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

  1. Yuan Hu
  2. Lee W. Riley

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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.

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  1. ScreenIT

    SciScore for 10.1101/2020.07.13.20152959: (What is this?)

    Please note, not all rigor criteria are appropriate for all manuscripts.

    Table 1: Rigor

    Institutional Review Board Statementnot detected.
    Randomizationnot detected.
    Blindingnot detected.
    Power Analysisnot detected.
    Sex as a biological variablenot detected.

    Table 2: Resources

    Software and Algorithms
    SentencesResources
    Duplicate and low-quality sequences (>5% NNNNs) were removed and alignment of 34,417 sequences was created based on the sequence multiple alignment program MAFFT (20) by GISAID.
    MAFFT
    suggested: (MAFFT, RRID:SCR_011811)
    Subclade analysis: All analysis was conducted with R package dplyr (23) and graphically plotted with ggplot2 (24).
    ggplot2
    suggested: (ggplot2, RRID:SCR_014601)

    Results from OddPub: We did not detect open data. We also did not detect open code. Researchers are encouraged to share open data when possible (see Nature blog).

    Results from LimitationRecognizer: We detected the following sentences addressing limitations in the study:
    The limitation of the findings of our study is that they are based on sequences deposited in the GISAID database, most of which do not have patient clinical data. Hence, the associations we found between high CFRs and co-circulation of the dominant SARS-CoV2 lineages are an ecologic observation. In addition, the number of sequences submitted from each country and region vary greatly and may not necessarily be representative of the strains circulating in these places. Nevertheless, it is striking that the two subclades of the virus were consistently observed to dominate in Europe and the United States. A similar observation was reported by others based on analyses of the sequences deposited in the GISAID database from earlier periods (3, 12, 13).

    Results from TrialIdentifier: No clinical trial numbers were referenced.

    Results from Barzooka: We did not find any issues relating to the usage of bar graphs.

    Results from JetFighter: We did not find any issues relating to colormaps.

    Results from rtransparent:
    • Thank you for including a conflict of interest statement. Authors are encouraged to include this statement when submitting to a journal.
    • Thank you for including a funding statement. Authors are encouraged to include this statement when submitting to a journal.
    • No protocol registration statement was detected.

    About SciScore

    SciScore is an automated tool that is designed to assist expert reviewers by finding and presenting formulaic information scattered throughout a paper in a standard, easy to digest format. SciScore checks for the presence and correctness of RRIDs (research resource identifiers), and for rigor criteria such as sex and investigator blinding. For details on the theoretical underpinning of rigor criteria and the tools shown here, including references cited, please follow this link.

  2. ScreenIT

    SciScore for 10.1101/2020.07.13.20152959: (What is this?)

    Please note, not all rigor criteria are appropriate for all manuscripts.

    Table 1: Rigor

    NIH rigor criteria are not applicable to paper type.

    Table 2: Resources

    Experimental Models: Cell Lines
    SentencesResources
    Indeed, another report showed that the SARS-CoV2 G614 spike protein is more stable than the D614 protein and that a pseudovirus (based on Maloney murine leukemia virus) expressing G614 was able to infec human ACE2-expressing HEK293T cells more efficiently than that expressing the D614 protein (18).
    HEK293T
    suggested: None
    Software and Algorithms
    SentencesResources
    Duplicate and low-quality sequences (>5% NNNNs) were removed and alignment of 34,417 sequences was created based on the sequence multiple alignment program MAFFT (20) by GISAID.
    MAFFT
    suggested: (MAFFT, SCR_011811)
    Subclade analysis: All analysis was conducted with R package dplyr (23) and graphically plotted with ggplot2 (24).
    ggplot2
    suggested: (ggplot2, SCR_014601)

    About SciScore

    SciScore is an automated tool that is designed to assist expert reviewers by finding and presenting formulaic information scattered throughout a paper in a standard, easy to digest format. SciScore is not a substitute for expert review. SciScore checks for the presence and correctness of RRIDs (research resource identifiers) in the manuscript, and detects sentences that appear to be missing RRIDs. SciScore also checks to make sure that rigor criteria are addressed by authors. It does this by detecting sentences that discuss criteria such as blinding or power analysis. SciScore does not guarantee that the rigor criteria that it detects are appropriate for the particular study. Instead it assists authors, editors, and reviewers by drawing attention to sections of the manuscript that contain or should contain various rigor criteria and key resources. For details on the results shown here, including references cited, please follow this link.

  3. Version published to 10.1101/2020.07.13.20152959 on medRxiv