Escape from neutralizing antibodies by SARS-CoV-2 spike protein variants

Abstract

Neutralizing antibodies elicited by prior infection or vaccination are likely to be key for future protection of individuals and populations against SARS-CoV-2. Moreover, passively administered antibodies are among the most promising therapeutic and prophylactic anti-SARS-CoV-2 agents. However, the degree to which SARS-CoV-2 will adapt to evade neutralizing antibodies is unclear. Using a recombinant chimeric VSV/SARS-CoV-2 reporter virus, we show that functional SARS-CoV-2 S protein variants with mutations in the receptor binding domain (RBD) and N-terminal domain that confer resistance to monoclonal antibodies or convalescent plasma can be readily selected. Notably, SARS-CoV-2 S variants that resist commonly elicited neutralizing antibodies are now present at low frequencies in circulating SARS-CoV-2 populations. Finally, the emergence of antibody-resistant SARS-CoV-2 variants that might limit the therapeutic usefulness of monoclonal antibodies can be mitigated by the use of antibody combinations that target distinct neutralizing epitopes.

A Neutralizing Monoclonal Antibody for Hospitalized Patients with Covid-19

“…The enrollment of such patients before the early futility assessment was by design, under the assumption that the greatest effect of an antiviral agent would be observed in patients with less severe illness. Reasons for the lack of benefit for LY-CoV555 in this trial are unknown and may include slow or ineffective penetration of the antibody into infected tissue, minimal intrinsic potency, rapid selection of escape mutants no longer neutralized by the agent, 11 , 12 and harmful effects of the antibody. It has been hypothesized that such harmful effects (which have been described as “antibody-dependent enhancement”) could theoretically be associated with increased viral replication or exaggerated inflammation.…”

Evolution of Antibody Immunity to SARS-CoV-2

“…To determine whether the antibodies expressed by memory B cells at the late time point also showed altered breadth, we compared them to earlier clonal relatives in binding assays using control and mutant RBDs: The mutations E484K and Q493R 15 were selected for resistance to class 2 antibodies such as C144 and C121 that bind directly to the ACE2 interaction ridge in the RBD 1,[16][17][18] while R346S, N439K, and N440K were selected for resistance to class 3 antibodies such as C135 that do not directly interfere with ACE2 binding 1,[15][16][17][18] (Fig.3c). In addition, V367F, A475V, S477N, and V483A represent circulating variants that confer complete or partial resistance to class 1 and 2 antibodies 15,16,19 (Fig. 3c).…”

A human coronavirus evolves antigenically to escape antibody immunity

“…In these respects, coronaviruses unfortunately seem more similar to influenza than measles. The neutralizing antibody response to SARS-CoV-2 is often focused on just a small portion of spike (Barnes et al, 2020;Liu et al, 2020b;Piccoli et al, 2020;Weisblum et al, 2020), and key receptor-binding loops are mutationally tolerant in the spikes of both 229E (Li et al, 2019;Wong et al, 2017) and SARS-CoV-2 (Starr et al, 2020a). Therefore, even though mutations to coronaviruses occur at a lower rate, they are acted on by selection in a fashion more similar to influenza than measles (Kistler and Bedford, 2020).…”

“…Overall, these results suggest that when the neutralizing activity of potent human sera is rapidly eroded by viral evolution this is often due to mutations within the RBD, but that antigenic evolution also occurs elsewhere in the spike. In this respect, it is worth noting that while the neutralizing activity of SARS-CoV-2 immunity elicited by infection primarily targets the RBD (Piccoli et al, 2020), mutations to the NTD also reduce neutralization by some antibodies and sera (Chi et al, 2020;Kemp et al, 2020;Liu et al, 2020a;McCarthy et al, 2020;Weisblum et al, 2020;Zhou et al, 2019)-and some regions of the NTD undergo significant sequence evolution in 229E ( Figure 4A).…”