merck and GlaxoSmithKline (GSK), continued with research and development of vaccines against the virus. It is estimated that GSK has invested at least $500 million in the development of Rotarix and Merck up to $1 billion on RotaTeq.

Jesse Goodman, director of the FDA’s Center for Biologics Evaluation and Research, the center responsible for approval of vaccines, believes that the pharmaceutical firms that continued to invest in R&D recognized the importance of rotavirus as a public health problem and present and future product needs in the United States and around the world. Goodman said that there is increasing recognition of “the promise and contributions of vaccines in addressing global health needs in a cost-effective manner, and this, combined with an increasing appreciation of global health and global markets, may also be increasing interest in vaccines in general.”

“We are all excited. We have a tool that works in many children, and we need to learn if it will work for children in developing countries. If it does not work as well, we need to work through ways that kids in greatest need can receive the benefit.”

Roger Glass (HMS ’72), head of the viral gastroenteritis section at the CDC and a leading researcher in the field, believes that the companies’ decisions to move forward with rotavirus vaccine research and development was a complicated one in which the science of developing a safe and effective vaccine and the potential global market were considered. “The global market,” he said, “is well defined. There are 135 million births each year, representing a huge global market for this childhood vaccine.” Nevertheless, according to Glass, it was a “risky call” by the companies, because a few cases of intussusception during clinical trials might have changed the entire economic environment.

RotaTeq was recently approved by the FDA while Rotarix is approved for use in many Latin American countries and is in the approval process for the United States and Europe. The two vaccines are different, but have been shown to have excellent safety and efficacy profiles in large-scale clinical trials involving tens of thousands of children. In addition to safety and efficacy, clinical trials have demonstrated clear economic benefits. Not only do the vaccines reduce morbidity and mortality, but they also decrease the number of hospitalizations for diarrhea by from 42 to 63 percent and the number of lost work days for adult caregivers by 87 percent.

Private Push
During these drug development efforts, the private sector may have gotten a boost from the philanthropic sector. In 2002, the Bill and Melinda Gates Foundation set aside $30 million to encourage manufacturers to invest in rotavirus vaccine R&D. Further, the foundation’s creation and support of the Global Fund for Children’s Vaccines, part of the Global Alliance for Vaccines and Immunization (GAVI), is leading the way in introducing new vaccines to poor regions while sending the message to manufacturers that new vaccines will make it to developing markets. Though the vaccine for Hepatitis B took about 20 years to make it from the United States to developing countries, Glass believes that the Gates Foundation and GAVI’s efforts may shorten this time to five to 10 years for newer vaccines.

Despite the challenges and uncertainty regarding the success of the rotavirus vaccines globally, Glass is optimistic: “We are all excited. We have a tool that works in many children, and we need to learn if it will work for children in developing countries. If it does not work as well, we need to work through ways that kids in greatest need can receive the benefit.”

Whether or not the promise of the rotavirus vaccines is fulfilled in developing countries depends on biology and economics. Both Merck and GSK’s trials in developing countries will take two to four years to complete, according to Glass, and it is not clear whether or not the vaccines will have the same safety and efficacy profiles in these settings.

Pricing of rotavirus vaccine and the availability of adequate immunization infrastructure will also influence the reach of the vaccine. Glass is encouraged that the manufacturers have committed to tiered pricing—in which public-sector buyers pay less than private-sector purchasers—and believes that the cost of the vaccine will decline in the future. “As we have more experience with the vaccine and companies are able to recoup investment costs and learn more about the safety,” he said, “the price may come down further.”

—Erica Seiguer is an MD–PhD student studying economics in Harvard’s Doctoral Program in Health Policy.

Related Websites

Global Alliance for Vaccines and Immunization

Rotavirus Vaccine Program at PATH

Rotavirus (CDC)

The opinions expressed in this column are not necessarily those of Harvard Medical School, its affiliated institutions, or Harvard University.

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