Female-male differences in COVID vaccine adverse events have precedence in seasonal flu shots: a potential link to sex-associated baseline gene expression patterns

  1. AJ Venkatakrishnan
  2. Praveen Kumar-M
  3. Eli Silvert
  4. Enrique Garcia-Rivera
  5. Mariola Szenk
  6. Rohit Suratekar
  7. Patrick Lenehan
  8. Emily Lindemer
  9. John C. O’Horo
  10. Amy W. Williams
  11. Andrew D. Badley
  12. Abinash Virk
  13. Melanie D. Swift
  14. Gregory J. Gores
  15. Venky Soundararajan

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Abstract

Nearly 150 million doses of FDA-authorized COVID vaccines have been administered in the United States. Sex-based differences of adverse events remain poorly understood, mandating the need for real-world investigation from Electronic Health Records (EHRs) and broader epidemiological data sets. Based on an augmented curation of EHR clinical notes of 31,064 COVID-vaccinated individuals (19,321 females and 11,743 males) in the Mayo Clinic, we find that nausea and vomiting were documented significantly more frequently in females than males after both vaccine doses (nausea: RR Dose 1 = 1.67, p Dose 1 <0.001, RR Dose 2 = 2.2, p Dose 1 < 0.001; vomiting: RR Dose 1 = 1.58, p Dose 1 < 0.001, RR Dose 2 = 1.88, p Dose 1 = 3.4×10 −2 ). Conversely, fever, fatigue, and lymphadenopathy were more common in males after the first dose vaccination (fever RR = 0.62; p = 8.65×10 −3 ; fatigue RR = 0.86, p = 2.89×10 −2 ; lymphadenopathy RR = 0.61, p = 3.45×10 −3 ). Analysis of the Vaccine Adverse Events Reporting System (VAERS) database further confirms that nausea comprises a larger fraction of total reports among females than males (RR: 1.58; p<0.001), while fever comprises a larger fraction of total reports among males than females (RR: 0.84; p<0.001). Importantly, increased reporting of nausea and fever among females and males, respectively, is also observed for prior influenza vaccines in the VAERS database, establishing that these differences are not unique to the recently developed COVID-19 vaccines. Investigating the mechanistic basis underlying these clinical findings, an analysis of bulk RNA-sequencing data from 12,158 human blood samples (8626 female, 3532 male) reveals 85 genes that are not only significantly different in their gene expression between females and males at baseline, but also have established literature-based associations to COVID-19 as well as the vaccine-related adverse events of clinical consequence. The NLRP3 inflammasome and the NR3C1 glucocorticoid receptor emerge as particularly promising baseline links to sex-associated vaccine adverse events, warranting targeted investigation of these signaling pathways and associated cell types. From a public health standpoint, our clinical findings shall aid in educating patients on the sex-associated risks they should expect for COVID-19 vaccines and also promote better clinical management of vaccine-associated adverse events.

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    SciScore for 10.1101/2021.04.01.21254798: (What is this?)

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

    Table 1: Rigor

    Institutional Review Board StatementIRB: This study was reviewed by the Mayo Clinic Institutional Review Board (IRB) and determined to be exempt from the requirement for IRB approval (45 CFR 46.104d, category 4).
    Randomizationnot detected.
    Blindingnot detected.
    Power Analysisnot detected.
    Sex as a biological variableOverall, we mainly assessed a cohort of 31,064 individuals who were administered with a COVID-19 vaccine at the Mayo Clinic Health system between the time period December 15, 2020 and February 8, 2021. 31,064 individuals (19,321 females, 11,743 males) had received the first dose of the vaccine and 17,063 individuals had received the second dose of the vaccine.

    Table 2: Resources

    No key resources detected.

    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: An explicit section about the limitations of the techniques employed in this study was not found. We encourage authors to address study limitations.

    Results from TrialIdentifier: No clinical trial numbers were referenced.

    Results from Barzooka: We found bar graphs of continuous data. We recommend replacing bar graphs with more informative graphics, as many different datasets can lead to the same bar graph. The actual data may suggest different conclusions from the summary statistics. For more information, please see Weissgerber et al (2015).

    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 10.1101/2021.04.01.21254798v1 on medRxiv