Research Project
6846186
DESCRIPTION (provided by applicant): Severe Acute Respiratory Syndrome (SARS) is an acute infectious pneumonia caused by a new airborne coronavirus (SARS-CoV), which, in an epidemic of only a few months during 2003, affected approximately 8000 people with over 800 deaths. The SARS epidemic caused global panic and significant economical damage to the Asian economy, and was contained mostly by aggressive quarantine, as no specific therapies or vaccines were available. Now, in January 2004, SARS may be returning, as two new confirmed cases of community acquired SARS have been reported in China, indicating the possibility that SARS-CoV will dramatically re-emerge in the human population. A safe and effective vaccine would offer the ideal solution to this new infectious disease. We propose here to further develop two independent approaches toward a vaccine against SARS-CoV infection. In one aspect, a traditional whole-virion "killed" virus approach is likely to represent the shortest development path, and leverages decades of Chiron experience in developing, manufacturing and administering vaccines based on inactivated viruses. In another aspect, we will utilize the knowledge that protection from coronavirus infection generally depends on neutralizing antibodies against the "Spike" envelope glycoprotein, and bypass the requirement for propagation of infectious SARS-CoV under BSL-3, by also developing a vaccine based on recombinant spike protein expressed in mammalian cells. We have now shown that a prototype vaccine generated by beta-propiolactone inactivation of SARS-CoV and purified by ion exchange chromatography elicited in mice and rabbits neutralizing serum antibody titers that were comparable to or higher than the neutralizing titers reported for human convalescent sera. Moreover, mice vaccinated with this candidate vaccine were completely protected from challenge with infectious SARS-CoV. Furthermore, we have identified purified recombinant Spike antigen for preclinical evaluation and final selection as a vaccine candidate. In specific Aim 1, we will produce the inactivated SARS-CoV vaccine under cGMP and complete a preclinical package, including efficacy studies in ferrets and monkeys, which will provide the basis for a subsequent clinical trial under Specific Aim 2. In parallel, Specific Aim 3 will include selection and characterization of a recombinant Spike vaccine, which will then be produced as a cGMP vaccine in Specific Aim 4 and evaluated for efficacy in ferrets and monkeys before proceeding to human safety and immunogenicity studies in Specific Aim 5. An extension of these during the final stages of Specific Aim 4.
