D614G Spike Mutation Increases SARS CoV-2 Susceptibility to Neutralization

Abstract

The SARS-CoV-2 Spike protein acquired a D614G mutation early in the COVID-19 pandemic that appears to confer on the virus greater infectivity and now globally is the dominant form of the virus. Certain of the current vaccines entering phase 3 trials are based on the early D614 form of Spike with the goal of eliciting protective neutralizing antibodies. To determine whether D614G mediates neutralization-escape that could compromise vaccine efficacy, sera from Spike-immunized mice, nonhuman primates and humans were evaluated for neutralization of pseudoviruses bearing either D614 or G614 Spike on their surface. In all cases, G614 Spike pseudovirions were moderately more susceptible to neutralization, indicating this is not an escape mutation that would impede current vaccines. Rather, the gain in infectivity provided by D614G came at the cost of making the virus more vulnerable to neutralizing antibodies.

Paired heavy and light chain signatures contribute to potent SARS-CoV-2 neutralization in public antibody responses

“…Conversely, a sustained RBD 'up' also could make the virus more sensitive to neutralization, as the exposed 'up' RBD enhances exposure of vulnerable epitopes (Mansbach et al, 2020;Zhou et al, 2020c). We outlined differences in RBD display caused by the D614G mutation that enhance antibody class recognition of spike across a broad pH range, and we show that D614G had no detrimental impact on IGHV3-53/3-66 antibody class neutralization, which agrees with prior reports (Plante et al, 2020;Weisblum et al, 2020;Weissman et al, 2020). Interestingly, only the most potent antibodies could bind to the D614 variant at endosomal pH which demonstrated that high-affinity antibody recognition can prevent D614 RBD from rotating down at pH 5.5-4.5.…”

Safety and immunogenicity of an inactivated SARS-CoV-2 vaccine, BBV152: a double-blind, randomised, phase 1 trial

“…The BBV152 vaccine strain, based on the Asp614Gly mutation, has been reported to have differential sensitivity to neutralisation by vaccine-elicited antibodies or by antibodies produced by natural infection. 36 , 37 The increase in Asp614Gly infectivity results in the virus being more susceptible to neutralising antibodies, 38 which is corroborated by marginal reductions in neutralising titres in the PRNT 50 assays with heterologous strains, which are devoid of the Asp614Gly mutation.…”

Anti-SARS-CoV-2 neutralizing monoclonal antibodies: clinical pipeline

“…The SARS-CoV-2 spike protein mutated after few months of viral circulation, 59 with one mutation outside the receptorbinding motif (23403A >G single nucleotide polymorphism, corresponding to D614G amino acid change), currently defining a dominant clade 60 characterized by reduced S1 shedding and increased infectivity. 61 Althouh particular mutation increases the susceptibility to neutralization, 62,63 only a few of these candidate drugs have been tested for their capability of neutralizing different strains of SARS-CoV-2. Antibody cocktails theoretically reduce the ability of mutant viruses to escape treatment and protect against spike variants that have already arisen in the human population.…”