A Pan-Beta-Coronavirus Vaccine Bearing Conserved and Asymptomatic B- and T-Cell Epitopes Protect Against Highly Pathogenic Delta and Highly Transmissible Omicron SARS-CoV-2 Variants of Concern

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-γ-producing CD4 ⁺ /CD8 ⁺ T cells and Follicular helper CD4 ⁺ T (T _FH ) 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.