Genome-Wide B Cell, CD4+, and CD8+ T Cell Epitopes That Are Highly Conserved between Human and Animal Coronaviruses, Identified from SARS-CoV-2 as Targets for Preemptive Pan-Coronavirus Vaccines

Abstract

Over the last two decades, there have been three deadly human outbreaks of coronaviruses (CoVs) caused by SARS-CoV, MERS-CoV, and SARS-CoV-2, which has caused the current COVID-19 global pandemic. All three deadly CoVs originated from bats and transmitted to humans via various intermediate animal reservoirs. It remains highly possible that other global COVID pandemics will emerge in the coming years caused by yet another spillover of a bat-derived SARS-like coronavirus (SL-CoV) into humans. Determining the Ag and the human B cells, CD4 1 and CD8 1 T cell epitope landscapes that are conserved among human and animal coronaviruses should inform in the development of future pan-coronavirus vaccines. In the current study, using several immunoinformatics and sequence alignment approaches, we identified several human B cell and CD4 1 and CD8 1 T cell epitopes that are highly conserved in 1) greater than 81,000 SARS-CoV-2 genome sequences identified in 190 countries on six continents; 2) six circulating CoVs that caused previous human outbreaks of the common cold; 3) nine SL-CoVs isolated from bats; 4) nine SL-CoV isolated from pangolins; 5) three SL-CoVs isolated from civet cats; and 6) four MERS strains isolated from camels. Furthermore, the identified epitopes: 1) recalled B cells and CD4 1 and CD8 1 T cells from both COVID-19 patients and healthy individuals who were never exposed to SARS-CoV-2, and 2) induced strong B cell and T cell responses in humanized HLA-DR1/HLA-A*02:01 double-transgenic mice. The findings pave the way to develop a preemptive multiepitope pancoronavirus vaccine to protect against past, current, and future outbreaks.

Impaired Priming of SARS-CoV-2-Specific Naive CD8+ T Cells in Older Subjects

“…SARS-CoV-2 is the causative agent of the coronavirus disease 2019 (COVID- 19), whose mortality rate progressively increases with age (1). Although clear correlates of protection are still unknown, studies suggest that an uncoordinated adaptive immunity, and in particular the lack of virus-specific cellular responses, is associated with severe forms of disease (2,3).…”

Possible Targets of Pan-Coronavirus Antiviral Strategies for Emerging or Re-Emerging Coronaviruses

“…However, under the pressure of host selections (including gene editing and immune response) [ 76 ], viral mutations in the prevalent strains can weaken the recognition mediated by the monoclonal antibodies and polyclonal human serum [ 77 , 78 ]. For example, SARS-CoV-2 undergoes continuous mutations and may finally exist as more toxic and/or more infectious variants [ 79 ], which have been circulating in Britain (B.1.1.7), South Africa (B.1.351), Brazil (P.1), India (B.1.617), and other countries recently. Furthermore, SARS-CoV-2 isolated from an immunocompromised person contains 57% and 38% mutations in the spike and its RBD, respectively [ 80 ].…”

“…Another strategy is to identify cross-reactive CD4 + and CD8 + T cell epitopes, which are highly conserved in human and animal coronaviruses, as the immune targets of the pan-coronaviruses vaccines [ 79 , 89 , 101 , 102 ]. Using immuno-informatics and sequence alignments, Prakash and colleagues identified 27 highly conserved potential human CD8 + T cell epitopes and 16 potential CD4 + T cell epitopes, which are conserved in the genome of SARS-CoV-2 and its circulating variants, the four major common cold coronaviruses (hCoV-OC43, hCoV-229E, hCoV-HKU1, and hCoV-NL63), and several SARS-like-CoV strains from bats and pangolins [ 79 ]. The replicase polyprotein ORF1ab appeared to be the most immunodominant Ag to stimulate cross-reactive CD4 + and CD8 + T cells and recall specific memory CD4 + T and CD8 + T cells, followed by the spike glycoprotein [ 79 ].…”

“…Using immuno-informatics and sequence alignments, Prakash and colleagues identified 27 highly conserved potential human CD8 + T cell epitopes and 16 potential CD4 + T cell epitopes, which are conserved in the genome of SARS-CoV-2 and its circulating variants, the four major common cold coronaviruses (hCoV-OC43, hCoV-229E, hCoV-HKU1, and hCoV-NL63), and several SARS-like-CoV strains from bats and pangolins [ 79 ]. The replicase polyprotein ORF1ab appeared to be the most immunodominant Ag to stimulate cross-reactive CD4 + and CD8 + T cells and recall specific memory CD4 + T and CD8 + T cells, followed by the spike glycoprotein [ 79 ]. The memory CD4 + T cells stimulated by intranasal vaccination in the airway have strong protection against human coronaviruses [ 101 ].…”

Degenerate CD8 Epitopes Mapping to Structurally Constrained Regions of the Spike Protein: A T Cell-Based Way-Out From the SARS-CoV-2 Variants Storm

“…Thirty-one amino acid substitutions and three amino acid deletions arising from multiple selected mutations have been identified by comparing the in silico translated spike polypeptide sequences derived from the UK (Alpha), South-African (Beta), Brazilian (Gamma), Californian (Epsilon), Indian (Delta) VoCs, as well as Nigerian (Eta) and New Yorker (Iota) VoIs with the sequence of the original Wuhan SARS-Cov-2 strain (GISAID data base -https://cov.lanl.gov/content/index) (44)(45)(46)(47)(48)(49)(50)(51)(52)(53)(54)(55). Twentythree of these amino acid changes are located in spike regions that encompass recently described CD8 epitopes and account for a total of 35 CD8 T cell epitopes with mutated sequences (56)(57)(58)(59)(60)(61)(62). The remaining 11 variant mutations, instead, do not affect any known CD8 epitope.…”