The morning Shelly Kendeffy received her second dose of the Moderna Covid-19 vaccine, she felt great. In the afternoon she noticed arm pain and body aches, and in the evening it was like the flu.
“My teeth were chattering, but I was sweating – like soaked, but frozen,” said Kendeffy, 44, a medical technician at State College in Pa.
The next day, she went to work and asked her colleagues – eight men and seven women – about their vaccination experiences. Six of the women had body aches, chills and fatigue. The only woman who didn’t have flu-like symptoms vomited most of the night.
The eight men gave radically different reports. One had a slight pain in his arm, a headache and body aches. Two described mild fatigue and a bit of stiffness. One has a headache. And four had no symptoms.
“I work with very tough women,” Kendeffy said. But “it is clear that we women have experienced severe side effects.” She felt better after 24 hours and is delighted to have received the vaccine. “I wouldn’t change a thing, because it certainly beats the alternative,” she said. “But I didn’t know what to expect either.”
The differences that Kendeffy sees among his colleagues are evident across the country. In a study published last month, researchers from the Centers for Disease Control and Prevention analyzed safety data from the 13.7 million first doses of the Covid-19 vaccine given to Americans. Of the side effects reported to the agency, 79.1% were from women, although only 61.2% of vaccines were given to women.
Almost all of the rare anaphylactic reactions to Covid-19 vaccines have also occurred in women. CDC researchers reported that the 19 people who had such a reaction to the Moderna vaccine were women, and women made up 44 of the 47 who had anaphylactic reactions to the Pfizer vaccine.
“I’m not at all surprised,” said Sabra Klein, a microbiologist and immunologist at the Johns Hopkins Bloomberg School of Public Health. “This sex difference is very much in line with previous reports on other vaccines.”
In a 2013 study, scientists at the CDC and other institutions found that four times as many women as men aged 20 to 59 reported allergic reactions after receiving the 2009 pandemic influenza vaccine, although more men than women have been vaccinated. Another study found that between 1990 and 2016, women accounted for 80% of all adult anaphylactic reactions to vaccines.
In general, women “have more reactions to a variety of vaccines,” said Julianne Gee, a physician in the CDC’s office of immunization safety. This includes influenza vaccines given to adults, as well as some given during infancy, such as hepatitis B and measles, mumps and rubella (MMR) vaccines.
However, not all news is bad for women. Side effects are usually mild and short-lived. And those physical reactions are a sign that a vaccine is working – that “you build a very robust immune response, and you’ll probably be protected as a result,” Klein said.
But why do these sex differences occur? Part of the answer could be behavioral. It’s possible that women are more likely than men to report side effects even when their symptoms are the same, said Rosemary Morgan, international health researcher at the Johns Hopkins Bloomberg School of Public Health. There is no vaccine-specific research to support this claim, but men are less likely than women to see a doctor when they are sick, so they may also be less likely to report side effects, a- she declared.
Yet there is no doubt that biology plays an important role. “The female immune response is distinct, in many ways, from the male immune response,” said Eleanor Fish, an immunologist at the University of Toronto.
Research has shown that, compared to their male counterparts, women and girls produce more, sometimes twice as much, anti-infective antibodies in response to vaccines against influenza, MMR, yellow fever, rabies and hepatitis A and B. Stronger responses of immune fighters called T cells, too, Gee noted. These differences are often strongest in young adults, which “suggests a biological effect, possibly associated with reproductive hormones,” she said.
Sex hormones, including estrogen, progesterone, and testosterone, can bind to the surface of immune cells and influence how they work. Exposure to estrogen causes immune cells to make more antibodies in response to the flu shot, for example.
And testosterone, Klein said, “is sort of beautifully immunosuppressive.” The flu shot tends to be less protective in men with high testosterone than in men with less sex hormones. Among other things, testosterone suppresses the body’s production of immune chemicals known as cytokines.
Genetic differences between males and females can also influence immunity. Many genes related to the immune system are found on the X chromosome, of which women have two copies and men have only one. Historically, immunologists believed that only one X chromosome in women was activated and the other was inactivated. But research now shows that 15% of genes escape this inactivation and are more highly expressed in women.
These robust immune responses help explain why 80% of autoimmune diseases affect women. “Women have greater immunity, whether it’s against ourselves, whether it’s against a vaccine antigen, whether it’s against a virus,” Klein said.
The size of a vaccine dose can also be important. Studies have shown that women absorb and metabolize drugs differently from men, often needing lower doses for the same effect. But until the 1990s, clinical trials of drugs and vaccines largely excluded women. “Recommended drug dosages are historically based on clinical trials involving male participants,” Morgan said.
Today’s clinical trials include women. But in trials for the new COVID vaccines, the side effects haven’t been sufficiently separated and analyzed by gender, Klein said. And they didn’t test whether lower doses could be just as effective for women but cause fewer side effects.
Until they do, Klein said, health care providers should talk to women about the side effects of vaccines so they aren’t frightened of them. “I think it’s helpful to prepare women to experience more adverse reactions,” she said. “This is normal and probably reflects how their immune system is working.”