Rotaviruses (RVs) are consistently shown to be the single most important etiologic agents of severe diarrhea of infants and young children in both developed and developing countries. They are egalitarian agents that infect infants and young children with similar frequency in countries with high or low socio-economic conditions. 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 formulated to protect against the four epidemiologically important serotypes, numbered 1, 2, 3, or 4. 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 was comprised of representatives of each of these 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 especially against severe diarrheal disease, the U.S. Advisory Committee on Immunization Practices (ACIP), which advises the CDC, recommended its routine use for infants at 2, 4, and 6 months of age. Subsequently, in August, 1998 the U.S. FDA granted a Biologics License for the vaccine (RotaShield [RRV-TV])) to Wyeth Laboratories. However, in July 1999, after over one million doses of the vaccine had been given, the CDC recommended suspending further vaccination because post-licensure surveillance suggested that the vaccine was linked with the adverse event of intussusception. Following additional CDC investigations, in October 1999 the ACIP withdrew its recommendation because of additional data which supported the vaccine's link with intussusception notably in the first two weeks after administration, predominantly after the first dose. In conjunction with these events, Wyeth Laboratories 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 of intussusception, a risk estimate that has ranged widely depending on the study, from 1:2500 to nil in the less than one year age group, (ii) a risk of about 1:32000 in the target population for vaccination comprised of 45-210 day old infants, (iii) a decrease in intussusception among vaccinees beyond the immediate 3-week post vaccination period which has been suggested to be a compensatory decrease, which may explain the inability to detect excess cases in the less than one-year age group as it may have counterbalanced the increase in intussusception in the early post-vaccination period, (iv) a protective effect of vaccination against the development of intussusception, (v) risk/benefit issues, and (vi) the direct and indirect effects of the withdrawal recommendation on the implementation of a rotavirus vaccine strategy in developing countries. In other activities, the code was broken by Wyeth Laboratories for the Wyeth-University of Tampere-NIH collaborative controlled clinical study of Finnish infants and young children. The goals of this study were (1) to evaluate the reactogenicity, immunogenicity and protective efficacy of our second generation vaccine, a quadrivalent bovine (UK) RV-based reassortant vaccine (BV-TV) that possesses a single VP7 gene from a human RV strain with serotype 1, 2, 3, or 4 specificity and the remaining ten genes from RV(UK) and (ii) the reactogenicity, immunogenicity, and protective efficacy of RRV-TV vaccine. The BV-TV vaccine was administered in a two-dose schedule in Tampere, whereas, the RRV-TV vaccine which was also given in a two dose schedule, was evaluated predominantly in Lahti. Preliminary analysis of this study has been very promising with both vaccines demonstrating modest efficacy against any RV diarrhea and a high level of efficacy against severe RV diarrhea. In addition, the BV-TV did not induce a significantly greater number of febrile episodes after vaccination when compared to controls whereas RRV-TV did. We are awaiting the finalizing of results for publication of a Wyeth-University of Tampere-NIH collaborative study in Finland evaluating the effect of administering RRV-TV vaccine or placebo in different schedules during the neonatal period and 2, 4, or 6 months of age. There has been continued interest in rotavirus vaccines for the developing countries where the toll from diarrheal diseases is immense, It is estimated that up to 592,000 deaths occur annually in the under 5-year age group, predominantly in the developing countries. In this regard, the NIH placed a notice that was published in the February 14, 2003 issue of the Federal Register indicating that it was contemplating the granting of an exclusive license to BIOVIRx, Inc. of Shoreview, MN for the NIH-developed technology for RRV-TV. The negotiation for implementation of this exclusive license is in its final stages. It is anticipated that after the license is granted, BIOVIRx will secure a site(s) outside the United States for producing the RRV-TV vaccine for evaluation in developing country(ies). We have also been interested in implementing our second generation vaccine, BV-TV, for the developing countries predominantly. In this regard, we responded to a Request for Proposals from The Global Alliance for Vaccines and Immunization (GAVI) which had formed Accelerated Development and Introduction Plans (ADIP) for both rotavirus and pneumococcal conjugate vaccines. We proposed the availability of our single gene (VP7) substitution human rotavirus-bovine rotavirus reassortants representing the 4 overall major serotypes 1, 2, 3, and 4, which were available with final passages in vero cells. We also indicated that human-bovine reassortants for serotypes G 5, 8, and 9 and bovine-bovine reassortant G 10 had been prepared. One or more of the latter 4 strains might be important for selected locations. In addition, we offered for vaccine production, single gene (VP4) substitution human-bovine rotavirus reassortants representing the VP4 of two of the frequently occurring strains, in an attempt to broaden immunogenicity: a VP4:1A[8] or VP4:1B[4] strain. In addition to the bovine-based vaccines, we also offered the RRV-TV vaccine grown in FRhL2 cells (the substrate for the final passages of RotaShield) which would provide the most rapid deployment of a RV vaccine for developing countries. We have been in communication with the Program for Appropriate Technology in Health (PATH) Rotavirus Vaccine Program which is administering the Rotavirus Vaccine Program ADIP for GAVI and are awaiting a final response from The GAVI ADIP regarding our proposals.
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