Health equity necessitates the inclusion of gender identity data in COVID-19 clinical trials

Abstract

COVID-19 has highlighted the importance of studying differences by sex and gender. The underreporting of gender identity in COVID-19 studies limits the generalizability of study results to nonbinary persons. Some of the data on sex-assigned associated complications of both COVID-19 infection and COVID-19 immunizations is presented in this manuscript.

The inclusion of diverse populations in clinical trials improves the generalizability of study results and health equity. In 2016, the National Institutes for Health (NIH) put forward a policy that recognized how sex and gender influence health and disease processes, and specifically called for the addition of these variables to research designs, analyses, and reporting. In line with health equity research, this policy brings to the forefront the importance of promoting and capturing sex-assigned at birth and diverse gender identities, which includes cisgender, transgender, and nonbinary (trans) populations, particularly in clinical trials and surveillance systems. Gender identity data remain to be underreported in clinical trials, including NIH-funded COVID-19 studies.

The inclusion of gender identity questions in population surveys acknowledges the existence of trans people in the general population. In their latest report using 2017-2019 Youth Risk Behavioral Survey and 2017-2020 Behavioral Risk Factor Surveillance System (BRFSS), the Williams Institute estimated that 1.6 million US adults and youths identify as trans, with evidence indicating double in population size growth among younger trans people (ages 13 to 24) [1].

Unfortunately, including trans populations in recruitment strategies and data collection design in most clinical trials remains scant, including the recent COVID-19 vaccine studies ( Table 1) as most of the vaccine clinical trials categorized sex as binary without further specifying gender identity. Previous researchers have noted potential pathways to understanding COVID-19 vaccine efficacy and gender-affirming hormones (e.g., estrogen, progesterone, antiandrogens, testosterone) at the biomedical level, and have only been able to refer to in vivo trials [2]. Specifically, they postulate that transfeminine individuals who take estrogen may have heightened protection from experiencing severe COVID-19, whereas transmasculine individuals who take testosterone may face increased risk. To our team’s knowledge, there are no human clinical trials or formative studies that specifically aim to examine the biological and physiological impacts of COVID-19 vaccine among trans populations. Specifically, the extent to which vaccine efficacy has been studied in the context of gene expressions based on existing sex-based chromosomes that can recognize and activate innate immunity in combination with gender-affirming hormones among trans populations has not been explored. Moreover, while the use of hormones for gender affirmation is a key component of trans people’s health and well-being, not all trans people pursue such medical interventions [3] and decisions to take hormones vary across gender groups of trans populations over time [4]. As such, in addition to understanding COVID-19 vaccine efficacy at the biomedical level, understanding its impact at the social and behavioral levels among trans populations who are and are not taking gender-affirming hormones is warranted.

Table 1.

Phase 3 COVID-19 Vaccine Studies in Adults in the United States.

Brand	Pfizer/BioNTech	Moderna	Johnson & Johnson/Janssen	AstraZeneca	Novavax
Vaccine Name	BNT162b2	mRNA-1273	Ad26.COV2.S	ChAdOx1nCoV-19/AZD 1222	NVX-CoV2373
Vaccine Platform	mRNA	mRNA	Adenovirus	Adenovirus	Recombinant nanoparticle vaccine
Age	16 years and older	18 years and older	18 years and older	18 years and older	18 years and older
Total Number Participants	37,706	30,351	43,783	32,379	14, 039
Sex
Male Female Nonbinary Unknown	19,075 (50.6) 18,631 (49.4)	15,985 (52.7) 14,366 (47.3)	24,053 (54.9) 19,722 (45.0) 6(<0.1) 2(<0.1)	18,015 (55.6) 14,364 (44.4)	7,238 (51.6) 6,801 (48.4)

Of the Phase 3 adult COVID-19 vaccine trials conducted in the United States, only the Johnson & Johnson/Janssen vaccine efficacy study included nonbinary gender as a potential response (conflated as a sex marker in the trial). It also did not examine hormone use specifically. However, the inclusion of nonbinary gender category in the Johnson and Johnson/Janssen study demonstrates the feasibility of conducting a gender-inclusive approach to data collection [5] such that gender responses recognize and affirm trans identities in clinical studies, and confirm nonbinary people’s participation in vaccine clinical trials. A few recent clinical trials like cabotegravir for HIV prevention have demonstrated feasibility in recruiting with gender-inclusive approach and analyzing trans cohorts with cisgender cohorts [6].

COVID-19 has highlighted the importance of studying differences by sex and gender. Several associations between sex-assigned at birth and COVID-19 outcomes have been reported with multiple studies demonstrating poorer outcomes in men than in women. In a large 2020-2021 COVID-19 cohort study (n=4930), participants with male sex-assigned at birth were significantly more likely to experience in-hospital mortality (OR 1.24, 95% CI 1.06–1.44), intubation (OR 1.22, 95% CI 1.03–1.46), and ICU level care (OR 1.37, 95% CI 1.19–1.59), controlling for other demographics and comorbidities [7]. Although mortality rates from COVID-19 in trial participants assigned male at birth appear to be higher than those assigned female at birth, confounding factors including comorbidities, smoking and alcohol use, healthcare utilization, and handwashing practices may contribute to differences in reported outcomes.

Differences in immunologic responses to infection between trial participants assigned male and female at birth have been reported for multiple pathogens, including SARS-CoV-2. Sex steroids have immune modulating effects, and differential levels of estrogens, progesterone, and androgens may contribute to the immune response against SARS-CoV-2. Because of these sex differences in COVID-19 outcomes, hormone therapy has been explored as treatment for COVID-19. In a pilot randomized study of participants assigned male at birth (n=41) with moderate-severe COVID-19 disease receiving standard of care plus progesterone 100 mg twice daily for 5 days versus standard of care, the progesterone group reported a median 1.5-point improvement in clinical status, decreased supplemental oxygen use, and duration of hospitalization [8]. However, comorbidities increasing the risk for severe COVID-19, were not equally distributed between study arms. Such studies points to further investigation into the impact of endogenous and exogenous hormones on COVID-19 outcomes, and trials that include trans populations undergoing hormone therapy are warranted.

The association between binary gender and adverse events following COVID-19 vaccinations has also been described. Anaphylaxis is reported more often in cisgender women following the SARS-CoV-2 vaccines [9]. Of 66 confirmed anaphylaxis cases following SARS-CoV-2 mRNA vaccines to the Vaccine Adverse Event Reporting System (VAERS), 96% of cases occurred in women [9]. Another rare adverse event, myocarditis/pericarditis, associated with mRNA vaccines (Pfizer-BioNTech BNT162b2 and Moderna mRNA-1273), occurs more frequently in adolescent cisgender boys and young men compared with cisgender women. In a review of 1626 confirmed cases of myocarditis reported in VAERS, 82% were in cisgender men with a median age of 21 years [10]. The rates of myocarditis were highest following the second dose of vaccine, in adolescent cisgender boys and young men (12-17 years old), with an estimated rate of 70.7 per million doses of the BNT162b2 vaccine [10]. Similarly in Israel, following 2 doses of BNT162b2 mRNA vaccine, of persons with proven/probable myocarditis/pericarditis, over 90% of cases were cisgender men, and most were less than 30 years of age. Such outcomes among trans populations have not been explored.

Another example of gender-based differences associated with two adenoviral vector vaccines, namely Ad26.COV2.S (Johnson & Johnson/Janssen) and ChAd0x1 nCoV-19 (AstraZeneca), is with thrombosis and thrombocytopenia, a rare adverse event with an estimated incidence of 3.23 per million doses of Johnson & Johnson/Janssen vaccine administered. In an early case series, the FDA and CDC confirmed 80% of 60 TTS cases were observed in cisgender women, suggesting rates were highest in this group [11]. While mostly observed in cisgender women, there is insufficient data to date to infer contraceptives or estrogen therapy increase the risk for TTS. Trans populations may have a different risk profile, particularly among those who use exogenous hormones. Understanding whether risk for sex-specific adverse events is attributable to sex assigned at birth, gender identity, and/or exogenous hormone therapy may further elucidate the pathophysiology of vaccine-related myocarditis and TTS and inform clinicians about risks for trans patients.

The extent of trans populations’ participation in clinical trials remains unknown and traditional recruitment strategies, study questionnaires, and data analysis of binary sex alone are outdated. The underreporting of trans participants must be addressed in future in clinical trials, especially given the sex-assigned associated complications of both COVID-19 and COVID-19 immunizations. While enrollment of racial and ethnic minorities into clinical trials is critical and has been emphasized to reduce health disparities, diverse gender identities that include transgender and nonbinary populations have not been routinely captured. As such, to address gender inequities and move towards equitable and inclusive approaches in COVID-19 clinical studies, we recommend adopting gender-specific and inclusive approaches to clinical trials [5]. This includes addressing binary-centered surveys and data collection methods may create an uncomfortable setting for participants and do not foster a setting of trust or inclusivity. Best practice in trans research also necessitates the inclusion of trans people throughout all stages of research, including as key personnel and leaders (e.g., trans-led studies) and community and scientific advisory board members, in addition to being participants [12]. As such, investing in the training and leadership of trans people in COVID-19 biomedical research is necessary for successful gender inclusion. Moreover, funding and regulatory agencies are encouraged to revise binary sex reporting in clinical trials by adding questions to encompass all gender identities.

Funding

AW reports receiving funding from the National Institutes of Health (NIH), including as a coinvestigator in the Novavax and Gritstone COVID-19 vaccine trials. She also reports receiving financial support through her institution from Sanofi and GSK for research unrelated to COVID-19. AR is supported by The Research Education Institute for Diverse Scholars (REIDS) Program at Yale University School of Public Health, funded by the National Institute of Mental Health (R25MH087217).

Supported by the Infectious Diseases Clinical Research Consortium through the National Institute for Allergy and Infectious Diseases of the National Institutes of Health, under award number UM1AI148684. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health.

Declaration of Competing Interest

The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: Tara Babu reports article publishing charges was provided by IDCRC through the National Institutes of Health. Anna Wald reports a relationship with National Institutes of Health that includes: funding grants. Anna Wald reports a relationship with Sanofi that includes: consulting or advisory. Anna Wald reports a relationship with GSK that includes: consulting or advisory. Arjee Restar reports a relationship with National Institutes of Health that includes: funding grants.