Diarrheal diseases consistently rank as one of the top ten causes of death from all causes worldwide and are estimated to account for almost two million deaths. The major impact of diarrheal diseases occurs in children under five years of age who suffer approximately 18% (about 2 million) of 10.6 million deaths in this age group annually, 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 accounting for approximately 500,000 deaths in the under five year age group, mostly in developing countries. RVs are uniquely egalitarian 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 oral, 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 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 vaccines safety, immunogenicity and efficacy especially against severe diarrheal disease, the ACIP, which advises the CDC, 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 RRV-TV)) to Wyeth Laboratories. However, in July 1999, after over one million doses 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 vaccines 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. Later data demonstrated that age of vaccination was a critical factor regarding the link 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 within 2 weeks of vaccination, even though they received only 38% of all first doses. Thus, catch-up vaccination of older infants during the age period of high vulnerability to intussusception (3 or 4 to 9 months of age) contributed disproportionately to the number of cases. In addition, there are lingering questions regarding the vaccines actual attributable risk of intussusception, a risk estimate that has ranged widely depending on the study. Because the RRV-TV vaccine was associated with a transient and characteristically low grade fever in up to about 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, a formulation that represented the 4 epidemiologically-important RV 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 RV diarrhea over two RV seasons. 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 three different schedules, approximately 0-2-4, 0-4-6 or 2-4-6 months of age,showed that neonates did not develop a febrile response after the neonatal dose. In addition,the neonatal dose induced significant protection 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. The NIH granted an exclusive license to BIOVIRx, Inc., a U.S. company, for the NIH-developed technology for RotaShield (RRV-TV). This effort with RRV-TV stalled initially. However, efforts to implement our second generation vaccine, BRV-TV, for the developing countries predominantly, have advanced. The NIH OTT has granted licenses to develop and commercialize the bovine RV-based vaccine to 8 institutions, one in the U.S. and seven in developing countries (Brazil, China and India). As of 2008, there is encouraging progress as vaccine production has reached the point that 3 companies are planning phase I studies for the end of this year or the beginning of next year. Our laboratory continues to serve as the unofficial reference laboratory for this program. 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 intussusception under natural conditions. 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. Our goal of vaccine implementation for the developing world was given an unanticipated, unsolicited boost, when we were notified in October 2006 by PATH that the Gates Foundation had approved their application with funding "...at a level of Approx $17 million over five years to support the process and clinical development of the NIH bovine rotavirus vaccine through Phase 2 at two selected manufacturers; and address product development challenges relevant to all emerging manufacturers of this vaccine." This PATH-NIH-licensee effort has been very fruitful as PATH is providing an"enabling platform" to facilitate the vaccine develpment process. In 2008, progress has been made with RotaShield as the license granted by NIH to BIOVIRx, has been transferred to a Foundation which is funding its development at a company in Germany. The vaccine is being developed currently in preparation for a placebo-controlled safety and efficacy trial in 2 African countries with two doses of vaccine, the first during the neonatal period and the second about three weeks later. This will commence in early 2009. Our laboratory has been participating in the planning phase of this trial and is also engaged in collaborative activities with the vaccine manufacturer.
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