Since their discovery in 1973 in Australia, rotaviruses (RVs) have consistently been found in cross-sectional studies 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, infecting 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. 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 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 an estimated one million of the 3.8 to 4.0 million of the U.S. birth cohort had received at least one dose, 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 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 less than one year age group, (ii) risk/benefit issues, and (iii) the direct and indirect effect of the withdrawal on the implementation of a rotavirus vaccine strategy in developing countries where the mortality from rotavirus illnesses is staggering. With this continuing debate and open differences of opinion regarding the withdrawal decision, the ACIP reconsidered the question about the use of the rotavirus vaccine at their February 2002 meeting. The ACIP voted against changing the withdrawal recommendation and maintained its previous position. A compromise wherein a permissive recommendation might free up the vaccine for further study and encourage developing countries to implement a rotavirus vaccine strategy was also rejected . A key factor in not seriously considering a permissive recommendation was felt to be Wyeth's position that it would only consider re-making the vaccine if a routine immunization recommendation had been granted. In other activities we are still awaiting the final results of a collaborative study in Finland evaluating the efficacy of (i) 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 RV(UK) and (ii) the efficacy of RRV-TV vaccine. In addition, we are awaiting the finalizing of results for publication of a Finnish study describing the effect of administering RRV-TV vaccine to neonates in different administration schedules.
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