A major area of research in the Epidemiology Section is the development of a rotavirus vaccine. The first vaccine candidates to be evaluated in human efficacy trials by various groups were live, attenuated orally-administered bovine or simian rotavirus strains. Because these vaccines induced variable protection against rotavirus diarrhea in placebo-controlled phase II studies in young infants, this project was initiated with the intent of dissecting serotype-specific responses to the two major neutralization antigens following immunization and identifying laboratory correlates of resistance to rotavirus illness. In the last four years, advances have been made by us and others in the molecular characterization of different rotavirus VP7 and VP4 serotype- specific antigenic sites. Three antigenic sites, A, B, and C were defined by an Australian research group on the outer capsid glycoprotein VP7 by sequence analysis of neutralization-resistant mutants selected in the presence of serotype-specific neutralizing monoclonal antibodies. Two major antigenic sites were identified on the outer capsid spike protein, VP4, by a similar approach. Serotype-specific monoclonal antibodies from the U.S., Australia, and Japan became available and several large surveys of the epidemiologic distribution of human rotavirus serotypes were conducted. It was observed that there are four predominant VP7 serotypes (1, 2, 3, and 4) worldwide that can circulate concurrently in the same geographic area. Our inability to predict the distribution of individual serotypes for a given season suggested that a rotavirus vaccine must simultaneously induce immunity against multiple circulating serotypes. by studying the repertoire of rotavirus-specific serum antibody responses in adults and infants who receive rotavirus vaccine candidates, we are attempting to delineate the immune correlates of protection against rotavirus illness.
