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

ABSTRACT 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 (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. Competing Interest Statement LB has an equity interest in TechImmune, LLC., a company that may potentially benefit from the research results and serves on the company Scientific Advisory Board. LB relationship with TechImmune, LLC., has been reviewed and approved by the University of California, Irvine by its conflict-of-interest policies. Authors, HV, JU, and DG were employed by TechImmune, LLC. No potential conflict of interest was reported by the remaining authors. DATA AVAILABILITY STATEMENT The original contributions presented in the study are included in the article/supplementary material. Further inquiries can be directed to the corresponding author.