Vahed, H.; Prakash, S.; Quadiri, A.; Ibraim, I. C.; Omorogieva, E.; Patel, S. J.; Tadros, J. M.; Liao, E. J.; BENMOHAMED, L.

SARS CoV-2 continues to evolve into new viral variants due to mutation, primarily in the Spike protein. Existing Spike-based vaccines are less effective because these variants can be more transmissible and evade vaccine-induced immunity. By targeting more conserved, Spike, and non-Spike, viral antigens using both arms of the adaptive immune system, i.e. B and T cells, we aim to reduce the reliance on neutralizing antibodies and avoid potential mismatches between the COVID-19 vaccines and circulating virus strains. In this way, enhanced immune memory function and broad-spectrum protection against existing and evolving virus variants can be attained. We have developed a mRNA-LNP-based multi-epitope vaccine incorporating conserved CD8+ T-cell, CD4+ T-cell, and B-cell epitopes. These conserved epitopes were selected as being highly recognized by B- and T-cells from unvaccinated asymptomatic COVID-19 patients. To evaluate the effectiveness of this multi-epitope asymptomatic vaccine, we utilized a novel triple transgenic h-ACE-2-HLA-A2/DR mouse model to enable the assessment of human T cell epitopes. Key observations include induction of: (i) robust protection against infection and disease caused by SARS-CoV-2 Delta (B.1.617.2) and Omicron (XBB.1.5) variants, as measured by reduced weight loss, virus replication, and lung pathology; (ii) strong antibody responses,; and (iii) potent SARS-CoV-2 epitope-specific IFN-gamma-producing CD4+/CD8+ T cells and Follicular helper CD4+ T (TFH) cells. These data support the strategy of targeting B-cells and T-cells directed toward highly conserved and asymptomatic epitopes, from both structural and non-structural viral protein antigens, to generate a broad-spectrum protective immunity to minimize disease impact across multiple SARS-CoV-2 variants.