Women tend to report more side effects from vaccines of any kind, including the novel coronavirus vaccines, than do men. Writing for the New York Times, Melinda Wenner Moyer investigates the factors behind this discrepancy—and shares how physicians can help women prepare accordingly for the Covid-19 vaccine.

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Background

According to Julianne Gee, a medical officer in CDC's Immunization Safety Office, women in general "have more reactions to a variety of vaccines" than men do. Those vaccines include not only the newly authorized Covid-19 vaccines, but also the seasonal influenza vaccine, some vaccines administered during infancy—including the hepatitis B and measles, mumps, and rubella (MMR) vaccines—and more.

For instance, in a 2013 study, researchers at CDC and other organizations found that four times as many women as men between 20 and 59 who received the 2009 pandemic flu vaccine said they experienced allergic reactions, even though more men than women received the inoculation. Similarly, a separate study found that women accounted for 80% of all anaphylactic reactions to vaccines administered to adults between 1990 and 2016.

And just last month, CDC researchers published a study in which they examined the safety data from the first 13.7 million Covid-19 vaccine doses administered to Americans and found that 79.1% of reported side effects occurred in women—even though women received only 61.2% of administered doses.

Further, CDC has also found that all but three of the rare anaphylactic reactions to Covid-19 vaccines occurred in women. Specifically, according to the agency, women accounted for all 19 of the individuals who experienced such a reaction to the Moderna vaccines, and they accounted for 44 of the 47 who had such a reaction to the Pfizer/BioNTech vaccine.

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Why do women report more side effects?

There are several reasons behind this discrepancy in vaccine reactions and experiences, Moyer writes.

One factor may be behavioral, according to Rosemary Morgan, an international health researcher at the Johns Hopkins Bloomberg School of Public Health. She explained that men are less likely than women to visit their care providers when ill, so they may be less likely to report vaccine side effects as well—although no research has specifically examined this possibility.

That said, Eleanor Fish, an immunologist at the University of Toronto, noted that biology plays a large part in why women experience vaccines so differently than men. "The female immune response is distinct, in many ways, from the male immune response," she said.

For instance, according to Gee, research has shown that women, when compared with men, produce up to twice as many infection-fighting antibodies—and frequently mount stronger T cell responses—in reaction to the vaccines for hepatitis A and B, influenza, MMR, rabies, and yellow fever. The discrepancies are strongest in young adults, which "suggests a biological effect, possibly associated with reproductive hormones," Gee said.

According to Moyer, sex hormones such as estrogen, progesterone, and testosterone can bind to immune cells' surfaces and affect how they operate. For example, immune cells that are exposed to estrogen tend to produce more antibodies in response to the flu vaccine.

Meanwhile, testosterone "is kind of beautifully immunosuppressive," Sabra Klein, a microbiologist and immunologist at the Johns Hopkins Bloomberg School of Public Health, said. Men who have high testosterone levels generally derive less protection from the flu vaccine than do men with lower levels, for instance, Moyer writes. And testosterone, in addition to other effects, lowers the body's production of cytokines.

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Another factor to consider is genetics, Moyer adds. Many genes related to immunity are found on the X chromosome, of which women usually have two and men have just one. And while immunologists have historically believed that only one X chromosome in women was activated, modern research indicates at least 15% of genes escape the "inactivation" of the second X chromosome and are in fact "more highly expressed in women," Moyer writes.

According Moyer, that more robust immune response may help explain why 80% of autoimmune diseases affect women. As Klein put it, "Women have greater immunity, whether it's to ourselves, whether it's to a vaccine, whether it's to a virus."

Still another factor that could influence women's experience with vaccines is the size of the dose, Moyer writes. Research shows that women—who absorb and metabolize medicine differently than men—can generally get the same effect from a drug with a lower dose, Moyer writes. Even so, clinical trials for drugs and vaccines up until the 1990s traditionally excluded women. "The drug dosages that are recommended are historically based on clinical trials that involve male participants," Morgan explained.

And while trials today generally include female participants, Klein said, the clinical trials for the currently authorized Covid-19 vaccines did not distinguish and examine side effects by sex, nor did they assess whether women could generate a sufficient immune response with a lower dose that causes fewer side effects.

Until they do, Klein recommended that health care providers proactively talk to women about the potential for more severe side effects so they are not disturbed by them. "I think there is a value to preparing women that they may experience more adverse reactions," she said. "That is normal, and likely reflective of their immune system working" (Moyer, New York Times, 3/8).