mRNA-BASED VACCINE AGAINST MULTIPLE COVID-19 VARIANTS

SUMMARY Over the last 25 months humanity has been confronting COVID-19 pandemic caused by the new Corona Virus 2 (SARS-CoV-2) infection. Mutations and deletions often occur in the genome of SARS-CoV-2 (predominantly in the Spike protein) resulting in more transmissible and pathogenic "variants of concern" (VOCs). Our long- term goal is to develop a potent COVID-19 vaccine to stop/reduce SARS-CoV-2 infections and/or COVID-19 disease caused by multiple VOCs. Major gaps: Out of the 50 mutations that occur in the genome of OMICRON variant, 32 mutations are concentrated in the Spike protein sequence alone. Because most mutation and deletion that produced the 20 known VOCs are mostly concentrated on the Spike protein sequence, there is a risk that some of current COVID-19 sub-unit vaccines, that used mainly the Spike protein as antigen, fail to protect against future VOCs despite inducing strong virus-specific neutralizing antibodies. This emphasizes two major gaps in knowledge: The need to design alternative second-generation coronaviruses vaccines that (1) will include non- structural epitopes and antigens (Ags), other than the Spike protein; and (2) will incorporate conserved B and T cell epitopes to induce cell-mediated immune responses (in addition to humoral responses). Preliminary Results: We: (1) Identified potential human T cell target epitopes (the part of a virus antigens that the immune system recognizes) from the whole SARS-CoV-2 genome; and (2) Produced a first prototype multi-epitope COVID-mRNA vaccine candidate using the scalable and proven mRNAs vaccine platform, and (3) Generated a novel "humanized" susceptible HLA-DR/HLA-A*0201/hACE2 triple transgenic mouse model in which to test additional COVID-mRNA-based vaccine candidates. We hypothesize that one of our 5 COVID-19 vaccine candidates will protect "humanized" mice from infection and COVID-like disease caused by intranasal inoculation with SARS-CoV-2 a, b, g, d and Omicron VOCs. Our Specific Aims are: Aim 1: To construct 5 additional multi- epitopes COVID-mRNA-based vaccine candidates, that will incorporate conserved B and T cell epitopes from SARS-CoV-2 VOCs that circulate in the United Sates and other 200 other countries. Aim 2: To test in our novel "humanized" mouse model the safety, immunogenicity, and protective efficacy against SARS-CoV-2 a, b, g, d or Omicron VOCs of 5 multi-epitope COVID-mRNA vaccine candidates, delivered intranasally. The durability of protection and its correlation with blocking/neutralizing antibodies and the number and function of tissue-resident SARS-CoV-2-specific CD4+ and CD8+ TRM cells in the lungs and brains will be determined. If successful, the lead vaccine that protects against most VOCs, will be tested in non-human primate for safety (SBIR Phase II) and subsequently could be moved quickly into an FDA Phase 1 clinical trial.