Al Kapikian

The sands have once again shifted in the status of the world’s first licensed rotavirus vaccine—and NIH’s Al Kapikian, who headed the research culminating in the vaccine’s approval, continues to explore avenues of rotavirus vaccine research.

An international assembly of vaccinologists, epidemiologists, and public health officers has recommended the resumption of field trials to determine the safety and efficacy in developing countries of the rotavirus vaccine whose approved use in the United States was suspended after the emergence postmarketing of vaccine-related cases of intussusception, or intestinal prolapse, a serious but poorly understood condition in which the intestine telescopes into itself. Treatment may require surgery, which can be problematic in developing countries.

Convened by the World Health Organization, the assembly met in Geneva in February to consider future rotavirus vaccine development in developing countries, with a special focus on the risks and benefits of RotaShield, the Wyeth-Ayerst product brought to the U.S. market in the summer of 1998 but withdrawn by the manufacturer last October. That action had ended activity the world over involving the only vaccine licensed for use against rotavirus."The basic ethical question the Geneva group had to address," said Kapikian, head of the Epidemiology Section in NIAID’s Laboratory of Infectious Diseases, "was: ‘Can a vaccine withdrawn from use in the United States be used in developing countries? Would this be dispensing second-class medicine to developing countries?’"

The group concluded it would be "immoral not to proceed" with the testing of RotaShield in developing nations, where rotaviral diarrhea kills almost 100 children under age 5 every hour.

"They agreed that inaction is not a morally neutral position" when the death toll is about 800,000 worldwide yearly, and researching another vaccine could take perhaps four to seven additional years—with no guarantee that safety and efficacy would exceed RotaShield’s.

"The hurdle now," Kapikian added, "is the availability of the Wyeth-Ayerst vaccine," a subject he addressed in a letter to the company immediately upon his return from the Geneva meeting. At the time the company withdrew the vaccine, it had supplied only the U.S. market and had not begun distributing the product to the 15 Western European nations that had also registered it for use or to any developing nations. Representatives of the company were at the Geneva proceedings—but not the ultimate "decision-makers," he said.

RotaShield’s future had been in limbo since last July when the Food and Drug Administration (FDA) advised physicians to suspend its use until the emerging risk of vaccine-related intussusception was clarified. A few months later, in October, the Advisory Committee on Immunization Practices (ACIP) of the Centers for Disease Control and Prevention withdrew its recommendation that babies be vaccinated against rotavirus at 2, 4, and 6 months. The manufacturer then withdrew the product.

The vaccine had been endorsed by ACIP and approved by FDA in the summer of 1998, the capstone of a quarter-century of basic and clinical research with a strain of rhesus rotavirus that produced a quadrivalent, live-virus oral vaccine. The vaccine had proved safe and efficacious in preventing severe rotaviral-related diarrhea in clinical trials involving more than 7,000 children. The research program was carried out under Kapikian’s direction (see "More than Two Decades of Research Culminates in Rotavirus Vaccine," The NIH Catalyst, March–April 1999).

But within a year of the vaccine’s marketing, there appeared a report in the July 16, 1999, MMWR (Morbidity and Mortality Weekly Report) of 15 cases of intussusception among vaccinated infants. (Original ACIP recommendations may be viewed here; CDC withdrawal of recommendation may be viewed here.) Thirteen of the 15 occurred after the first dose; in 12 of 15, onset occurred within one week of any dose. The cases had been reported to the joint CDC-FDA Vaccine Adverse Events Reporting System. Further investigation of this phenomenon uncovered 102 confirmed or presumptive cases of intussusception following the administration of about one and a half million vaccine doses.

"We need to understand just what happened here. It was such a surprise to everybody," Kapikian said in an earlier interview with the Catalyst late last year, after he’d detailed the chain of events for the NIH community at a Kinyoun lecture here. An increased intussusception rate had not been observed in any of the clinical trials that led to FDA approval, raising the question of just how many infants need to be included in the testing of this and any other rotavirus vaccine before an increased rate of a rare event like intussusception emerges.

Based on New York State’s 1991–1997 hospitalization rate for intussusception of 51/100,000 infants during the first year of life, the expected yearly background intussusception rate would be about 500 per million in the unvaccinated population over a one-year period. Although reviews of the outcomes among various cohorts of vaccinated babies reveal rates that appear to be lower than that, the time periods covered have not been comparable, Kapikian noted. Also unclear are whether wild-type rotavirus infection increases intussusception risk and whether an effective rotavirus vaccine would, therefore, decrease the overall rate in the long-term. "That clustering in the first week after the first dose is significant, but we really don’t know what happens over a year’s time," Kapikian observed. "Is there a compensatory decrease after that first week?"

Once the rate of infant intussusception attributable to rotavirus vaccine is established, the risk-benefit ratio among different populations of infants may be assessed and public health decisions made. Suspended WHO studies planned in Asia and Africa to address these issues can now resume, contingent on the availability of the vaccine itself.

Kapikian’s team has been collaborating with researchers in Finland and at Johns Hopkins University in Baltimore in studies of a "second-generation" rotavirus vaccine based on a bovine strain, which is less likely to induce fevers in the week after vaccination. He and his team had developed a six-antigen construct before the hiatus.

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