Summary: The major impact of diarrheal diseases occurs in children under 5 years of age who suffer approximately 18% (about 2 million) of over 10 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 5 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. We developed an oral, live, attenuated RV vaccine in a quadrivalent formulation to protect against the four epidemiologically important serotypes (G1-4).The vaccine was comprised of representatives of each of the following 4 serotypes: rhesus rotavirus (RRV), a G3 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 G1, G2, or G4 specificity (the modified Jennerian approach). Following clinical studies which demonstrated the candidate vaccine's 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 vaccine's link with intussusception. In conjunction with these events, Wyeth Laboratories withdrew the vaccine from the market. Later data demonstrated that age of vaccination was a critical factor in 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. In addition, there are questions regarding the vaccine's actual attributable risk of intussusception, a risk estimate that has ranged widely. 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-Univ.of Tampere-NIH collaborative clinical study in Finland, 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 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, another Wyeth-University of Tampere-NIH collaborative study in Finland evaluating the effect of administering RRV-TV vaccine or placebo in three different schedules, 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 (which has now been transferred to the non-profit International Medica Foundation IMF) for the NIH-developed technology for RotaShield. This effort with RRV-TV stalled initially but was revived when funding became available from the IMF. Thus, quadrivalent RRV-TV vaccine was produced as a clinical product by The IDT Biologika GmbH in Germany, and became available in 2009 for clinical trial. Initial steps were taken to carry out a clinical trial in Malawi in 2009 but it was cancelled because of a mismatch of the circulating serotypes with those in the vaccine. Other sites were evaluated under the auspices of the IMF by Kendle International and a site in Ghana was selected for the clinical trial. A placebo-controlled phase II safety and efficacy trial began with RotaShield in Ghana in August 2009 and will include approximately 1000 neonates. The vaccine is given in two doses, one at 0-4 weeks of age and a second at 4-8 weeks of age with a minimum interval of three weeks between doses and no catch-up vacation beyond 8 weeks of age. This schedule will take advantage of the observation that there is a relatively refractory period for developing intussusception during the first two months of life. The first dose of vaccine or placebo was given to 9 neonates on August 28, 2009. In addition,efforts to implement our second generation vaccine, the human RV-bovine RV reassortant vaccine for the developing countries 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 2009, there is encouraging progress as vaccine production has reached the point that one company in Brazil has initiated phase I studies in adults. Two companies in India are engaged in vaccine development and are planning phase I studies for the end of this year or early next year. One company in China is now producing the reagents such as master virus seeds etc and is anticipated to begin phase I studies late next year. Our laboratory continues to serve as the unofficial reference laboratory. 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, (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 unsolicited boost, when we were notified in October 2006 by PATH that the Gates Foundation had approved their application with funding "... 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." In certain countries, an alternative schedule may be adopted which takes advantage of the experience gained from observations described above and from Rotateq and Rotarix, two recently licensed RV vaccines, with regard to the first dose: administer the first dose at 6-12 weeks with no catch-up vaccination and administer the second and third doses at 3-4 week intervals.