Could COVID-19 mutations affect transmissibility, outcomes?

The substitution of glycine for aspartic acid at the 614th residue (D614G) of the SARS-CoV-2 spike protein may lead to higher viral loads in younger patients, but has no apparent effect on clinical outcomes and mortality, according to a recent UK study.

“Our analysis emphasizes that while laboratory experiments can identify changes in virus biology, their extrapolation to identify population level effects on transmission requires caution,” the researchers said. “In the case of D614G, a large increase in cellular infectivity results in a weak population-level signal that nonetheless produces a discernible effect on transmissibility.”

From collections between 29 January and 16 June 2020, 21,231 whole genome sequences had the 614G variant, while 5,755 had the 614D variant. The former spike genotype was found in more phylogenetic clusters in the UK and seemed to have arisen later. Compared to 614D, 614G was detected 16 days later on average. [Cell 2020;doi:10.1016/j.cell.2020.11.020]

Early in the course of the pandemic, in February and early March, the frequencies of both variants were near equal. By the end of March, 614G had already become the predominant variant.

Moreover, despite the later emergence of the 614G variant, its infection clusters were on average 59 percent larger than 614D clusters (p=0.008). To examine if this mutation conferred a selective advantage, the researchers fit a logistic growth model to the chronological date of specimen sampling.

They found that 614 polymorphisms in the spike protein alone explains only about 1 percent of the variance in growth rate among clusters. There was also no significant difference in median initial growth rates between the D and G variants (11y vs 169 year^–1; p=0.13), corresponding to similar basic reproduction numbers (3.1 vs 4.0).

Linking viral genome sequence with clinical data, the researchers looked at disease outcomes in 9,782 and 2,533 patients carrying the 614G and 614D spike variants, respectively.

Initial and unadjusted analyses revealed that the G polymorphism seemed to exert a protective effect against mortality (odds ratio [OR], 0.82, 95 percent confidence interval [CI], 0.74–0.90), though this was completely attenuated after controlling for other known risk factors of severe novel coronavirus disease (COVID-19; OR, 1.09, 95 percent CI, 0.97–1.23).

In addition, the D614G substitution did not seem to significantly impact COVID-19 severity.

On the other hand, male sex emerged as a significant risk factor for death (OR, 2.15, 95 percent CI, 1.95–2.36). The same was true for a later chronological time of sampling (coefficient, –5.6, 95 percent CI, –6.68 to –4.62), reflecting on-ground trends in hospitalization priorities and access.

A significant effect of the polymorphism in terms of age distribution was observed. Younger patients tended to carry the 614G variant; women carrying the 614D virus, for instance, were older by a median of 5 years than their 614G counterparts. The median age difference in men was 4 years.

“The probability of carrying 614G virus seems to decrease continuously with age,” the researchers pointed out, explaining that “[t]his is possibly due to an increased viral load in younger patients associated with 614G variants leading to higher detection rates.”

“While we believe an effect on SARS-CoV-2 transmissibility caused by D614G is likely to be present, it is important to note that the estimation of the absolute size of this effect is uncertain and much harder to predict,” they added.