Dissemination and co-circulation of SARS-CoV2 subclades exhibiting enhanced transmission associated with increased mortality in Western Europe and the United States

Abstract

Mechanisms underlying the acute respiratory distress syndrome (ARDS)-like clinical manifestations leading to deaths in patients who develop COVID-19 remain uncharacterized. While multiple factors could influence these clinical outcomes, we explored if differences in transmissibility and pathogenicity of SARS-CoV2 variants could contribute to these terminal clinical consequences of COVID-19. We analyzed 34,412 SARS-CoV2 sequences deposited in the Global Initiative for Sharing All Influenza Data (GISAID) SARS-CoV2 sequence database to determine if regional differences in circulating strain variants correlated with increased mortality in Europe, the United States, and California. We found two subclades descending from the Wuhan HU-1 strain that rapidly became dominant in Western Europe and the United States. These variants contained nonsynonymous nucleotide mutations in the Orf1ab segment encoding RNA-dependent RNA polymerase (C14408T), the spike protein gene (A23403G), and Orf1a (G25563T), which resulted in non-conservative amino acid substitutions P323L, D614G, and Q57H, respectively. In Western Europe, the A23403G-C14408T subclade dominated, while in the US, the A23403G-C14408T-G25563T mutant became the dominant strain in New York and parts of California. The high cumulative frequencies of both subclades showed inconsistent but significant association with high cumulative CFRs in some of the regions. When the frequencies of the subclades were analyzed by their 7-day moving averages across each epidemic, we found co-circulation of both subclades to temporally correlate with peak mortality periods. We postulate that in areas with high numbers of these co-circulating subclades, a person may get serially infected. The second infection may trigger a hyperinflammatory response similar to the antibody-dependent enhancement (ADE) response, which could explain the ARDS-like manifestations observed in people with co-morbidity, who may not mount sufficient levels of neutralizing antibodies against the first infection. Further studies are necessary but the implication of such a mechanism will need to be considered for all current COVID-19 vaccine designs.

GESS: a database of global evaluation of SARS-CoV-2/hCoV-19 sequences

“…Even though there were very limited SARS-CoV-2 complete genome data, many individual studies reported that the virus had gradually accumulated genomic sequence alterations, which were commonly seen in different widely spread viral strains. Particularly, single-nucleotide variants (SNVs) and other types of mutations were found in diverse countries/areas and across multiple time points ( 2 , 3 ) within the 29 903-nucleotide (nt) SARS-CoV-2 complete genome. The SNVs might have potential influence on the viral infectivity, or affect the biological functions, or shape protein structures, such as A23403G causing an AA change on Spike protein: D614G, and mutations on the viral Nsp6 and ORF10 ( 4–6 ).…”

Dominant Clade-featured SARS-CoV-2 Co-occurring Mutations Reveals Plausible Epistasis: An in silico based Hypothetical Model

“…The GH strains were mainly restricted to the USA and partly Eastern Mediterranean (Fig. 1), and mostly spread by cryptic 159 and pre/a-symptomatic transmission 160 . These variants might trade-off virulence by a slower release of virions, and in exchange, benefited from the induction of low immune response in asymptomatic hosts.…”

“…After the public awareness and other social interventions, these strains, especially GR have probably increased in fitness. Although Hu and Riley 159 have recently reported the co-circulation of both G and GH strains correlating with mortality in different states, how the association among multiple clades would modulate the evolutionary dynamics is now a burning question. With the new data of GV strains as shown in our study, the previous analysis by Hodcroft et al (2020) 24 can be updated to recent time that may change result of the association.…”

Infection with different strains of SARS-COV-2 in patients with COVID-19

“…This limitation in viral confrontation can be attributed to many causes, such as failure to adhere to measures of social distancing, the presence of concomitant chronic diseases strongly correlated to mortality (comorbidities), the preparedness of health systems to cope with the pandemic, and other related factors [3]. Despite the rapid progress of phylogenetic analysis and genetic mapping of SARS-CoV-2, the incidence of concomitant mixed infections with different strains has not been reported [4]. SARS-CoV-2 is similar to SARS-CoV, which resulted in an epidemic in China in 2002.…”