Lone Simonsen (left), senior epidemiologist in the NIAID Office of Global Affairs,reanalyzed the CDC data that led to the withdrawal of the orginal rotavirus vaccine from the U.S. market. Her work counters the CDC intussusception projections and establishes a basis for a different rotavirus vaccine dosage schedule. "Her data are key," says Al Kapikian (right), to the confidence with which he and his team present their new rotavirus vaccine and schedule to the world. Companion articles* by Kapikian et al. (*1) and Simonsen et al.(*2) on the safety of rotaviral vaccines and prospects for eradicating severe rotaviral disease will be published in September in a supplement to the Journal of Infectious Diseases

After nearly six years in limbo, rotavirus vaccines developed in Al Kapikian’s NIAID lab are back on track to worldwide distribution and the prevention of the severe rotavirus-associated diarrhea that kills 500,000 to 600,000 infants and young children annually.

Over the past few years, 10 companies in the United States and abroad have been negotiating licensing agreements with the NIH Office of Technology Transfer (OTT) for the right to manufacture and market one or the other of the NIH rotavirus vaccine inventions (see "OTT and Rotavirus Vaccine").

One company has secured the rights to RotaShield, which was the first and only FDA-approved rotavirus vaccine and had been on the market only nine months when it was withdrawn in 1999 on the heels of a CDC report showing a vaccine-asociated risk of intussusception (intestinal prolapse). Nine other companies have scrambled to pick up where testing left off for the second-generation version of the vaccine.

Chief among the factors contributing to this revived interest are:

A reanalysis of the intussusception data from the CDC study pointed to a compensatory decreased risk within the first year of life, suggesting the overall risk had been overestimated.

Further analysis uncovered an age-related vulnerability that pointed to an even safer alternative vaccine-delivery schedule than originally recommended.

Kapikian believes that this revised schedule has the potential to eliminatethe risk of intussusception following vaccination—and he is jubilant that the vaccines are on the threshold of delivery to high-mortality areas.

Global Distribution

"It will be a great thing to be able to say that this vaccine is finally where it is most needed—in the developing countries where so many children have died from this preventable disease," Kapikian said in an interview in April, shortly after his return from Brazil, where he was honored at a ceremony to celebrate the signing of a licensing agreement between OTT and the Butantan Institute of São Paulo.

"And what is really wonderful," he said of the situation in Brazil, "is that the vaccine will be free for every child. The Butantan Institute is state funded and produces 81 percent of all the vaccines in the country—that’s 188 million doses."

The vaccine licensed to the Butantan Institute is the second-generation bovine rotavirus–human rotavirus reassortant vaccine, which was developed alongside the rhesus-human reassortant vaccine that was licensed and marketed as RotaShield (see "The Ups and Downs").

For use in Brazil, the basic quadrivalent vaccine will be augmented with the serotype 9 strain. Serotype 9, says Kapikian, has emerged as an important strain in Latin America and the most important serotype in parts of Brazil. Serotype 8, he notes, is prevalent in certain African countries—"and we will put that strain in our vaccine for Africa. And when we do the vaccine for India, we will undoubtedly put in serotype 9."

In a paper1 that will be published in September in a supplement to the Journal of Infectious Diseases, Kapikian and his colleagues recommend a hexavalent design (strains 1, 2, 3, 4, 8, and 9) for many of the developing countries. "The first four of these reassortants were made by Dr. Karen Midthun and others in our lab, and serotypes 8 and 9 were made later by Dr. [Yasutaka] Hoshino—next door—and they are available to be added to the vaccine," Kapikian notes. As licenses with OTT are concluded, the team will be sending relevant strains to each licensee.

He expects his work for the next few years will be focused on assisting the licensees in adapting the vaccine to the realities in their areas. His lab will provide technical assistance and, as space permits, will serve as a training site for those seeking to update relevant lab skills. Such a request has already come from China, where licenses are pending with three different entities.

Kapikian is pleased to point out that the advice he gives—regarding vaccine design, dosage schedule, and clinical trial protocol—to the many manufacturers who would bring the vaccine to their countries is part and parcel of his responsibilities as an NIH scientist with a public health mission.

The Road to Establishing Safety

From the time the rug was pulled out from under RotaShield, NIAID scientists set to work to understand theunexpected turn of events. Lone Simonsen, now senior epidemiologist in the NIAID Office of Global Affairs, recalls that NIAID was "caught unaware" when the CDC reported on the intussusception association in the MMWR of May 16, 1999. "They had never seen the data." Simonsen was called in to take a look at the evidence.

She cites three major findings in a series of reports from 2001 to the present. (see the two papers cited below^3,4.)

First, during the nine-month period the vaccine was used, there was no increase in intussusception in states using the vaccine, contradicting the impression that the increased relative risk in the immediate postvaccination week would mean the vaccine had caused a substantial number of intussusception events.

"The important point was that, no, this was not a public health disaster," Simonsen said in an interview. "To explain the unchanging intussusception rates during the nine-month use period, we hypothesized that the vaccine was harvesting events that would have happened anyway—and then, working further with the CDC case-control database, we found the phenomenon of compensatory decrease over time. This observation strongly supported our harvesting hypothesis."

Still concerned about the intussusception risk in the immediate postvaccination weeks, Simonsen and her colleagues set out to study carefully the role of age as a risk factor, analyzing data from the CDC, the National Center for Health Statistics National Immunization Survey, and hospital discharge data from the Agency for Healthcare Research and Quality.

During the nine-month introductory period for RotaShield use, many infants received the first dose beyond 2 months of age—so they could "catch-up" to the recommended schedule. More than 35 percent of first doses were given to "catch-up" infants between 3 and 7 months of age, and more than 80 percent of all implicated intussusception cases were amongst these older infants, Simonsen said.

"Were immunization to be completed before 3 months of age, we project that the intussusception risk would be far lower than previously thought—and comparable to severe adverse events linked to other approvedvaccines currently in use," she said. In this scenario, RotaShield could be reconsidered for use—even in the United States, where the rotavirus burden of disease (though real, with 50,000 hospitalizations and 20 deaths a year) pales before the global toll.

Kapikian notes that in the natural history of intussusception, the first two months of life is a relatively refractory period, while peak incidence is between 3 to 4 months and 9 months. The cause of intussusception is not known, but, he says, it makes sense to give the vaccine before the peak period of susceptibility.

Lone Simonsen and Al Kapikian wish to acknowledge the late John La Montagne, NIAID deputy director who died in November 2004, for being a source of strength, support, and encouragement in this unfolding rotavirus vaccine saga.

* The two companion papers to appear in a September supplement to the Journal of Infectious Diseases are:

* 1. A. Kapikian, L. Simonsen, T. Vesikari, Y. Hoshino, D. Morens, R. Chanock, J. La Montagne, and B. Murphy, "A hexavalent human-bovine reassortant vaccine designed for use in developing countries and delivered in a schedule with the potential to eliminate the risk of intussusception," J.Infect.Dis. (in press, 2005)

* 2. L. Simonsen, C. Viboud, A. Elixhauser, R. Taylor, and A. Kapikian,"More on RotaShield and intussusception: the role of age at vaccination," J.Infect.Dis. (in press, 2005).

3. L. Simonsen, D. Morens, A. Elixhauser, M. Gerber, M. Van Raden, and W. C. Blackwelder, "Effect of rotavirus vaccination programme on trends in admission of infants to hospital for intussusception," Lancet 358:1224 (2001).

4. B. Murphy, D. Morens, L. Simonsen, R. Chanock, J. La Montagne, and A. Kapikian, "Reappraisal of the association of intussusception with the licensed live rotavirus vaccine challenges initial conclusions," J.Infect.Dis.187:1301 (2003).

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