This SARS-CoV-2 Variant Correlates Strongly with Fatality Rates Across Countries
By Shin Jie Yong, May 30, 2020. G614 variant evades the host immune response, molecular modeling finds, which could complicate vaccine design.

Image by Inactive_account_ID_249 from Pixabay

SARS-CoV-2, the virus that causes Covid-19, mutates like any other viruses. An early bioinformatics study has documented mutations in SARS-CoV-2 isolated from Italy. Another phylogeny study, which I narrated here, revealed three clusters of SARS-CoV-2 — with isolates from Italy and Iran being in a group rather distinct from that of other countries.

Soon, scientists started naming the different SARS-CoV-2 variants. Though variants of a virus do not necessarily mean it’s medically relevant. Some mutations simply do not lead to a change in function. However, one variant called the G614 has probed much curiosity within the scientific community.

Note that this article is not about the pre-print paper — suggesting that G614 mutation confers increased transmissibility — that has sparked controversy.


G614 Variant and Case Fatality Rates (CFRs)

“Among such variants, 23403A>G variant (p.D614G) in spike protein B-cell epitope is observed frequently in European countries, such as the Netherlands, Switzerland, and France, but seldom observed in China,” researchers in the United States discovered in their bioinformatics study.

The D614G mutation results from the change in the amino acid at position 614, from aspartic acid (D) to glycine (G) — thus, D-614-G.

This mutation gives rise to two variants — D614 and G614 — implying either D or G amino acid at position 614.

Later, a study published this May took the implications of the G614 variant to the next level. Researchers at the NYU Langone Health institute correlate the prevalence of G614 variant to the case fatality rates (CFRs; deaths divided by the total number of diagnoses within a specific time frame) of Covid-19 in 12 different countries.

European countries such as Italy, Belgium, France, and Brazil have the highest prevalence of the G614 variant. In contrast, countries in the Far East, such as China, Australia, and Japan, have the lowest.

And the G614 variant prevalence correlated strongly with the CFRs across countries.

“For example, the proportion of recorded viruses in China exhibiting G614 was less than 1%, and this country exhibited the second-lowest average or median CFRs,” the study authors wrote.

The data also explains the higher death toll in New York compared to other states in the United States. The prevalence of G614 in New York is 82.5% with total deaths of 6268 as of 9th of April 2020. Other states like Washington, Oregon, and California have low G614 prevalence (16.3%, 25%, and 26.7%, respectively) and death toll (431, 38, and 507, respectively) — “revealing dramatically lower G614 and the absolute number of fatalities in Western USA states,” they wrote.

The authors admitted a few flaws in their analysis. Disease comorbidity, diagnostic testing, fatality reporting, social distancing practices may differ between countries. Also, the United Kingdom has unusually high CFRs which weakens the correlation strength (see the red dot), from statistically significant R² of >0.45 to nonsignificant R² >0.2.


Free-access source: Becerra-Flores M, Cardozo T. SARS-CoV-2 viral spike G614 mutation exhibits higher case fatality rate [published online ahead of print, 2020 May 6]. Int J Clin Pract. 2020;10.1111/ijcp.13525. doi: 10.1111/ijcp.13525


G614 Variant and Molecular Modelling

The same Langone Health study further did biophysical molecular modeling of SARS-CoV-2 variants. Compared to the original D614, the new G614 variant has a less stable spike protein. So, the G614 variant has a less binding affinity to host cell receptors and is less infectious. Although whether this variant has a different transmission capacity is not yet determined.

“This suggests that the mechanism by which G614 viruses cause greater fatality is immunologic rather than virologic,” the authors wrote. “Namely, that the form that binds the receptor less well is also better shielded from the host immune system attack.”

As a result, the immune system may deploy ineffective antibodies against the virus. Essentially, the G614 variant better evades the immune system than the D614 variant. And this phenomenon is not new to SARS-CoV-2. Viruses like HIV and respiratory syncytial virus (RSV) use a similar tactic to hide from antibodies generated by the immune system, they said.


Could G614 Variant Complicate Vaccine Development?

Whether the G614 variant will be called a new strain of SARS-CoV-2 would require further consensus. Any genetic mutation in the virus genome can be referred to as variant. To qualify as a strain, the new variant has to exhibit a distinct biological function.

If it does, then the G614 variant may impede vaccine design. “One of the immediate questions involves the impact of this and other mutations on vaccine efficiency and the potential need to develop multiple candidate vaccines that cover a range of epitopes and their variants,” the professor of medicine and director of the Urban Community Cardiology Program at New York University, Richard A. Stein wrote in an editorial response to the Langone Health study.

Going back to the US study that discovered the G614 variant, the authors stated that “the highly prevalent [G614] variant in the European population may cause antigenic drift, resulting in vaccine mismatches that offer little protection to that group of patients.” This possibility must be considered “in the design of a “one size fits all” universal vaccine to offer protection against the deadliest outbreak in this century.”