As the first wave of COVID-19 vaccines enter the market, and global immunisation programmes are implemented, the time is right to remind researchers and regulatory agencies of the critical importance of including biological sex as a variable in trial data analysis and reporting.1 The phase 3 Oxford–AstraZeneca trial interim report indicates more participation from women, which the investigators attribute to a recruitment focus on health-care workers,2 but they have not yet reported or discussed how biological sex could influence the data. Future reporting of sex-disaggregated data and a discussion of how sex factors influence the trial outcomes would benefit regulatory and public decision making and the design of mass vaccination programmes.
Why is biological sex relevant, and sex-disaggregated analysis important? A growing body of research highlights the influence of biological sex in clinically relevant health outcomes, including sex-specific differences in immunity, pharmacology, and vaccines outcomes (side-effects and efficacy).3 In vaccine studies, cisgender females tend to develop higher antibody response and, relatedly, higher efficacy and more side-effects, suggesting the need for sex-differentiated dosing regimens.3, 4 Previous influenza vaccine research suggests that women can produce the same immunological response to half-dose vaccine as men do to full dose.5 According to research findings in preprint,6 sex-based differences in innate and adaptive immunity in SARS-CoV-2 infections are probable contributors to the increased risk of intensive care unit admission and overall mortality in men, and increased reports of long-COVID symptoms in women. These hypotheses and evidence on the sex determinants of immune responses could also be present in COVID-19 vaccine-induced immunity and adverse outcomes.
Taking a cue from the remarkable achievements in vaccine innovation and research during the COVID-19 pandemic, we have an opportunity to course-correct the integration of biological sex as a core variable in study design, analysis, and reporting. Sex factors, including sex-disaggregated analysis and reporting, are still neglected across the continuum of medicines research and regulation.7 This is also the case in COVID-19 trial data reporting. According to an evaluation in preprint8 of nearly 2500 COVID-19-related studies, less than 5% of investigators had pre-planned for sex-disaggregated data analysis in their studies. We note and applaud those vaccine trial reports that did include sex-disaggregated primary outcomes data.9, 10 A further mention of sex-disaggregated adverse events and secondary outcomes in future reports would be beneficial. This would collectively set an analysis and reporting benchmark not just for the many COVID-19 candidate vaccines in the research pipeline, but also for all future pharmaceuticals, biologics, and other medical interventions.
For the Gender and COVID-19 Agenda-setting Initiative see www.ghhbuzzboard.org
Acknowledgments
LV reports grants to her organisation from the Bill and Melinda Gates Foundation, during the conduct of the study. EB reports grants from Krebsliga Schweiz and non-financial support from the Women's Brain Project, an international non-profit organisation advocating for and carrying out research on gender differences in brain and mental health diseases, unrelated to this Correspondence. EB is also an unpaid voluntary member of the executive board of the Women's Brain Project. JW declares no competing interests.
References
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