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D614G Spike Mutation Increases SARS CoV-2 Susceptibility to Neutralization

Our take —

The D614G mutation in SARS-CoV-2 spike protein is unlikely to alter immunogenicity and derail current mRNA vaccines in development. Other vaccine platforms remain to be tested, but there is no evidence to suggest that their efficacy would be compromised by D614G. These results are altogether not surprising, as residue 614 in the spike proteiin is not part of the receptor-binding domain (RBD), and regions within the RBD are thought to be the primary immunodominant epitopes. Thus, relatively little concern was present a priori that this mutation would drastically alter SARS-CoV-2 immunogenicity.

Study design

Other

Study population and setting

The mutation D614G in the spike glycoprotein (S) has garnered much attention and concern with SARS-CoV-2. Recent findings suggest this mutation may increase the in vitro infectivity of the virus and possibly the viral load in patients, although it is not thought to increase virulence. This study assessed the in vitro neutralization titers of sera from mice, non-human primates, and humans immunized with one of four different mRNA vaccines against lentiviral particles pseudotyped with full-length SARS-CoV-2 S bearing either the D614 or G614 polymorphism.

Summary of Main Findings

All four versions of the mRNA vaccine tested, which included the immunogens used in both the Moderna and BioNTech vaccines, which are currently in clinical trials, elicited similar in vitro neutralizing titers against both D614 and G614, with slightly higher neutralizing titers against the latter. Furthermore, sera from humans and macaques, which received mRNA vaccines encoding only for secreted RBD, also demonstrated this trend, suggesting that despite not being a structural component of the RBD, changes in residue 614 may elicit a conformational change in the RBD that simultaneously renders it both more capable of binding its ACE2 receptor and more susceptible to neutralizing antibodies.

Study Strengths

Sera from both vaccinated animals and humans (from Phase I/II clinical trials) is utilized. The pseudotyped lentiviral particle system provides a very controlled environment in which to test only one variable: the D614G mutation.

Limitations

Only mRNA vaccine platforms were tested, as the authors note, and these constitute only a portion of the vaccine candidates currently in clinical and preclinical development. The in vitro studies performed with HEK293T/ACE2 cells and pseudotyped lentiviral particles, rather than SARS-CoV-2, are highly artificial, and the real-world applicability of the results is likely limited to some degree, as the authors acknowledge. Finally, the immunological correlates of protection against SARS-CoV-2 are yet to be definitively established, and although evidence suggests that neutralizing antibodies likely play an important role, other parameters (e.g. T-cell response) may prove equally important and are not evaluated here.

Value added

This is the first study to evaluate neutralizing titers generated from vaccination with mRNA platforms in the context of the prevalent D614G S mutation.

This review was posted on: 14 August 2020