“Abstract: The spike protein receptor-binding domain (RBD) of SARS-CoV-2 is the molecular target for many vaccines and antibody-based prophylactics aimed at bringing COVID-19 under control. Such a narrow molecular focus raises the specter of viral immune evasion as a potential failure mode for these biomedical interventions. With the emergence of new strains of SARS-CoV-2 with altered transmissibility and immune evasion potential, a critical question is this: how easily can the virus escape neutralizing antibodies (nAbs) targeting the spike RBD? To answer this question, we combined an analysis of the RBD structure-function with an evolutionary modeling framework. Our structure-function analysis revealed that epitopes for RBD-targeting nAbs overlap one another substantially and can be evaded by escape mutants with ACE2 affinities comparable to the wild type, that are observed in sequence surveillance data and infect cells in vitro. This suggests that the fitness cost of nAb-evading mutations is low. We then used evolutionary modeling to predict the frequency of immune escape 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 high numbers due to neutral genetic variation, and consequently resistance to vaccines or other prophylactics that rely on one or two antibodies for protection can develop quickly and repeatedly- under positive selection. Predicted resistance timelines are comparable to those of the decay kinetics of nAbs raised against vaccinal or natural antigens, raising a second potential mechanism for loss of immunity in the population. Strategies for viral elimination should therefore be diversified across molecular targets and therapeutic modalities…
Introduction: … [T]he evolutionary rate prior to the widespread deployment of vaccines or development of natural immunity (based primarily on neutral genetic drift) may underestimate the evolutionary potential of the virus to evade nAbs deployed as active immunity (vaccines) or passive immunity (nAb prophylactics). When nAbs are broadly present in the population, population-level selection for antibody-evading, infection-competent viral mutants may result in a rapid resurgence of SARS-CoV-2 infections…
Discussion: … Evidence from multiple experimental studies … suggests that specific single mutants may be able to evade spike-targeting vaccinal immunity in many individuals and rapidly lead to spread of vaccine-resistant SARS-CoV-2. One variant that can escape convalescent plasma neutralization is already circulating in South Africa and could experience greater positive selection pressure once vaccines are deployed widely…
Finally, the overall size of the pandemic in terms of number of active infections will play a significant role in whether the virus can be brought under control with nAb prophylactics or vaccines. The speed at which nAb resistance develops in the population increases substantially as the number of infected individuals increases, suggesting that complementary strategies to prevent SARS-CoV-2 transmission that exert specific pressure on other proteins (e.g., antiviral prophylactics) or that do not exert a specific selective pressure on the virus (e.g., high-efficiency air filtration, masking, ultraviolet air purification) are key to reducing the risk of immune escape. In this context, vaccines that do not provide sterilizing immunity (and therefore continue to permit transmission) will lead to the buildup of large standing populations of virus, greatly increasing the risk of immune escape.”
This paper was published under Open Access.