Development of a rapid response nucleic acid vaccine strategy for coronavirusepidemics

In response to the emerging COVID-19 (SARS-CoV-2) pandemic, this supplement proposal to R44 AI138733-01 will leverage our cutting-edge nucleic acid vaccine strategies, some of which that were developed under thisparent grant. Here, we request supplement funding to develop candidate COVID-19 DNA and RNA vaccinesexpressing optimally designed immunogens for the SARS-CoV-2 spike protein. Nucleic acid (DNA and RNA)vaccines offer significant promise for providing a rapid response solution to emerging infectious diseasesbecause only a partial genetic sequence of the pathogen is needed to generate a new vaccine. Following in vivodelivery, DNA and RNA vaccines lead to in situ production of antigens, negating the need for a complexmanufacturing and process development required for purified recombinant protein, inactivated or live attenuatedvaccines. Nucleic acids can also be manufactured at low cost and are very stable at room temperatureeliminating the need for a cold chain. This provides a significant savings in the time needed to advance a newvaccine from identification of genetic sequence to clinical testing and distribute it to the population. In addition,possibly due to the ability of nucleic acid vaccines to present antigens in their natural conformation in vivo,antibody responses are generally of higher avidity and broader specificity when compared to antibody inducedby subunit protein vaccines. Further, the intracellular expression of antigens also induces robust T cell responsesincluding potent CD8+ T cell responses that can more broadly recognize different viral strains and mediateprotection via enhanced clearance of the infection. Our approach will compare our optimized DNA and RNAvaccine platform technologies alone and in combinations to identify a lead approach that induces the highestand most rapid development of protective levels of neutralizing antibody after a single administration. In addition,since nucleic acid vaccines tested in our lab have been shown to induce antibody and/or T cell responses thatinduce cross-protective immunity in our universal influenza vaccine studies under our parent grant, we willdetermine if the candidate vaccines exhibit cross reactivity against other coronavirus strains for broaderprotection against future coronavirus strains with epidemic or pandemic potential. Our Aims include: Aim 1-Design and compare immunogenicity of candidate SARS-CoV-2 DNA and RNA vaccines. Aim 2 - Maximizeimmunogenicity of nucleic acid vaccines and rapid manufacture by combining DNA and replicon mRNA vaccinestogether or with recombinant protein and optimizing DNA and mRNA formulations. Aim 3 - Safety andimmunogenicity of the lead COVID-19 nucleic acid ± protein vaccine in the preclinical nonhuman primate model.If successful, should identify a lead candidate COVID-19 nucleic acid vaccine for phase I human clinical trials.