key: cord-0958819-t3exxyxb
authors: Jensen, Adelaide; Stromme, Masha; Moyassari, Shayda; Chadha, Antonella Santuccione; Tartaglia, Maria Carmela; Szoeke, Cassandra; Ferretti, Maria Teresa
title: COVID-19 vaccines: Considering sex differences in efficacy and safety
date: 2022-02-08
journal: Contemp Clin Trials
DOI: 10.1016/j.cct.2022.106700
sha: 9f939dbbf26c80e592ea12164b12dc555b684c9b
doc_id: 958819
cord_uid: t3exxyxb

The development of SARS-CoV-2 vaccines represents a significant breakthrough for managing the COVID-19 pandemic, however their approval process has exposed a crucial limitation in clinical trial reports—that is, a disregard for sex differences in response to vaccines. Historically, males and females have shown different reactions to vaccines of many kinds, which have become apparent with the arrival of COVID-19 vaccines in late-2020. In this article, we review both regulatory data from Phase III vaccine trials as well as peer-reviewed reports from vaccines administered to the general population, many of which failed to stratify results by sex. We also discuss the exclusion of pregnant and lactating women in drug development and the regulatory guidelines for use of COVID-19 vaccines in such populations. We conclude by proposing some questions to stimulate discussion with the intent to advance the field toward one of precision medicine.

In addition to data used for regulatory approval, several peer-reviewed papers have been published on interim and real world data since initiation of vaccine rollout. A summary of vaccine-related data from peer-reviewed Phase III studies is reported in Table 2 .

In reviewing interim safety and efficacy trial studies, we found that efficacy data were in most cases stratified by age and sex. In those studies which reported sex-specific efficacy data for the first shot of the vaccine, vaccine efficacy was consistently found to be higher in males than in females (see Table 2 ). However, in the same studies, safety data were only stratified by age; these analyses revealed a generally higher number of solicited injection-site and systemic adverse events in younger individuals (aged 18-65 years) for the Moderna vaccine (Baden et al., 2021) . On the other hand, safety analyses for the Pfizer-BioNTech vaccine indicated that local reactions (e.g., pain) were reported more frequently among older participants (aged >55 years) than younger participants (aged 16-55 years), while systemic adverse events (e.g., headache, fatigue) were more common among younger than older vaccine recipients (Polack et al., 2020) .

For the AstraZeneca jab, no stratification was reported; indeed, 'gender' was indicated as an additional, but not primary, subgroup of interest in their statistical analysis plan (Voysey et al., 2021) . A more recent report on the Janssen vaccine also reported sex-specific efficacy results, however, out of all safety analyses (i.e., solicited and unsolicited local and systemic adverse events), only descriptions of grade 3 unsolicited adverse events post-vaccination were reported separately for males and females (Sadoff et al., 2021) . Similarly, only Phase III Sputnik V vaccine efficacy, and not safety, data was disaggregated by sex (Logunov et al., 2021) . Based on the strong real-world evidence demonstrating that sex differences exist in the safety profiles of many vaccines, an a priori stratification of the data by sex is important to establish the J o u r n a l P r e -p r o o f Journal Pre-proof IN EFFICACY AND SAFETY   8   distribution of adverse events within male and female populations not only in Phase III trials,   but also in Phase I and II when studying vaccine dose, pharmacokinetics, and pharmacodynamics.

In the past months, peer-reviewed studies examining the safety and efficacy of the COVID-19 vaccines in the general population have allowed the implementation of pharmacovigilance steps and the identification of rare side effects that were not detected during clinical trials. Importantly, such studies indicated clinically-relevant sex differences in vaccine safety profiles. Among the first 13.7 million COVID-19 vaccine doses administered to Americans, a report from the CDC found that, while females represented only 61.2% (or 8 436 863) of all 13 794 904 vaccine dose recipients, 79.1% (or 5 413) of the 6 994 reported adverse events concerned females (Gee et al., 2021) . In another study, following the administration of the mRNA COVID-19 vaccines in the U.S. between December 14 th , 2020 and January 18 th , 2021, all 19 individuals who experienced adverse reactions to the Moderna vaccine were females, as were 44 of the 47 individuals who reported anaphylactic reactions to the Pfizer-BioNTech vaccine .

Pfizer-BioNTech vaccines out of approximately 2.8 million doses administered in Switzerland (as of May 4 th , 2021). They reported that 69.2% of adverse side effects affected females, whereas only 27.8% were experienced by males, with severity ranging from mild (e.g., injection site erythema) to serious (e.g., death) (Swissmedic, 2021) .

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A unique safety signal associated with the SARS-CoV-2 vaccines is represented by thrombotic events including cerebral venous sinus thrombosis (CVST) and thrombocytopenia.

Out of the first 34 million doses administered in Europe and the UK as of April 4 th , 2021, the EMA has reported 169 cases of CVST and 53 cases of splanchnic vein thrombosis following the first dose of the AstraZeneca vaccine, the majority of which occurred in females below 60 years of age (EMA, 2021). All cases were spontaneous reports to EudraVigilance, the European Union drug safety database, which collects electronic reports of adverse events to medicines from clinical trial sponsors. Although these numbers might seem large, it is important to note that the rate of occurrence of thrombosis with thrombocytopenia is less than 1 in 10 000 people (EMA, 2021) . In addition, 28 confirmed cases of thrombosis with thrombocytopenia (out of approximately 8.7 million doses administered as of May 7 th , 2021) have been reported to the CDC's Vaccine Adverse Events Reporting System (VAERS) following the Janssen vaccine in the U.S., most (22 out of 28) occurring in females between 30 and 49 years of age (Shimabukuro, 2021) . It should be noted however that specific sex-stratified vaccination rates were not available at the time these adverse events were published. On April 13 th , 2021, the CDC and FDA published a joint statement wherein they recommended to pause the Janssen vaccine rollout in the U.S. in response to the aforementioned concerns (FDA, 2021). On April 23 rd , this halt was lifted and a warning of rare clotting events is now being included with use of the Janssen vaccine in individuals aged 18-49 years (CDC, 2021) . Furthermore, the EMA has officially acknowledged a possible causal link between thrombotic events and the AstraZeneca and Janssen vaccines. Such events are now listed as very rare side effects for these vaccines. An aberrant immune response, with high levels of antibodies to platelet factor 4 reminescent of heparin-induced thrombocytopenia, has been proposed as a mechanism underlying thrombotic events as adverse side effects to the COVID-19 vaccine (Greinacher et al., 2021; Muir et al. 2021; Schultz et al., 2021) . As females tend to have higher prevalence of autoimmune reactions compared to males (Klein & Flanagan, 2016) , it is possible that such side effects affect females more often than males. It should also be noted that females, especially those using oral contraceptives, have been shown to be more at risk of CVST than males in the general population (Coutinho et al., 2009; Hinnell et al., 2012; Ozcan et al., 2013) . However, a detailed analysis by sex including a comparison in prevalence of CVST in the general young female population versus the vaccinated female young population is currently lacking, but is much needed. It would also be important to evaluate concomitant risk factors such as hormonal treatment, immune conditions, and other conditions that may show sex differences.

Such information, collected but not examined, might have a considerable impact on the current halt or restrictions to vaccinations in many countries. For instance, the AstraZeneca vaccine is not recommended for use in Denmark, Cameroon, and Norway, or has age restrictions (ranging from 50 to 65 years) in Australia, Britain, Canada, France, Italy, and Spain, among other nations. These modifications have led several countries to alter their planned vaccination program timelines. However, if the risk is confined to females, this would not impact the rollout in half the population under 50 years of age. As many studies have noted, the risk of death from COVID-19 is more common than the risk from the rare complications of current vaccines, and even more so for males who have a higher risk of severe infection and death due to COVID-19 than females (Dhindsa et al., 2021) . In fact, early data described above suggest that males have a lower adverse risk than females. The lack of sex-specific advice on this issue is therefore causing considerable limitations on vaccine programs across the globe.

An additional aspect related to sex differences in the safety and efficacy profile of the vaccines is their use in specific periods across the female reproductive life course, such as pregnancy and post-partum lactation. As illustrated in Table 3 , and in line with clinical research programs, pregnant and lactating females have been excluded from all initial COVID-19 vaccine trials due to the required safety standards for these populations (Doshi, 2020; Smith et al., 2020; Van Spall, 2021) . Consequently, at the time of regulatory approval, it was unknown whether the SARS-CoV-2 vaccines would be safe to administer in pregnant or breastfeeding females; thus, public and medical debates ensued on the use of these vaccines in these groups.

Several regulatory agencies issued specific recommendations for such groups (summarized in Table 3 ); most of them allowing the use in pregnant females at high risk of infection, also considering that pregnancy has been associated with an increased risk for experiencing severe illness and death due to COVID-19 (Mayo Clinic, 2021; Zambrano et al., 2020) .

While the literature is currently in its infancy, several researchers have begun to explore the pregnancy and lactation outcomes of COVID-19 vaccines in the general population. For instance, a team of researchers at the CDC has recently published their preliminary findings on the safety of mRNA COVID-19 vaccines in 3 958 pregnant individuals across all three trimesters of pregnancy who were enrolled using the v-safe COVID-19 Vaccine Pregnancy Registry . Reports of adverse events in pregnant persons received by the Vaccine Adverse Event Reporting System (VAERS) were also analyzed. These researchers found J o u r n a l P r e -p r o o f Journal Pre-proof no evidence of safety signals, such that reported adverse outcomes were similar between groups of pregnant and nonpregnant females, and comparable to those in studies conducted prior to the COVID-19 pandemic. The most common adverse event reported to the VAERS among vaccinated pregnant females was miscarriage. Interestingly, compared to nonpregnant individuals, pregnant participants more frequently reported injection-site pain and, less frequently: headache, myalgia, chills, and fever.

[ Table 3 ]

Currently, several studies have been published exploring the effects of COVID-19 vaccines (i.e., the Moderna and Pfizer-BioNTech vaccines) in pregnant females (See Table 4 ).

Preliminary evidence overall indicates safe use in pregnant individuals and their offspring (Beharier et al., 2021; Collier et al., 2021; Gray et al., 2021; Male, 2021; Martins et al., 2021; Riley & Jamieson, 2021; Shanes et al., 2021; Shimabukuro et al., 2021; Zdanowski & Wasniewski, 2021) . A recent study preprint reported that pregnant (N=84) and lactating (N=31) females who received one of the mRNA vaccines generated an immune response to SARS-CoV-2, with immunogenicity and reactogenicity comparable to that in non-pregnant participants (N=16). This study also found that SARS-CoV-2 antibodies were present in the placenta and could be passed to newborns through breastmilk (Gray et al., 2021) . Similarly, Collier et al.

found vaccine-elicited SARS-CoV-2 antibodies in umbilical cord blood as well as in the breast milk of vaccinated mothers in their sample of 103 females (including 30 pregnant and 16 lactating persons) (Collier et al., 2021) . Furthermore, a recent study has found that the mRNA vaccines provide immunogenicity in pregnant persons and do not cause certain placental lesions which have come to be associated with SARS-CoV-2 infection (Shanes et al., 2021) . [ Table 4 ]

In this narrative review, we explored sex differences in COVID-19 vaccine response using the currently available data from vaccine safety and efficacy studies. We found that, while most studies included sex-disaggregated efficacy data, very few safety analyses were reported by sex. This was true for both reports from regulatory bodies (i.e., FDA, EMA, and Health Canada) and clinical trials. On the other hand, peer-reviewed studies investigating vaccine safety and efficacy outcomes in the general population reported generally higher rates of adverse reactions to the vaccines in females compared to males. Thrombotic events were also more The COVID-19 vaccine approval process has exposed a number of fundamental issues in drug development and clinical trials related to a disregard of individual patient characteristics, such as sex differences, in biological responses to drugs. It is important to note that the collection of such information would not delay the availability of medications at the bedside, as both sex and side effect data have already been collected-they have just not been reported. A vast body of evidence has indicated that a "one-size-fits-all" approach in medicine, which has informed most clinical research conducted in the past decades, is failing to address the heterogeneity in patient populations and the specific needs of patient subgroups (Schork, 2015) . Clinical differences between males and females, which are well-established in several fields including vaccine biology, are a very clear example of patient heterogeneity that needs to be addressed. The world has shown an incredible capacity for an accelerated COVID-19 vaccine development process. Even with this fast-tracked approach, the data on sex, therapeutic interventions, and side effects were all collected. We argue that this experience should be used as an opportunity to reiterate the importance of implementing regulatory mandates to report sex differences in both safety and efficacy of new drugs and vaccines, with the goal of moving the field towards precision medicine. Some important aspects that must be considered include:

1. Careful characterization of safety profile of drugs by sex during drug development. Is a drug equally safe, in terms of frequency and types of events, in males and females? How does the frequency of adverse events compare with that in the general population (i.e. comparing frequency among young, vaccinated females with that of young females in the general population)?. How should we make sure that female-specific risk factors (such as hormonal contraceptive or hormone therapy use) are factored into the analysis? Considering the wellknown stronger effect of vaccines in females (e.g., higher frequency of adverse reactions), should the dosage of vaccines be tested separately in each sex?

2. Regulatory analysis of safety and efficacy data by sex. How can we increase the ability of the regulatory bodies to identify critical sex differences in efficacy and safety, before they emerge in pharmacovigilance stage (e.g., Zolpidem; U.S. FDA, 2018)? What is the best approach to characterize rare events in subgroups, such as females? Should sex-stratification of data be mandatory for drug approval? By addressing the previous points, we can provide policy makers, regulators, and drug developers with tools to address and possibly prevent issues such as those that have emerged during the COVID-19 vaccination campaign.

It is well known that females generally respond differently than males to many vaccines and experience more side effects, which may be due in part to their heightened immune response. In this review we show that this trend is also true for the novel SARS-CoV-2 vaccines.

However, despite numerous calls for the reporting of sex-disaggregated data in clinical trials, considerations of sex differences in drug development have generally been overlooked. In writing this review, we hope to spark a discussion in the field surrounding the systematic incorporation of sex-based analyses in drug development, reporting of sex-disaggregated clinical data by regulatory bodies, and inclusion of pregnant and lactating individuals in clinical trials, with the overarching goal of achieving precision medicine.

The Women's Brain Project is a non profit organization studying sex and gender determinants of brain and mental health.  Animal studies do not show any harmful effects in pregnancy, however data on the use during pregnancy are very limited.  Although there are no studies on breast-feeding, no risk for breast-feeding is expected.  The decision on whether to use the vaccine in pregnant women should be made in close consultation with a healthcare professional after considering the benefits and risks. U.S. Food and Drug Administration (FDA)

Comirnaty -COVID mRNA vaccine (Pfizer/BioNTech), COVID-19 Vaccine Janssen-Ad26.COV2-S recombinant, Covid-19 Vaccine Moderna-mRNA vaccine (nucleoside modified)  Clinical trials that look at the safety and how well the COVID-19 vaccines work in pregnant people are underway or planned. Vaccine manufacturers are also monitoring data from people in the clinical trials who received vaccine and became pregnant.  Studies in animals receiving Moderna, Pfizer-BioNTech, or Johnson & Johnson's Janssen (J&J/Janssen) COVID-19 vaccines before or during pregnancy found no safety concerns.  If you are pregnant, you may choose to receive a COVID-19 vaccine. While a conversation with your healthcare provider may be helpful, it is not required prior to vaccination.  Any pregnant woman who has had vaccine is advised to enrol into the v-safe health checker to monitor their side effects.  Most reports to the Vaccine Adverse Event Reporting System (VAERS) among pregnant women (73%) involved non-pregnancy-specific adverse events (e.g., local and systemic reactions). Miscarriage was the most frequently reported pregnancy-specific adverse event to VAERS, but the number was not concerning considering the expected background rate  Safety monitoring in pregnant women is ongoing/planned in v-safe, Vaccine Safety Datalink (VSD), and Clinical Immunization Safety Assessment (CISA) Medicines & Healthcare products, Regulatory Agency (MHRA) and Joint Committee on Vaccination and Immunisation (JCVI)

Comirnaty -COVID mRNA vaccine (Pfizer/BioNTech), Vaxzevria (previously COVID-19 Vaccine AstraZeneca), Covid-19 Vaccine Moderna-mRNA vaccine (nucleoside modified)  There is no evidence the COVID-19 vaccine is unsafe if you're pregnant. More evidence is needed before you can routinely be offered the vaccine.  The Joint Committee on Vaccination and Immunisation (JCVI) has updated its advice to recommend you may be able to have the vaccine if you're pregnant and: -At high risk of getting coronavirus because of where you work -Have a health condition that means you're at high risk of serious complications of coronavirus  You can have the COVID-19 vaccine if you're breastfeeding.  Speak to a healthcare professional before you have the vaccine. They will discuss the benefits and risks with you.  There's no evidence that the COVID-19 vaccine has any effect on your chances of becoming pregnant.

There's no need to avoid pregnancy after vaccination.  For some specific populations (including pregnant and breastfeeding women) who were either excluded from, or were represented by small numbers of participants in clinical trials, the National Advisory Committee on Immunization (NACI) recommends that a complete vaccine series with a currently authorized COVID-19 vaccine may be offered, if a risk assessment deems that the benefits of vaccination outweigh the potential risks for the individual (e.g., where the risk of severe outcomes of COVID-19 and/or risk of exposure to SARS-CoV-2 is high) or for the foetus/infant (in the case of pregnancy/breastfeeding) and if informed consent includes discussion about the insufficient evidence in these populations. These recommendations may change as more evidence on safety and/or efficacy/effectiveness in these populations becomes available.

 Clinical trials assessing COVID-19 vaccines should continue to be encouraged to include individuals with potential vulnerabilities to disease related to biological (e.g., pre-existing medical conditions, frailty, pregnancy and breastfeeding, immunocompromised), and social (e.g., residence in long term care facilities or crowded/remote locations, belonging to a racialized population, occupation) factors to ensure that vaccine options are informed by robust safety, immunogenicity, and efficacy data as outlined in the NACI's guidance on Research Priorities for COVID-19 Vaccines to Support Public Health Decisions. Furthermore, NACI recommends the continuation of clinical trials and ongoing follow-up of participants for as long as it is ethically feasible to determine the level of immunity needed to prevent disease, duration of protection, efficacy in different sub-populations, and medium-and long-term safety.

 In addition to ongoing vaccine pharmacovigilance activities in Canada with Phase 4 clinical trials and postmarketing studies, additional research and surveillance of COVID-19 vaccination, particularly in populations not currently included in clinical trials (e.g., pregnant, breastfeeding, immunosuppressed, seniors living in congregate care settings, children and adolescents) is recommended. 

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Gender differences in vaccine therapy: where are we in COVID-19 pandemic?

Cerebral venous and sinus thrombosis in women

Association of circulating sex hormones with inflammation and disease severity in patients with COVID-19

Will covid-19 vaccines save lives? Current trials aren't designed to tell us

Policy Brief: Sex and Gender in Medicines Regulation

AstraZeneca's COVID-19 VACCINE: EMA finds possible link to very rare cases of unusual blood clots with low platelets

COVID-19 vaccine safety update

Sex and gender impact immune responses to vaccines among the elderly

Sex differences in vaccine-induced humoral immunity

The X-files in immunity: sex-based differences predispose immune responses

Sex and gender differences in the outcomes of vaccination over the life course

Sex differences in the vaccinespecific and non-targeted effects of vaccines

First month of COVID-19 vaccine safety monitoring-United States

Understand how covid-19 might affect your pregnancy

Thrombotic thrombocytopenia after Ad26.COV2.S vaccination

Cerebral venous sinus thrombosis: gender differences in ten years experience

Safety and efficacy of the BNT162b2 mRNA COVID-19 vaccine

Inclusion of pregnant and lactating persons in COVID-19 vaccination efforts

The influence of sex and gender on immunity, infection and vaccination. Annali dell'Istituto superiore di sanita

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Personalized medicine: time for one-person trials

Thrombosis and Thrombocytopenia after

Vaccination

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) vaccination in pregnancy

ACIP May 12, 2021 presentation slides

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Exclusion of Pregnant Women from Clinical Trials during the Coronavirus Disease 2019 Pandemic: A Review of International Registries

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Side effects of COVID-19 vaccines in Switzerland -update

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gov/science-J o u r n a l P r e -p r o o f Journal Pre-proof COVID-19 VACCINES: CONSIDERING SEX DIFFERENCES IN EFFICACY AND SAFETY 25 research/womens-health-research/regulations-guidance-and-reports-related-womenshealth U.S. Food and Drug Administration

Exclusion of pregnant and lactating women from COVID-19 vaccine trials: a missed opportunity

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COVID-19 VACCINES: CONSIDERING SEX DIFFERENCES IN EFFICACY AND SAFETY

The authors declare no other competing interests.