Increased SAR-CoV-2 shedding associated with reduced disease severity despite continually emerging genetic variants

  1. Cynthia Y. Tang
  2. Yang Wang
  3. Cheng Gao
  4. David R. Smith
  5. Jane A. McElroy
  6. Tao Li
  7. Karen Segovia
  8. Tricia Haynes
  9. Richard Hammer
  10. Christopher Sampson
  11. Detlef Ritter
  12. Christopher Schulze
  13. Robin Trotman
  14. Grace M Lidl
  15. Richard Webby
  16. Jun Hang
  17. Xiu-Feng Wan

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Abstract

Since the first report of SARS-CoV-2 in December 2019, genetic variants have continued to emerge, complicating strategies for mitigating the disease burden of COVID-19. Positive SARS-CoV-2 nasopharyngeal swabs (n=8,735) were collected from Missouri, USA, from March-October 2020, and viral genomes (n=178) were sequenced. Hospitalization status and length of stay were extracted from medical charts of 1,335 patients and integrated with emerging genetic variants and viral shedding analyses for assessment of clinical impacts. Multiple introductions of SARS-CoV-2 into Missouri, primarily from Australia, Europe, and domestic states, were observed. Four local lineages rapidly emerged and spread across urban and rural regions in Missouri. While the majority of Missouri viruses harbored Spike-D614G mutations, a large number of unreported mutations were identified among Missouri viruses, including seven in the RNA-dependent RNA polymerase complex and Spike protein that were positively selected. A 15.6-fold increase in viral RNA levels in swab samples occurred from March to May and remained elevated. Accounting for other comorbidities, individuals test-positive for COVID-19 with high viral loads were less likely to be hospitalized (odds ratio=0.39, 95% confidence interval [CI]=0.20, 0.77) and had shorter hospital stays (hazard ratio=0.34, p=0.003) than those with low viral loads. Overall, the first eight months of the pandemic in Missouri saw multiple locally acquired mutants emerge and dominate in urban and rural locations. Although we were unable to find associations between specific variants and greater disease severity, Missouri COVID-positive individuals that presented with increased viral shedding had less severe disease by several measures.

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  1. ScreenIT

    SciScore for 10.1101/2021.02.03.21250928: (What is this?)

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

    Table 1: Rigor

    Institutional Review Board StatementIRB: Ethical Approval: Approved by University of Missouri Institutional Review Board (#2025449).
    Randomizationnot detected.
    Blindingnot detected.
    Power Analysisnot detected.
    Sex as a biological variablenot detected.
    Cell Line Authenticationnot detected.

    Table 2: Resources

    Experimental Models: Cell Lines
    SentencesResources
    To determine virus replication kinetics, Vero E6 cells were infected at a starting multiplicity of infection (MOI) of 0.01, and supernatants were harvested and titrated using plaque assays (eMethods)
    Vero E6
    suggested: RRID:CVCL_XD71)

    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:
    There are several limitations to this study. Analyses with viral loads are limited by variability in nasopharyngeal swabbing techniques, which may cause inconsistencies in Ct-values, although the same sampling and processing protocol was used throughout this study. Additionally, during the initial phases of the pandemic, testing was generally limited to patients with more severe symptoms, potentially skewing viral load findings. Despite these limitations, we analyzed a large, representative sample, and adjusted for these confounders. In summary, multiple novel lineages were identified, and locally acquired mutations, present at both the urban and rural levels, remained predominant in the community. Although we were unable to find associations between specific variants and greater disease severity, Missouri COVID-positive individuals that presented with increased viral shedding had less severe disease by several measures. Continued monitoring of the impacts of these novel variants, particularly of those in the regions of vaccine targets, will be essential to the management of this pandemic.

    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. Version published to 10.1101/2021.02.03.21250928v1 on medRxiv