Sex-disaggregated data in COVID-19 vaccine trials
Authors: Lavanya Vijayasingham, Evelyne Bischof, Jeannette Wolfe
Journal: The Lancet (2021)

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.1Bischof E Wolfe J Klein SL Clinical trials for COVID-19 should include sex as a variable.J Clin Invest. 2020; 130: 3350-3352Crossref PubMed Scopus (73) Google Scholar 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,2Voysey M Clemens SAC Madhi SA et al.Safety and efficacy of the ChAdOx1 nCoV-19 vaccine (AZD1222) against SARS-CoV-2: an interim analysis of four randomised controlled trials in Brazil, South Africa, and the UK.Lancet. 2021; 397: 99-111Summary Full Text Full Text PDF PubMed Scopus (3260) Google Scholar 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).3Flanagan KL Fink AL Plebanski M Klein SL Sex and gender differences in the outcomes of vaccination over the life course.Ann Rev Cell Develop Biol. 2017; 33: 577-599Crossref PubMed Scopus (316) Google Scholar 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.3Flanagan KL Fink AL Plebanski M Klein SL Sex and gender differences in the outcomes of vaccination over the life course.Ann Rev Cell Develop Biol. 2017; 33: 577-599Crossref PubMed Scopus (316) Google Scholar, 4Zimmermann P Curtis N Factors that influence the immune response to vaccination.Clinl Microbiol Rev. 2019; 32: e0084-e0118Crossref PubMed Scopus (493) Google Scholar Previous influenza vaccine research suggests that women can produce the same immunological response to half-dose vaccine as men do to full dose.5Engler RJM Half- vs full-dose trivalent inactivated influenza vaccine (2004–2005): age, dose, and sex effects on immune responses.Arch Intern Med. 2008; 1682405Crossref PubMed Scopus (243) Google Scholar According to research findings in preprint,6Sudre CH Murray B Varsavsky T et al.Attributes and predictors of long-COVID: analysis of COVID cases and their symptoms collected by the Covid Symptoms Study App.medRxiv. 2020; (published online Oct 21.) (preprint).https://doi.org/10.1101/2020.10.19.20214494Google Scholar 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.7Ravindran TS Teerawattananon Y Tannenbaum C Vijayasingham L Making pharmaceutical research and regulation work for women.BMJ. 2020; 371m3808Crossref PubMed Scopus (25) Google Scholar This is also the case in COVID-19 trial data reporting. According to an evaluation in preprint8Brady E Nielsen MW Andersen JP Oertelt-Prigione S Lack of consideration of sex and gender in clinical trials for COVID-19.medRxiv. 2020; (published online Sept 14.) (preprint).https://doi.org/10.1101/2020.09.13.20193680Google Scholar 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.9Polack FP Thomas SJ Kitchin N et al.Safety and efficacy of the BNT162b2 mRNA Covid-19 vaccine.N Engl J Med. 2020; 383: 2603-2615Crossref PubMed Scopus (9498) Google Scholar, 10Baden LR El Sahly HM Essink B et al.Efficacy and safety of the mRNA-1273 SARS-CoV-2 vaccine.N Engl J Med. 2021; 384: 403-416Crossref PubMed Scopus (6551) Google Scholar 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 For the Gender and COVID-19 Agenda-setting Initiative see www.ghhbuzzboard.org 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. Safety and efficacy of the ChAdOx1 nCoV-19 vaccine (AZD1222) against SARS-CoV-2: an interim analysis of four randomised controlled trials in Brazil, South Africa, and the UKChAdOx1 nCoV-19 has an acceptable safety profile and has been found to be efficacious against symptomatic COVID-19 in this interim analysis of ongoing clinical trials. Full-Text PDF Open Access