The recent epidemic of the severe acute respiratory syndrome (SARS) is caused by a novel coronavirus, SARS-CoV. During the epidemic, more than 8,000 SARS cases and 812 deaths have been reported worldwide. With an ease of transmission and severity of the disease, SARS poses a great threat to public health and causes significant economic loss. It also presents a serious biodefense risk to the United States. To date, no effective anti-SARS drugs or vaccines are available. The long-term goal of this proposed research is to develop an efficacious vaccine for preventing future SARS epidemic. Current information obtained from studies on animal coronaviruses and their respective hosts suggests that the most promising vaccine for SARS would be a coronavirus-based live vaccine. However, the development of an attenuated, live SARS-CoV vaccine, though possible, is a long-term approach with an unpredictable outcome. Previously, the P.I. has isolated an enteric coronavirus from humans (termed HECoV), which is associated with acute, mild diarrhea but with no other severe clinical symptoms in children. Recent sequence analysis of the entire genome from our laboratory revealed that the HECoV isolate is most closely related to bovine coronavirus. Based on the tenet of a common mucosal immune system, antigenic stimulation by oral immunization is often very effective in inducing immunity to respiratory pathogens. Therefore, the P.I. proposes to develop a recombinant enteric HECoV expressing the antigenic proteins of the SARS-CoV as oral vaccines for SARS. Five aims are proposed: (1) to develop recombinant enteric HECoV expressing the ectodomain of the spike and other proteins of the SARS-CoV; (2) to characterize the biologic and genetic properties of the recombinant vaccines in cell culture; (3) to evaluate the safety and immunogenicity of the recombinant vaccines in germ-free calves; (4) to evaluate the safety, immunogenicity, and efficacy of the recombinant vaccines in non-human primates; (5) to develop a cell culture process for production of vaccines for human clinic trial (GMP).These studies will provide critical information for the development of an efficacious vaccine for SARS. The development of such a reverse genetic system will facilitate studies on molecular pathogenesis of coronaviruses and may provide potential avenues for development of vaccines for other severe infectious diseases such as AIDS.