Genome-Wide B Cell, CD4

Over the last two decades, there have been three deadly human outbreaks of Coronaviruses (CoVs) caused by emerging zoonotic CoVs: SARS-CoV, MERS-CoV, and the latest highly transmissible and deadly SARS-CoV-2, which has caused the current COVID-19 global pandemic. All three deadly CoVs originated from bats, the natural hosts, and transmitted to humans via various intermediate animal reservoirs. Because there is currently no universal pan-Coronavirus vaccine available, two worst-case scenarios remain highly possible: (1) SARS-CoV-2 mutates and transforms into a seasonal “flu-like” global pandemic; and/or (2) Other global COVID-like pandemics will emerge in the coming years, caused by yet another spillover of an unknown zoonotic bat-derived SARS-like Coronavirus (SL-CoV) into an unvaccinated human population. Determining the antigen and epitope landscapes that are conserved among human and animal Coronaviruses as well as the repertoire, phenotype and function of B cells and CD4 (+) and CD8 (+) T cells that correlate with resistance seen in asymptomatic COVID-19 patients should inform in the development of pan-Coronavirus vaccines (1) . In the present study, using several immuno-informatics and sequence alignment approaches, we identified several human B-cell, CD4 (+) and CD8 (+) T cell epitopes that are highly conserved in: ( i ) greater than 81,000 SARS-CoV-2 human strains identified to date in 190 countries on six continents; ( ii ) six circulating CoVs that caused previous human outbreaks of the “Common Cold”; ( iii ) five SL-CoVs isolated from bats; ( iv ) five SL-CoV isolated from pangolins; ( v ) three SL-CoVs isolated from Civet Cats; and ( vi ) four MERS strains isolated from camels. Furthermore, we identified cross-reactive asymptomatic epitopes that: ( i ) recalled B cell, CD4 (+) and CD8 (+) T cell responses from both asymptomatic COVID-19 patients and healthy individuals who were never exposed to SARS-CoV-2; and ( ii ) induced strong B cell and T cell responses in “humanized” Human Leukocyte Antigen (HLA)-DR/HLA-A*02:01 double transgenic mice. The findings herein pave the way to develop a pre-emptive multi-epitope pan-Coronavirus vaccine to protect against past, current, and potential future outbreaks.