Diarrheal diseases are the third most common cause of death and are estimated to be associated with approximately 18% (about 2 million) of the 10.6 million deaths annually in infants and young children worldwide, with the greatest toll in the developing countries. Rotaviruses (RVs) have emerged as the single most important cause of severe diarrhea of infants and young children in both developed and developing countries. They are uniquely egalitarian viruses as they infect infants and young children with similar frequency in countries with high or low socio-economic conditions. Therefore, the urgency for a RV vaccine for use in both developed and developing countries has been a very high public health priority. We developed an orally administered, live, attenuated RV vaccine in a quadrivalent formulation 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 an estimated 600,000 infants, the CDC recommended suspending further vaccination because post-licensure surveillance suggested that the vaccine was linked with 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.. Recent data demonstrated that age of vaccination was a critical factor regarding the link of this vaccine with intussusception. In the CDC case-control study, vaccinees who were 90 days of age or older at the time of the first dose developed 81% of all cases occurring withn 2 weeks of vaccination, even though they received only 38% of all first doses. Thus ?catch-up? vaccination of older infants (i.e. 1st dose given after the ideally recommended age of 2 months) during the age period of high vulnerability to intussusception (3 or 4 to 9 months of age) contributed disproportionately to the number of cases. Therefore the vaccination age had a striking effect on the absolute risk of intussusception.. In addition, there are 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 1:32000-1:302000 excess cases 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. Because the RRV-TV was associated with a transient and characteristically low grade fever in up to approximately one-third of vaccinees and the knowledge that bovine RV?based vaccines were characteristically non-reactogenic, in parallel with RRV-TV vaccine studies we had initiated studies with individual human-bovine rotavirus (UK) reassortants and found that they were safe and immunogenic. These were followed by clinical studies of the 4 reassortants combined, to represent the 4 important rotavirus serotypes, and showed that this vaccine (BRV-TV) was also safe and immunogenic. In a Wyeth-University of Tampere-NIH collaborative clinical study of Finnish infants and young children, in which the RRV-TV and BRV-TV were evaluated in a two-dose schedule , the BRV-TV and RRV-TV induced a high level of protection ((90% or greater) against severe diarrhea over two RVseasons. The BRV-TV vaccine did not induce a significantly greater number of febrile episodes after vaccination when compared to controls whereas RRV-TV did. In addition, the analysis of another Wyeth-University of Tampere-NIH collaborative study in Finland evaluating the effect of administering RRV-TV vaccine or placebo in different schedules 0-2-4, 0-4-6 or 2-4-6 months of age showed that neonates did not develop a febrile response after vaccination. 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.? We have pursued our continued interest in RV vaccines especially for the developing countries where the toll from diarrheal diseases is immense. It is estimated that 600,000 deaths occur annually in the under 5-year age group, predominantly in the developing countries. The NIH has granted an exclusive license to BIOVIRx, Inc., a U.S. company, for the NIH-developed technology for RRV-TV. We have also been keenly interested in implementing our second generation vaccine, BRV-TV, for the developing countries predominantly.The NIH OTT has granted licenses to develop and commercialize the bovine RV-based vaccine to 8 institutions. which include Aridis, a U.S.company, the Butantan Institute-Foundation in Brazil, two Institutes in China (Chengdu Institute for Biological Products and Wuhan Institute for Biological Products), and 4 companies in India (Biological E, Bharat, Shantha and The Serum Institute of India). The human-bovine (UK) reassortant RV strains have been sent during the past year to 5 of the 8 licensees. Vaccine production has been initiated by two of the licensees (Butantan and Shantha). We are proposing that (i) the second generation RV vaccine be comprised of 6 serotypes (G1-4, 8 and 9) as a universal vaccine or as a specifically designed vaccine for different areas of the world (i.e. tetravalent [G1-4], pentavalent [G1-4,9] or hexavalent [G1-4,8,9]) (ii) that it should be given in a two-dose schedule at 0-4 and 4-8 weeks of age which is a relatively refractory period for developing intussusception under natural conditions. 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 of the world.
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