Insights into the limited global spread of the immune evasive SARS-CoV-2 variant Mu

  1. Mary E. Petrone
  2. Carolina Lucas
  3. Bridget Menasche
  4. Mallery I. Breban
  5. Inci Yildirim
  6. Melissa Campbell
  7. Saad B. Omer
  8. Albert I. Ko
  9. Nathan D. Grubaugh
  10. Akiko Iwasak
  11. Craig B. Wilen
  12. Chantal B.F. Vogels
  13. Joseph R. Fauver

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Abstract

SARS-CoV-2 ‘Variants of Concern’ (VOCs) continue to reshape the trajectory of the COVID-19 pandemic. However, why some VOCs, like Omicron, become globally dominant while the spread of others is limited is not fully understood. To address this question, we investigated the VOC Mu, which was first identified in Colombia in late 2020. Our study demonstrates that, although Mu is less sensitive to neutralization compared to variants that preceded it, it did not spread significantly outside of South and Central America. Additionally, we find evidence that the response to Mu was impeded by reporting delays and gaps in the global genomic surveillance system. Our findings suggest that immune evasion alone was not sufficient to outcompete highly transmissible variants that were circulating concurrently with Mu. Insights into the complex relationship between genomic and epidemiological characteristics of previous variants should inform our response to variants that are likely to emerge in the future.

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  1. ScreenIT

    SciScore for 10.1101/2022.03.28.22273077: (What is this?)

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

    Table 1: Rigor

    EthicsIRB: Ethics: This study was approved by Yale Human Research Protection Program Institutional Review Board (IRB Protocol ID 2000028924).
    Consent: Informed consent was obtained from all enrolled vaccinated HCWs.
    Sex as a biological variablenot detected.
    RandomizationSampling Variants of Concern (Fig. 1b): We randomly sampled 50 genome sequences per Variant of Concern (Alpha, Beta, Gamma, Delta, Lambda, Mu, Omicron) based on GISAID accession numbers using a random sampler implemented in R v.4.0.2.
    Blindingnot detected.
    Power Analysisnot detected.
    Cell Line AuthenticationContamination: The cell line has been tested negative for contamination with mycoplasma.

    Table 2: Resources

    Experimental Models: Cell Lines
    SentencesResources
    Briefly, 300 µl of serial fold virus dilutions were used to infect Vero E6 cells in MEM supplemented NaHCO3, 4% FBS 0.6% Avicel RC-581.
    Vero E6
    suggested: None
    Calu-3 cells were cultured in Eagle’s minimal essential medium (EMEM) with 10% FBS and 1% Penicillin/Streptomycin.
    Calu-3
    suggested: None
    To generate the viral stock of gamma used to test replication competence, 107 Vero-E6 cells overexpressing ACE2 and TMPRSS2 were infected with SARS-CoV-2 Isolate hCoV-19/Japan/TY7-503/2021 (BEI Resources #NR-54982) at an MOI of approximately 0.02.
    Vero-E6
    suggested: None
    Software and Algorithms
    SentencesResources
    Ethics: This study was approved by Yale Human Research Protection Program Institutional Review Board (IRB Protocol ID 2000028924).
    Yale Human Research Protection Program
    suggested: None
    We visualized the plots using Prism v.9.3.1.
    Prism
    suggested: (PRISM, RRID:SCR_005375)
    Table 5), we aligned our genome sequences with MAFFT using MN908947.3 as the reference.
    MAFFT
    suggested: (MAFFT, RRID:SCR_011811)
    We performed phylogeographic reconstruction implemented in BEAST v1.10.5 using an asymmetric CTMC model for discrete state reconstructions and running for 1 million states 32.
    BEAST
    suggested: (BEAST, RRID:SCR_010228)
    We tabulated sustained introductions per regional sink in Python v.3.8.3.
    Python
    suggested: (IPython, RRID:SCR_001658)
    Reference based genome assembly pipelines, such as iVar40 used in this example, align reads to a reference genome using BWA41 to call variants and determine the most common nucleotide at any given position.
    BWA41
    suggested: None
    An intermediate .bam file is produced and can be visualized in common GUI software, such as Geneious.
    Geneious
    suggested: (Geneious, RRID:SCR_010519)
    Demographic information was aggregated through a systematic review and the clinical data were collected using REDCap.
    REDCap
    suggested: (REDCap, RRID:SCR_003445)

    Results from OddPub: Thank you for sharing your data.

    Results from LimitationRecognizer: We detected the following sentences addressing limitations in the study:
    Our study was not without limitations. The analysis presented above is retrospective and therefore not explicitly actionable. Rather, our intention was to examine genomic and clinical correlates of variant fitness that may inform the response to future variants. The data we have presented should be carefully interpreted. The experimental assays were performed in vitro, and therefore may not directly reflect biological dynamics in vivo. However, our objective was to compare specific characteristics in individual variants, which may be accomplished in vitro. Genomic frequencies should be interpreted with caution due to large fluctuations in the percentage of cases sequenced by week in each location. For this reason, long-term trends are more reliable than short-term trends. Lastly, the phylogeographic analyses presented comprised substantially downsampled data, potentially biasing our findings. In particular, characterizing patterns of sustained introductions should be interpreted with understanding. That is, the relative number of introductions across regions should be considered rather than the absolute number. This challenge is in part due to the retrospective nature of our study. Downsampling is less likely to be needed when a more recently emerged variant is the subject of analysis. Here, we present a multidisciplinary analysis of Mu, an immune evasive VOC that exhibited limited global spread. As new SARS-CoV-2 lineages emerge, their mutation profiles provide preliminary d...

    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.

    Results from scite Reference Check: We found no unreliable references.

    About SciScore

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  2. Version published to 10.1101/2022.03.28.22273077v1 on medRxiv