Genome-Wide Asymptomatic B-Cell, CD4⁺and CD8⁺T-Cell Epitopes, that are Highly Conserved Between Human and Animal Coronaviruses, Identified from SARS-CoV-2 as Immune Targets for Pre-Emptive Pan-Coronavirus Vaccines

Abstract

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.

Safety and Efficacy of Single-Dose Ad26.COV2.S Vaccine against Covid-19

“… 9 T-cell epitopes were shown to be conserved between SARS-CoV-2 variants according to immunoinformatics analyses. 33-35 These factors might contribute to the high efficacy against severe–critical disease, hospitalization, and death in South Africa, where the relatively neutralization-resistant 20H/501Y.V2 variant predominates. 26 , 36…”

SARS-CoV-2-Seronegative Subjects Target CTL Epitopes in the SARS-CoV-2 Nucleoprotein Cross-Reactive to Common Cold Coronaviruses

“…This study also reported recognition of newly defined HLA-I- and HLA-II-restricted T-cell epitopes by SARS-CoV-2-infected patients and SARS-CoV-2-seronegative subjects but none of our newly defined HLA-I restricted CTL epitopes was investigated in that study. Another recent study indicated that recognition of conserved CD4 epitopes within the SARS-CoV-2 sequence correlated with a less severe course of COVID, but not the overall frequency of SARS-CoV-2 specific CD8 + T-cells ( 12 ). Interestingly, they found that asymptomatic SARS-CoV-2 infected patients and healthy unexposed subjects showed a different pattern of recognized HLA-I-restricted T-cell epitopes than patients with a severe COVID-19.…”

“…In summary, our study and the already available publications strongly suggest that SARS-CoV-2 reactive CD4 + and CD8 + T-cells are prevalent in a substantial proportion of subjects in the human populations, presumably induced by circulating common cold coronaviruses. A growing number of studies is indicating that the SARS-CoV-2-specific T-cells seem to be beneficial in patients with SARS-CoV-2 infection ( 4 , 6 – 9 , 12 , 34 ). Although it is suggestive, that such pre-existing beta-coronavirus cross-reactive T-cells could influence the susceptibility to SARS-CoV-2 or the severity of COVID-19, prospective studies are needed to investigate whether the presence of cross-reactive T-cells before the acquisition of SARS-CoV-2 indeed contributes to the striking variation of the clinical course of COVID-19 in patients.…”

“…SARS-CoV-2-specific CD8 + T-cells have been reported both in patients with active COVID-19 disease ( 6 ) and in COVID-19 convalescent patients ( 4 ). Although recent reports indicated that patients with milder COVID-19 disease had stronger SARS-CoV-2-specific T-cell responses than patients with severe COVID-19 ( 10 , 11 ), the contribution of SARS-CoV-2-specific CD8 + T-cells and their targeted epitopes for the control of SARS-CoV-2 is still undefined ( 12 ). SARS-CoV-2-specific T-cells have also been described in SARS-CoV-2-uninfected subjects ( 4 , 6 , 8 , 9 , 13 ).…”

Immunoinformatics and reverse vaccinomic approaches for effective design

“…They also discovered cross-reactive asymptomatic epitopes that induced strong B-cell and T-cell responses in “humanized” human leukocyte antigen (HLA)-Dr/HLA-A*02:01 double transgenic mice and recalled B-cell, CD4+, and CD8+ T-cell responses in both asymptomatic COVID-19 patients and healthy individuals who had never been exposed to SARS-CoV-2. The findings herein pave the way to develop a preemptive multiepitope pan-Coronavirus vaccine to protect against past, current, and potential future outbreaks ( Prakash et al, 2020 ).…”