Sars-Cov-2 Multiepitope Vaccine Constructs Designed To Drive Long-Term Immunity In The Majority Of The Population.

The current SARS-CoV-2 pandemic has precipitated an urgent need for a safe and effective vaccine to bedeveloped and deployed in a highly accelerated timeframe as compared to standard vaccine developmentprocesses Upfront selection of epitopes most likely to induce a safe and effective immune response can acceleratethese efforts Optimally designed vaccines maximize immunogenicity towards regions of proteins that contributemost to protective immunity, while minimizing the antigenic load contributed by unnecessary protein domains thatmay result in autoimmunity, reactogenicity, or enhanced infectivity Adopting tools developed for population-scalecharacterization of HLA presentation of tumor antigens and cross-reactivity of TCRs with tumor self-antigens, wehave generated an immunogenicity map of SARS-CoV-2 to inform vaccine design based on analyses across fiveparameters: 1) stimulation of CD4 and CD8 T cells;2) immunogenicity across the majority of human HLA alleles;3)targeting both evolutionarily conserved regions, as well as newly divergent regions of the virus that increaseinfectivity;4) targeting linear and conformational B-cell epitopes;and 5) targeting viral regions with the highestdegree of dissimilarity to the self-immunopeptidome such as to maximize safety and immunogenicity Using theseanalyses, we have generated 11 SARS-CoV-2 vaccine constructs optimized for long-term immunity across themajority of the population These constructs contain combinations of epitopes selected from our analysis such as todrive affinity-enhanced memory response in combination with current spike protein vaccine strategies, for use as T-cell vaccines, and a stand-alone vaccine designed to drive memory B- and T-cell responses in the majority of thepopulation Epitopes were optimized using our immunogenicity algorithm to minimize immunogenicity across thejunctions between epitopes and cloned into pVAX vectors, using signal peptides targeting the lysosome, ER, andcytoplasmic secretion, such as to promote presentation to CD4, CD8, and B cells, respectively Finally, we describemethods for identifying immunodominant epitopes arising from vaccination using barcoded, multiplexed tetramers Vaccine constructs are currently undergoing testing in transgenic mice expressing human HLA-A2 We expect thatthese constructs will help drive long-term immunity across the population, targeting conserved regions acrossmultiple coronaviruses