Action 2: COVID-19 vaccine studies must be designed to adequately capture sex and gender differences in safety, efficacy and effectiveness of vaccines
Sex differences in the immune response to self-antigens, pathogens and vaccines across the life course are well documented.10 17 18 Females generally exhibit greater humoral and cell-mediated immune responses to antigens than males as well as upregulated expression of antiviral and proinflammatory genes, many of which are regulated by oestrogen.18 19 Similar patterns are observed in patients with COVID-19, where women with mild to moderate COVID-19 infection show more robust cellular responses and higher antibody levels than men, while men show higher levels of inflammatory cytokines and chemokines than women.20
Sex-based differences in vaccine-induced immune responses have been observed following administration of several vaccines, such as influenza, yellow fever and hepatitis A and B, with female adults showing protective antibody responses twice as high as males.19 21 The observed sex differences likely shrink following reproductive senescence due to a drop in circulating oestradiol in women.22 Sex steroids have immunoregulatory functions and influence B-cell activity, antibody production and vaccine efficacy.21 22
Differential adverse reactions have also been reported in studies of trivalent inactivated influenza vaccine (TIV), inactivated monovalent 2009 H1N1 vaccines and yellow fever vaccines, with women experiencing greater local and systemic adverse reactions, including higher allergic reactions, than men.2 5 22 ,23 Early data following administration of 1 893 360 first doses of the Pfizer-BioNTech COVID-19 vaccine in the USA reported 21 cases of anaphylaxis, 90% of which occurred in women.24 The majority (90%) of non-anaphylaxis allergic reactions were also in women.24 Similar data were reported following administration of 4 041 396 first doses of the Moderna COVID-19 vaccines (100% and 91% of anaphylaxis and non-anaphylaxis allergic reactions, respectively, occurred in women).25 The authors suggested that the female predominance may be attributed to women receiving two-thirds of the vaccines (64% of the Pfizer vaccine doses and 61% of Moderna), but other reasons cannot be ruled out. More recently, a very rare yet severe blood clotting condition—thrombosis with thrombocytopenia syndrome—was observed following administration of the AstraZeneca vaccine (24 reported cases, 18 of which were fatal, out of 25 million people who received the vaccine in the European Union and UK as of 22 March 202126) as well as the Janssen COVID-19 vaccine (22 out of a total of 28 cases in women following administration of more than 8.7 million doses in the USA as of 7 May 202127) mainly in women under the age of 60 years.28 At the same time, there has been an increase in the reported cases of myocarditis and pericarditis in the USA following mRNA COVID-19 vaccination (Pfizer-BioNTech and Moderna), predominantly in adolescent and young men, which are being further investigated.29 30 It is important to emphasise that these adverse events are very rare, and all events have been reported in both women and men. Nevertheless, additional research is warranted to understand the potential underlying mechanism for sex-related and age-related risks.28
Despite well-established evidence about the sex difference in immune response and adverse reactions following vaccinations, most vaccine studies do not systematically analyse either outcome data by sex or the clinical implications of differential immune responses in terms of efficacy, dosing or time interval optimisation.21 31 To our knowledge, one study has explored alternative dosing strategies and reported that women receiving a half dose of TIV exhibit similar or greater antibody response than men receiving a full dose.32 While the clinical implications of differential immune responses to vaccines remain to be investigated, sex- and gender-based analysis may provide important insights. Additional research is also needed to examine vaccine safety and efficacy among intersex and transgender populations.
While the gender balance in vaccine trials has substantially improved over the years, studies are rarely designed to capture sex or gender differences, seldom report outcome data by sex and inadequately examine implications in terms of gender.31 33 34 Some of the recent COVID-19 vaccine studies report the overall efficacy by sex. However, data on discontinuation after the first and second doses, or adverse reactions are not reported by sex, and studies do not examine possible sex differences across age groups or arms with differential dosing or interval.35 36 In the context of vaccine shortages, sex- and gender-based analysis of efficacy and adverse event profiles, or consideration of alternative dosage, frequency of administration or timing interval, could provide useful insights, suggest ways to enhance efficacy, reduce adverse reactions and improve overall acceptability and uptake.22 Evidence of an equal safety and efficacy profile of a potential alternative dosage for women (as may be expected based on preliminary immunogenicity data and indications from previous studies of influenza vaccines) could influence the availability, cost and affordability of COVID-19 vaccines. Although the programmatic and logistical implications of such ‘sex-specific’ vaccine dosing are unknown, experiences from differential dosing of medications may be informative.
Bringing about change requires gatekeepers in the health research system to ensure a systematic integration of these dimensions at all stages of vaccine research and development. Researchers must incorporate sex and gender dimensions at the time of design of studies (including preclinical and animal studies). To successfully enrol and retain sufficient numbers of women and men in vaccine trials, a gender lens must be applied to every aspect of trial design, including how information and invitation for recruitment are formulated and distributed; how trials are planned to facilitate participation in terms of timing, location and consideration of childcare issues; financial implications in terms of income loss or indirect costs related to participation; and whether accurate information about the potential experience of adverse effects is provided.
Ethics committees and data safety and monitoring boards must require consideration of sex and gender in study protocols and review these dimensions in interim analyses and monitoring. Editors and peer reviewers of scientific journals need to remind investigators and pharmaceutical companies to report baseline and outcome data (including data on adverse events and discontinuation) by sex, as a minimum, as recommended by the Sex and Gender Equity in Research (SAGER) guidelines.37 National regulatory agencies and WHO prequalification mechanisms should require complete data by sex (and, ideally, concurrently by sex and age) as well as sex- and gender-based analysis, to conduct a thorough review of equal safety and efficacy in both women and men and whether different dosing strategies may be justified. WHO, ministries of health and other international, regional or national bodies must adequately incorporate gender considerations in their recommendations in technical guidelines and be transparent about the underlying evidence (table 1).