Vaccine against COVID-19 (mRNA)Classification: A
Drug products: Comirnaty, Spikevax
ATC code: J07BN01
The pivotal clinical studies show similar efficacy of vaccine against COVID-19 (mRNA) in men and women. Significantly more of the spontaneously reported suspected adverse events are in women. Young men have an increased incidence of myocarditis after mRNA vaccination, although in very rare cases.
Men are at increased risk of worse outcome and mortality from COVID-19 compared to women. The sex difference is largest in the middle- and older age groups [1-6]. Generally, men have higher morbidity and mortality from lower respiratory tract infections [6, 7]. Possible explanations for these sex differences may be a combination of sex and gender factors. For example; the immunostimulatory effect of female sex hormones, higher levels of circulating ACE2 in women, and more women tend to follow hygiene and disease-preventive routines [1-3, 6, 8]. Other factors may also influence such as health-seeking behavior, smoking, obesity . So far, among published studies on pharmacological treatment in COVID-19 (including antiviral, antimalarial, and immune system modulating drugs), sex-specific analyses are rarely reported .
Pharmacokinetics and dosing
No pharmacokinetics studies of the active ingredients in mRNA-based vaccines against COVID-19 have been performed. This is in line with Note for guidance on preclinical pharmacological and toxicological testing of vaccines (CPMP/SWP/465/95) .
Generally about vaccines
Women generally develop stronger innate and adaptive immune responses, express higher antibody levels, and greater T-cell activation, compared to men. These sex differences are observed in response to a variety of vaccines, including vaccines against influenza, yellow fever, rubella, measles, mumps, hepatitis A and B, herpes simplex 2, rabies, dengue and smallpox [12, 13]. However, the mechanisms behind these sex differences in response to vaccines are unknown and may differ based on the recipient’s age, type of vaccine, and type of protective immune responses elicited .
Specific for vaccines against COVID-19 (mRNA)
The pivotal studies, on which registration of the vaccines was based, report that men and women have similar efficacy of mRNA vaccines against COVID-19 [14, 15]. The efficacy of Comirnaty was evaluated in a multinational, placebo-controlled, observer-blind trial including persons 16-91 years of age (19 075 men, 18 631 women; median age 52 years). Vaccine efficacy was measured as first COVID-19 occurrence from seven days after the second dose. Subgroup analyses showed similar efficacy in men and women (96.4% in men, 93.7% in women) . Furthermore, the efficacy of Spikevax was evaluated in a phase 3 randomized, observer-blind, placebo-controlled trial including adults (18-95 years) at high risk for SARS-CoV-2 infection or its complications (15 985 men, 14 366 women; mean age 51.4 years). Vaccine efficacy was measured as COVID-19 cases 17 days after the second dose. Subgroup analyses showed similar efficacy in men and women (95.4% in men, 93.1% in women) .
Some studies indicate that mRNA vaccination generates greater antibody response in women compared to men while other studies indicate no sex differences in antibody response [16, 17].
Generally about vaccines
Women generally have higher rates of adverse events including pain, fever, and inflammation to vaccines. These sex differences are observed in response to a variety of vaccines, including vaccines against influenza, yellow fever, and hepatitis B [12, 13]. However, information about adverse events is often self-reported and may thus reflect a gender difference, in which women are more likely to report adverse events [12, 18-21].
Specific for vaccines against COVID-19 (mRNA)
According to the pivotal clinical trials for Comirnaty, no clinically meaningful differences in adverse events were observed in men and women (sex-divided data not shown) . No sex-divided data on adverse events from Spikevax have been reported by the pharmaceutical company .
Among reports of suspected adverse reactions for the two vaccines Comirnaty and Spikevax registered in the European database EudraVigilance, the majority of individual cases are women . The most common adverse events reported are the same for both vaccines and same in both men and women: fever, fatigue, pain at the injection site, headache, dizziness, numbness, extremity pain, muscle pain, joint pain . Safety data show that inflammation of the heart (myocarditis) or membrane (pericarditis) can occur in very rare cases following vaccination with Spikevax or Comirnaty. The cases primarily occurred within 14 days after vaccination, more often after the second dose and in younger adult men [25, 26]. This has been confirmed in a large cohort study (11 515 016 men, 11 607 506 women) based on data from registers in Northern Europe, the prevalence of myocarditis was higher after the second dose and higher in younger men. The risk of myocarditis was higher after vaccination with two doses of Spikevax than two doses of Comirnaty (on average 18.4 vs 5.6 number of excess events in 28 days per 100 000 vaccinees . In general, the population prevalence of myocarditis is higher in men than women  The risk of myocarditis is higher after infections [29, 30].
Reproductive health issues
Regarding teratogenic aspects, please consult Janusmed Drugs and Birth Defects (in Swedish, Janusmed fosterpåverkan).
Date of litterature search: 2022-04-22
- Kelada M, Anto A, Dave K, Saleh SN. The Role of Sex in the Risk of Mortality From COVID-19 Amongst Adult Patients: A Systematic Review. Cureus. 2020;12(8):e10114. PubMed
- Lakbar I, Luque-Paz D, Mege JL, Einav S, Leone M. COVID-19 gender susceptibility and outcomes: A systematic review. PLoS One. 2020;15(11). länk
- Mesas AE, Cavero-Redondo I, Álvarez-Bueno C, Sarriá Cabrera MA, Maffei de Andrade S, Sequí-Dominguez I et al. Predictors of in-hospital COVID-19 mortality: A comprehensive systematic review and meta-analysis exploring differences by age, sex and health conditions. PLoS One. 2020;15(11):e0241742. PubMed
- Figliozzi S, Masci PG, Ahmadi N, Tondi L, Koutli E, Aimo A et al. Predictors of adverse prognosis in COVID-19: A systematic review and meta-analysis. Eur J Clin Invest. 2020;50(10):e13362. PubMed
- Ortolan A, Lorenzin M, Felicetti M, Doria A, Ramonda R. Does gender influence clinical expression and disease outcomes in COVID-19? A systematic review and meta-analysis. Int J Infect Dis. 2020;99:496-504. PubMed
- Centrum för epidemiologi och samhällsmedicin. Kön och risk för allvarlig sjukdom och död i covid-19. Stockholm: Centrum för epidemiologi och samhällsmedicin (CES); 2021.
- Falagas ME, Mourtzoukou EG, Vardakas KZ. Sex differences in the incidence and severity of respiratory tract infections. Respir Med. 2007;101(9):1845-63. PubMed
- Wray S, Arrowsmith S. The Physiological Mechanisms of the Sex-Based Difference in Outcomes of COVID19 Infection. Front Physiol. 2021;12:627260. PubMed
- Griffith DM, Sharma G, Holliday CS, Enyia OK, Valliere M, Semlow AR et al. Men and COVID-19: A Biopsychosocial Approach to Understanding Sex Differences in Mortality and Recommendations for Practice and Policy Interventions. Prev Chronic Dis. 2020;17:E63. PubMed
- Schiffer VMMM, Janssen EBNJ, van Bussel BCT, Jorissen LLM, Tas J, Sels JEM et al. The "sex gap" in COVID-19 trials: a scoping review. EClinicalMedicine. 2020;29:100652. PubMed
- European Medicines Agency (EMA). Note for guidance on preclinical pharmacological and toxicological testing of vaccines (CPMP/SWP/465/95) [updated 1997-12-17, cited 2021-04-08]. länk
- Klein SL, Marriott I, Fish EN. Sex-based differences in immune function and responses to vaccination. Trans R Soc Trop Med Hyg. 2015;109(1):9-15. PubMed
- Flanagan KL, Klein SL, Skakkebaek NE, Marriott I, Marchant A, Selin L et al. Sex differences in the vaccine-specific and non-targeted effects of vaccines. Vaccine. 2011;29(13):2349-54. PubMed
- Polack FP, Thomas SJ, Kitchin N, Absalon J, Gurtman A, Lockhart S et al. Safety and Efficacy of the BNT162b2 mRNA Covid-19 Vaccine. N Engl J Med. 2020;383(27):2603-2615. PubMed
- Baden LR, El Sahly HM, Essink B, Kotloff K, Frey S, Novak R et al; COVE Study Group. Efficacy and Safety of the mRNA-1273 SARS-CoV-2 Vaccine. N Engl J Med. 2021;384(5):403-416. länk
- Demonbreun AR, Sancilio A, Velez ME, Ryan DT, Pesce L, Saber R et al. COVID-19 mRNA Vaccination Generates Greater Immunoglobulin G Levels in Women Compared to Men. J Infect Dis. 2021;224(5):793-797. PubMed
- Wheeler SE, Shurin GV, Yost M, Anderson A, Pinto L, Wells A et al. Differential Antibody Response to mRNA COVID-19 Vaccines in Healthy Subjects. Microbiol Spectr. 2021;9(1):e0034121. PubMed
- Watson S, Caster O, Rochon PA, den Ruijter H. Reported adverse drug reactions in women and men: Aggregated evidence from globally collected individual case reports during half a century. EClinicalMedicine. 2019;17:100188. PubMed
- Kroenke K, Spitzer RL. Gender differences in the reporting of physical and somatoform symptoms. Psychosom Med. 1998;60(2):150-5. PubMed
- Barsky AJ, Peekna HM, Borus JF. Somatic symptom reporting in women and men. J Gen Intern Med. 2001;16(4):266-75. PubMed
- Holm L, Ekman E, Jorsäter Blomgren K. Influence of age, sex and seriousness on reporting of adverse drug reactions in Sweden. Pharmacoepidemiol Drug Saf. 2017;26(3):335-343. PubMed
- Assessment report - Comirnaty (tozinameran). European Medicines Agency (EMA) [www]. [updated 2021-02-19, cited 2021-04-08]. länk
- Assessment report - COVID-19 Vaccine Moderna (modified mRNA, encoding full length SARS-CoV-2 spike protein (CX-024414)). European Medicines Agency (EMA) [www]. [updated 2021-03-11, cited 2021-04-08]. länk
- EudraVigilance. Amsterdam: European Medicines Agency (EMA) [updated 2021-04-17, cited 2021-04-23.] länk
- COVID-19 vaccine safety update - SPIKEVAX. European Medicines Agency (EMA) [www]. [updated 2021-07-14, cited 2021-10-06]. länk
- COVID-19 vaccine safety update - COMIRNATY. European Medicines Agency (EMA) [www]. [updated 2021-07-14, cited 2021-10-06]. länk
- Karlstad Ø, Hovi P, Husby A, Härkänen T, Selmer RM, Pihlström N et al. SARS-CoV-2 Vaccination and Myocarditis in a Nordic Cohort Study of 23 Million Residents. JAMA Cardiol. 2022. PubMed
- Statistikdatabas för diagnoser. Stockholm: Socialstyrelsen. 2020 [cited 2021-10-06.] länk
- Cooper LT, Keren A, Sliwa K, Matsumori A, Mensah GA. The global burden of myocarditis: part 1: a systematic literature review for the Global Burden of Diseases, Injuries, and Risk Factors 2010 study. Glob Heart. 2014;9(1):121-9. PubMed
- Mattsson G, Levin C, Magnusson P. ABC om - perikardit och myokardit. Lakartidningen. 2018;115. PubMed
- Statistik för vaccination mot covid-19. Folkhälsomyndigheten [www]. [updated 2021-04-09, cited 2021-04-23]. länk
Reviewed by: Diana Rydberg, Carl-Olav Stiller
Approved by: Karin Schenck-Gustafsson