Discussion
Recent prior bioinformatics analyses have not evaluated the SARS-CoV-2
viral spike in isolation from the rest of the viral genome. The viral
spike protein is relatively invariant, when compared to influenza or
HIV, across worldwide strains, with essentially only one missense
variant so far in the viral spike at amino acid position 614 (D/G),
despite global spread. We here report that the G614 variant correlates
strongly with case fatality rate in a global survey of countries,
suggesting that a higher CFR possibly emerging in the USA East Coast or
other regions affected later in the pandemic may be at least partly a
consequence of this virus-autonomous factor.
Molecular modeling suggests that G614 destabilizes the infectious form
of the viral spike protein, thereby favoring the ground-state,
unliganded, “down” SARS-CoV-2 viral forms that would be expected to
infect less readily, due to masking of the host receptor binding
site. This suggests that the mechanism by which G614 viruses causes
greater fatality is immunologic rather than virologic: namely, that the
form that binds the receptor less well is also better shielded from host
immune system attack and/or elicits harmful anti-viral-spike antibodies
or other harmful immune responses. Indeed, there are several precedents
in other viral diseases: the viral spikes of both HIV and RSV exhibit
unliganded states that do not elicit protective antibodies via
vaccination, and indeed, may elicit antibodies that enhance
disease6,7. Furthermore, disease-enhancing,
immunodominant, antibody-targeted epitopes in the SARS viral spike have
been definitively identified8, and a recent report
emphasized that key cryptic antibody-targeted neutralization epitopes in
the SARS family of viral spikes are accessible only in the conformation
in which the ACE-2 binding site is exposed9.
There are several potential limitations and/or confounding issues in the
data we used to calculate country-by-country CFR. First, the data relies
heavily on diagnostic testing and fatality reporting, which have both
been highly variable in penetrance and accuracy across the countries
studies, at present. For example, China recently revised their fatality
count upward and the United Kingdom is an outlier with an unusually high
CFR, and when included, the correlation weakens (Figure S1 ).
This outlier may be caused by the unusually low incidence of active
cases being reported in the UK during the 2 weeks under study. Selection
bias is unlikely to be a confounder in this analysis, however, since the
same reporting bias would have to occur in the same direction and for
the same reason across all of the global regions, which is unlikely.
Social distancing measures have been implemented in a highly variable
fashion across the countries studied in this report, but the case
fatality rate should be unaffected by social distancing, as it does not
affect the clinical course of viral disease, only acquisition of virus.
Measuring this correlation at this early time point in the pandemic may
be optimal to avoid the confounder of successful medical treatment to
artificially reduce the CFR.
Based on our results, short-term epidemiologic models of the pandemic
that attempt to predict the incidence and prevalence of severe disease
and fatalities over time that do not take the D614 percentage of viruses
in a region into account may be inaccurate. The presence of G614 in a
virus detected in a patient may also have prognostic significance.