RBD E484K Escape Mutation From Convalescent Antibodies

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The most important site is E484, where neutralization by some sera is reduced >10-fold by several mutations, including one in emerging viral lineages in South Africa and Brazil. Going forward, these serum escape maps can inform surveillance of SARS-CoV-2 evolution.

https://www.biorxiv.org/content/10.1101/2020.12.31.425021v1.full.pdf+html

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Comprehensive mapping of mutations to the SARS-CoV-2 receptor-binding domain that affect recognition by polyclonal human serum antibodies

Allison J Greaney,  Andrea N Loes, Katharine HD Crawford, Tyler N Starr, Keara D Malone, Helen Y Chu, Jesse D Bloom

doi: https://doi.org/10.1101/2020.12.31.425021

This article is a preprint and has not been certified by peer review

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Abstract The evolution of SARS-CoV-2 could impair recognition of the virus by human antibody-mediated immunity. To facilitate prospective surveillance for such evolution, we map how convalescent serum antibodies are impacted by all mutations to the spike’s receptor-binding domain (RBD), the main target of serum neutralizing activity. Binding by polyclonal serum antibodies is affected by mutations in three main epitopes in the RBD, but there is substantial variation in the impact of mutations both among individuals and within the same individual over time. Despite this inter- and intra-person heterogeneity, the mutations that most reduce antibody binding usually occur at just a few sites in the RBD’s receptor binding motif. The most important site is E484, where neutralization by some sera is reduced >10-fold by several mutations, including one in emerging viral lineages in South Africa and Brazil. Going forward, these serum escape maps can inform surveillance of SARS-CoV-2 evolution.

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Introduction Neutralizing antibodies against the SARS-CoV-2 spike are associated with protection against infection in both humans (Addetia et al., 2020; Lumley et al., 2020) and animal models (Alsoussi et al., 2020; Walls et al., 2020; Zost et al., 2020a). However, other human coronaviruses undergo antigenic evolution that erodes neutralizing antibody immunity (Eguia et al., 2020). This antigenic evolution is driven by positive selection for mutations in the viral spike, particularly in regions involved in receptor binding (Kistler and Bedford, 2020; Wong et al., 2017). To monitor for similar antigenic evolution of SARS-CoV-2, it is important to determine which viral mutations impact human polyclonal antibody immunity. A multitude of recent studies have identified viral mutations that escape monoclonal antibodies targeting the SARS-CoV-2 spike (Baum et al., 2020; Greaney et al., 2020; Li et al., 2020; Liu et al., 2020b; Starr et al., 2020a; Weisblum et al., 2020). However, it remains unclear how mutations that escape specific monoclonal antibodies will affect the polyclonal antibody response elicited by infection or vaccination. Several recent studies have identified viral mutations that impact neutralization by polyclonal human sera. So far, these studies have relied on either selecting viral escape mutants with reduced neutralization sensitivity (Andreano et al., 2020; Weisblum et al., 2020), or characterizing the antigenic effects of specific mutations such as those observed in circulating viral isolates (Kemp et al., 2020b; Li et al., 2020; Liu et al., 2020b; Thomson et al., 2020). This work has shown that single mutations to the spike’s receptor-binding domain (RBD) or N-terminal domain (NTD) can appreciably reduce viral neutralization by polyclonal sera, sometimes by as much as 10-fold. However, a limitation of these studies is that they characterize an incomplete subset of all possible mutations, and thus do not completely describe the effects of viral mutations on recognition by polyclonal serum antibodies.

Here we comprehensively map how all amino-acid mutations to the SARS-CoV-2 spike RBD affect binding by the antibodies in plasma collected from convalescent individuals ~1 to ~3 months post-symptom onset. We focus on the RBD because prior studies have reported that RBD-binding antibodies contribute the majority of the neutralizing activity of most human sera (Piccoli et al., 2020; Steffen et al., 2020), a result we confirm. Our complete maps of how mutations impact serum antibody binding identify three major epitopes in the RBD. However, serum antibody binding from different individuals is impacted differently by mutations in these epitopes, and sometimes the impacts of mutations also change over time for longitudinal samples from the same individual. Some mutations that reduce serum antibody binding also reduce viral neutralization by >10 fold. The site where mutations tend to have the largest effect on binding and neutralization is E484, which unfortunately is a site where mutations are present in several emerging SARS-CoV-2 lineages (Tegally et al., 2020; Voloch et al., 2020). However, some sera are more affected by mutations at other sites, while others are largely unaffected by any single mutation. Overall, these systematic maps of how mutations to the SARS-CoV-2 RBD affect recognition by human antibody immunity can inform surveillance of ongoing viral evolution.