Significance
The rapid emergence of SARS-CoV-2 variants that efficiently spread and evade antibody-based treatments underscores the need for countermeasures that remain effective as the virus evolves. In this study, two human mAbs, TAU-1109 and TAU-2310, isolated from individuals who recovered from SARS-CoV-2 infection early in the pandemic, neutralize all tested variants of concern, including recent Omicron sublineages. Structural and functional analyses show that these antibodies recognize conserved, cryptic regions on the spike’s RBD and disable the virus by destabilizing the spike trimer and triggering premature loss of the S1 subunit, thereby preventing cell entry. These findings reveal a naturally occurring, broadly protective antibody mechanism and highlight conserved surfaces on the receptor-binding domain as promising blueprints for next-generation COVID-19 therapies and vaccines.
Abstract
The COVID-19 pandemic, which has resulted in over seven million global fatalities, poses a substantial threat to public health and precipitated a global economic crisis. Emerging variants of concern (VOCs) with enhanced transmissibility and improved immune evasion may compromise the efficacy of current antiviral and immunotherapies, necessitating comprehensive investigations into the immune response to SARS-CoV-2. The conformational dynamics of the receptor binding domain in SARS-CoV-2 spike and the presentation of neutralizing antibody epitopes influence viral transmission and infection rates. In this study, we have identified highly conserved non-receptor-binding motif epitopes for two potent monoclonal antibodies (mAbs), TAU-1109 and TAU-2310, isolated from convalescent human patients, which contribute to the broad neutralizing activity of these mAbs against all the circulating VOCs, including the recently emerged Omicron subvariants. We employed high-resolution structural data in conjunction with systematic biochemical investigation to elucidate the neutralization mechanism of TAU-1109 and TAU-2310. The mechanism involves antibody-mediated destabilization of the spike trimer, resulting in the premature shedding of the S1 subunit and rendering the spike incapable of mediating host cell entry. The identification of conserved cryptic epitopes in our study advances the mechanistic understanding of immune response against SARS-CoV-2, providing alternative avenues for the development of universal therapeutic antibodies and vaccines to combat COVID-19.
Source:
Link: https://www.pnas.org/doi/abs/10.1073/pnas.2523864123?af=R
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