Abstract
As COVID-19 cases continue to rise, it is imperative to learn more about antibodies and T-cells produced against the causative virus, SARS-CoV-2, in order to guide the rapid development of therapies and vaccines. While much of the current antibody and vaccine research focuses on the receptor-binding domain of S1, a less-recognized opportunity is to harness the potential benefits of the more conserved S2 subunit. Similarities between the spike proteins of both SARS-CoV-2 and HIV-1 warrant exploring S2. Possible benefits of employing S2 in therapies and vaccines include the structural conservation of S2, extant cross-reactive neutralizing antibodies in populations (due to prior exposure to common cold coronaviruses), the steric neutralization potential of antibodies against S2, and the stronger memory B-cell and T-cell responses. More research is necessary on the effect of glycans on the accessibility and stability of S2, SARS-CoV-2 mutants that may affect infectivity, the neutralization potential of antibodies produced by memory B-cells, cross-reactive T-cell responses, antibody-dependent enhancement, and antigen competition. This perspective aims to highlight the evidence for the potential advantages of using S2 as a target of therapy or vaccine design.
Highlights
The COVID-19 pandemic continues to be a global public health threat
This study found that nonCOVID-19 sera could neutralize pseudotypes of the S protein with roughly the same efficacy as COVID-19 sera
S2 is less likely than S1 to harbor mutations, and targeting S2 in a therapeutic or vaccine may reduce the risk of vaccine-evasive SARS-CoV-2 variants, which could improve epidemiological outcomes
Summary
The COVID-19 pandemic continues to be a global public health threat. As of January 31, 2021, there have been over 102 million confirmed cases and over 2.2 million confirmed deaths worldwide [1]. Research like this is key, as SARS-CoV-2 variants that are resistant to commonly-elicited nAbs are beginning to appear in humans Accumulation of such neutralization-evasive changes could lead to broader antibody resistance and complicate convalescent plasma and mAb therapies as well as vaccine development due to incomplete protective immunity. Memory B-cells (MBC) against S2 were not found, leading to the hypothesis that the threshold of S2 MBC detection was too high given the levels This hypothesis was consistent with the finding that most of the convalescent sera had higher levels of anti-S2 antibodies than anti-RBD antibodies, which could have been caused by provocation of S2 MBCs. It was hypothesized that MBCs could produce IgG protective against future infection of SARS-CoV-2 and other coronaviruses [41]. If existing T-cell memory due to common cold coronaviruses can combat SARS-CoV-2, a vaccine that elicits that memory could prove to be very effective
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