Abstract
Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2)-specific cellular immune response has been shown to play a critical role in preventing severe illness or death in patients infected with SARS-CoV-2 or its variants. Given the multiple T-cell epitopes shared by wild-type virus and its variants, we hypothesized that vaccines that target multiple T-cell epitopes of SARS-CoV-2 may provide a “universal protection” against the wild-type virus as well as its variants, even the heavily mutated ones. To test this, we assessed SARS-CoV-2-specific T-cell precursors in healthy individuals using overlapping peptide pools of SARS-CoV-2 structural and functional proteins, including spike (S), membrane (M), envelope (E), nucleocapsid (N), and protease (P) proteins as target antigens. Diverse T-cell precursor frequencies specific to these viral antigens were detected in healthy individuals, including high, medium, low, and no responders. This was further confirmed by efficient induction of anti-SARS-CoV-2 T-cell immune responses using ex vivo dendritic cell (DC)/T cell coculture. The results demonstrated T-cell responses consistent with the precursor frequencies of each of the individuals tested. Importantly, the combination of all five viral peptide pools induced the strongest cellular immune response, and further, after a DC-peptides re-stimulation, even the no responders developed an increased anti-viral T-cell response. These analyses recapitulate the presence of a broad anti-SARS-CoV-2 cellular immunity even in an immune naïve population, which could be enhanced by antigen presenting cells presenting the overlapping antigenic peptides. Given the critical role of cellular immunity in COVID-19 protection, these results have important implications for vaccine design and immunotherapy in fighting SARS-CoV-2 and its variants.
Highlights
The clinical manifestations of COVID-19 are variable, ranging from asymptomatic to mild, moderate, and severe illness with systemic complications, including acute respiratory distress syndrome (ARDS), acute heart injury, and secondary infections [1,2], as well as cytokine storm caused by acute and excessive inflammatory response locally and systemically [3]
Recent studies reveal the existence of broad virus-specific T-cell responses in asymptomatic carriers, which further highlights a critical role of cellular immunity in development of the COVID-19 vaccines [13,14]
To identify potential vaccine targets, we analyzed the genes of all structural proteins of SARS-CoV-2, including S, M, E, N, and the polyprotein cleavage protease (P), and synthesized selected pools of pentadecamer peptides spanning across functional domains of these polyproteins, including the receptor-binding domain (RBD) of S protein, the full-length of E and M proteins (M being the most abundant protein of coronavirus), and the nucleic acid binding domain (NBD) plus the serine-arginine rich (SR) domains including the helix-turn-helix motif of N protein, and the domain III of Mpro (Figure 1A,B)
Summary
The clinical manifestations of COVID-19 are variable, ranging from asymptomatic to mild, moderate, and severe illness with systemic complications, including acute respiratory distress syndrome (ARDS), acute heart injury, and secondary infections [1,2], as well as cytokine storm caused by acute and excessive inflammatory response locally and systemically [3]. Robust T-cell immunity was detected in convalescent individuals with asymptomatic or mild COVID-19, suggesting that T-cell immunity may play a key role in preventing the transition from mild to severe illness during infection. Antibody-dependent enhancement (ADE) of viral entry has been a major concern for viral epidemiology and vaccine development. There have been concerns for the ADE effect with the SARS-CoV-2 vaccines, where antibodies may facilitate viral entry into host cells and enhance viral infection, as has been observed in the dengue infection and HIV-1 vaccine development [9,10]. Recent studies reveal the existence of broad virus-specific T-cell responses in asymptomatic carriers, which further highlights a critical role of cellular immunity in development of the COVID-19 vaccines [13,14]
Sign-in/Register to view highlights & summary Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
