Abstract: In response to the NIH's call for countermeasures to prevent emerging infectious diseases, we will develop, test and manufacture the Middle East Respiratory Syndrome Coronavirus receptor binding protein (MERS-CoV RBD) vaccine as an innovative countermeasure. According to the WHO, MERS-CoV remains a serious global concern mainly due to its potential to cause explosive outbreaks with substantial socio-economic consequences, if not controlled adequately. Therefore, an effective and safe vaccine is urgently needed. We have identified and produced at bench-scale a highly promising lead candidate vaccine antigen for MERS-CoV comprised of the RBD of the spike (S) protein. This domain contains the major neutralizing epitopes and can induce potent neutralizing antibody response and protection in animals against infection without causing antibody-dependent enhancement or eosinophilic pathology. Our MERS-CoV RBD is the leading vaccine candidate because it elicits high titers of anti-RBD neutralizing antibodies, the major correlate of protection against MERS CoV infection. It induces protection without eosinophilic immunopathology, the major detrimental effect of vaccines that employ whole virus or full-length S protein constructs, and it is stable, enabling stockpiling for emergency use. To rapidly translate these laboratory findings, Texas Children's Hospital Center for Vaccine Development at Baylor College Medicine established a new Coronavirus Vaccine Development Product Development Partnership (CoV-PDP) comprised of New York Blood Center, UTMB Galveston, and PnuVax Ltd., as its industrial manufacturing partner. We have a proven track record of innovative and high impact scientific publications, the ability to develop and technology transfer recombinant protein vaccines under cGMP, as well as experience with IND preparations and regulatory filings with the U.S. FDA. Through previous NIAID NIH funding the CoV-PDP has already developed and manufactured a SARS- CoV RBD vaccine. The specific aims of this application are: (1) Process development, pilot scale production, technology transfer and cGMP manufacture of the MERS-CoV RBD vaccine. Activities include scale-up of expression, assay development, formulation, and stability profiling, followed by technology transfer to PnuVax, where an engineering run and two cGMP production runs will be conducted. (2) Assessment of functionality and antigenicity of MERS-CoV RBD vaccine, and demonstration of its immunogenicity in wild-type mice. Specifically, we will evaluate the vaccine for its functionality and antigenicity, followed by optimizing the antigen doses for optimal immunogenicity, including RBD-specific antibody and T-cell responses, as well as long-term immune responses. (3) Evaluation of the immunogenicity, efficacy and safety of the vaccine in young and aged hDPP4-trensgenic mice well-known to be highly permissive to MERS-CoV infection and disease, followed by testing in non-human primates. At the conclusion of these studies, cGMP-grade material will be available for GLP toxicology studies, IND preparation/submission, and first-in-humans clinical testing.

Project Narrative MERS-CoV constitutes a severe peril to public health, now and in the future. The project proposed here will address this problem through the development of an innovative, stable, and safe vaccine to protect the public from this continuing threat. We have already identified a safe and highly promising lead vaccine antigen candidate, and are now working to finalize all pre-clinical studies, and to produce the vaccine under cGMP conditions, as required for first-in-human testing.