Rotaviruses (RVs) are the single most important cause of severe diarrhea of infants and young children in both developed and developing countries. They are egalitarian viruses as they 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, and 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 the following 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 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 to a currently estimated 600,000 infants, 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 and predominantly after the first dose. In conjunction with these events, Wyeth Laboratories withdrew the vaccine from the market. The fate of this vaccine continues to generate national and international interest and controversy and has led to discussions at meetings, in the scientific literature and in the lay press 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 (a)1:2500 to nil in the less than one year age group, (b)about 1:32000 in the target group for vaccination comprised of 45-210 day old infants, (ii) 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, (iii) a protective effect of vaccination against the development of intussusception, (iv) risk/benefit issues, and (v) 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. Progress has been made in the analysis of this study: BV-TV and RRV-TV induced 53% and 60% protective efficacy, respectively against any rotavirus diarrhea and over 90% efficacy against severe 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. In addition, 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, has been analyzed. This study showed that neonates did not develop a febrile response after vaccination. In addition, the administration of a neonatal dose protected against the development of a febrile response when infants received a second dose at two 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 has granted an exclusive license to BIOVIRx, Inc. of Shoreview, MN for the NIH-developed technology for RRV-TV. BIOVIRx is in the process of securing a manufacturer(s) for the RRV-TV vaccine for further evaluation in developing country(ies). We have also been interested in implementing our second generation vaccine, BV-TV, for the developing countries predominantly. 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. We have also indicated that human-bovine reassortants for serotypes G 5, 8, and 9 and bovine-bovine reassortant G 10 had been prepared. Vaccine candidates for serotypes G8 and G9 may be important for selected locations. In addition, we have also indicated that single gene (VP4) substitution human-bovine rotavirus reassortants representing the VP4 of two of the frequently occurring strains,P1A and P1B, were available. On June 21, 2004, a notice was published in the Federal Register by the NIH Office of Technology Transfer (OTT) indicating that the NIH was contemplating the granting of an exclusive license (U.S., Europe, and Canada) for the human-bovine reassortant rotavirus vaccine technology to Aridis LLC, Pertola Valley CA. The OTT has also received licensing requests from various other vaccine producers as follows: three groups in China, three in India and one in Brazil. We are proposing that (i) the second generation rotavirus vaccine be comprised of 6 serotypes (G1-4, 8 and 9) in order to provide broader protection and (ii)that it should be given in a two-dose schedule at 0-4 and 4-8 weeks of age which is a period of low vulnerability to developing intussusception under natural conditions. This schedule results from recent findings that indicate that in CDC's case-control study of RRV-TV and intussusception, within two weeks after the first dose, there was a disproportionate occurrence of intussusception associated with """"""""catch-up"""""""" vaccination in the =>90 day old infants and no cases in infants vaccinated at <60 days of age. It should also be noted that the proposed manufacture of the vaccine in developing countries should result in its availability at a low-cost which would facilitate its implementation in these developing areas.
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