Risk of rapid evolutionary evasion of biomedical interventions targeting the SARS-CoV-2 spike protein


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PLoS One. April 28, 2021; 16 (4): e0250780. doi: 10.1371 / journal.pone.0250780. eCollection 2021.


The spike protein receptor (RBD) binding domain of SARS-CoV-2 is the molecular target of many vaccines and antibody-based prophylactics aimed at controlling COVID-19. Such a narrow molecular focus raises the specter of viral immune escape as a potential mode of failure for these biomedical interventions. With the emergence of new strains of SARS-CoV-2 with altered transmissibility and the potential for immune evasion, a crucial question is: how easily can the virus escape neutralizing antibodies (nAbs) targeting the peak RBD? To answer this question, we combined an RBD structure-function analysis with an evolving modeling framework. Our structure-function analysis revealed that the epitopes for nAbs targeting RBD overlap considerably and can be avoided by escape mutants with ACE2-comparable affinities to wild-type, which are observed in sequence surveillance data and infect cells in vitro. This suggests that the cost of reshaping nAb-avoiding mutations is low. We then used evolutionary modeling to predict the frequency of immune leakage before and after the widespread presence of nAbs due to vaccines, passive immunization or natural immunity. Our modeling suggests that SARS-CoV-2 mutants with one or two mildly deleterious mutations are expected to exist in large numbers due to neutral genetic variation, and therefore resistance to vaccines or other prophylactic agents that rely on one or two antibodies for protection can develop quickly. -and several times- under positive selection. The predicted times of resistance are comparable to those of the decay kinetics of nAbs raised against vaccine or natural antigens, which raises a second potential mechanism of loss of immunity in the population. Viral elimination strategies must therefore be diversified according to molecular targets and therapeutic modalities.

PMID:33909660 | DO I:10.1371 / journal.pone.0250780

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