Rotaviruses (RVs) are consistently recognized as the single most important etiologic agents of severe diarrhea of infants and young children worldwide. Therefore, the need for a vaccine for use in both developed and developing countries was clearly of public health importance. We developed an orally administered, live, attenuated vaccine with the goal of inducing an immunologic response that mimicked natural RV infection, especially with regard to induction of immunity at local intestinal sites. This quadrivalent RV vaccine was intended to protect against the four epidemiologically important serotypes. Although the relative importance of homotypic vs. heterotypic immunity was not established with certainty, it appeared from epidemiologic, clinical, animal and laboratory observations that serotype-specific immunity was a major component of protection against RV illness. The vaccine is comprised of representatives of each of 4 serotypes: rhesus rotavirus (RRV), a VP7 serotype 3 strain, (the Jennerian approach), and three human RV-RRV reassortants, each possessing ten RRV genes and a single human RV gene that encodes VP7 (a major outer shell protein) that is responsible for serotype 1, 2, or 4 specificity (the modified Jennerian approach). Following extensive clinical studies which demonstrated the candidate vaccine's safety, immunogenicity and efficacy, the Advisory Committee on Immunization Practices (ACIP) recommended its routine use for infants at 2, 4, and 6 months of age. Subsequently, in August, 1998 the FDA granted a Biologics License for the vaccine (RotaShield) to Wyeth Laboratories. However, in July 1999, after an estimated 1.2 million doses had been given to over 700,000 infants, the CDC recommended postponing further vaccination because post-licensure surveillance suggested that the vaccine was linked with the adverse event of intussusception. Following additional investigations by CDC, in October 1999 the ACIP withdrew its recommendation because of additional information which supported the vaccine's link with intussusception in the first two weeks after administration, predominantly after the first dose. In conjunction with these events, Wyeth withdrew the vaccine from the market. The fate of this vaccine has aroused considerable national and international interest and controversy and led to various focussed discussions at meetings and in the scientific literature because of lingering questions regarding (i) the vaccine's actual attributable risk with intussusception, a risk estimate that has ranged widely depending on the study, from 1:2500 to nil in the lesser than one year age group and (ii) risk/benefit issues. Thus, the decision regarding the vaccine's withdrawal is being revisited by the ACIP Rotavirus Working Group currently, with a discussion of the issues to be presented at the full ACIP meeting in October 2001 with a final decision due at the ACIP meeting in February 2002. In other activities, we have also evaluated collaboratively several second or third generation vaccines or approaches including: (a) the effect of administering the RRV-based quadrivalent vaccine to neonates to determine its reactogenicity and immunogenicity with different administration schedules; (b) a quadrivalent bovine (UK) RV-based reassortant vaccine that possesses a single VP7 gene from a human strain with serotype 1, 2, 3, or 4 specificity and the remaining ten genes from bovine RV (UK); (c) a reassortant vaccine (Wa x UK) that contains a single gene from the human RV Wa strain, that encodes VP4:1A specificity, in a background of 10 bovine RV (UK) genes; (d) a reassortant vaccine Wa x (DS-1 x UK) that possesses the VP4 gene from the human RV Wa strain (VP4:1A) as well as the VP7 gene from human strain DS-1 that encodes G2 specificity, in a background of 9 bovine (UK) genes; (e) and a 30 degree C cold-adapted, temperature-sensitive, VP7:1 strain (D[75-82]) (see Hoshino reports).
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