On the morning that Shelly Kendeffy received her second dose of the Moderna COVID-19 vaccine, she felt fine. By afternoon, she noticed a sore arm and body aches, and by evening, it felt like the flu.
“My teeth were chattering, but I was sweating — like soaked, but frozen,” said Kendeffy, 44, a medical technician in State College, Pennsylvania.
The next day, she went to work and surveyed her colleagues — eight men and seven women — about their vaccine experiences. Six of the women had body aches, chills and fatigue. The one woman who didn’t have flu symptoms was up much of the night vomiting.
The eight men gave drastically different reports. One had mild arm pain, a headache and body aches. Two described mild fatigue and a bit of achiness. One got a headache. And four had no symptoms at all.
“I work with some very tough women,” Kendeffy said. But “clearly, us women suffered a severity of the side effects.” She felt better after 24 hours, and is thrilled she got the vaccine. “I wouldn’t change a thing, because it sure beats the alternative,” she said. “But I also didn’t know what to expect.”
The differences Kendeffy observed among her co-workers are playing out across the country. In a study published last month, researchers from the Centers for Disease Control and Prevention analyzed safety data from the first 13.7 million COVID-19 vaccine doses given to Americans. Among the side effects reported to the agency, 79.1% came from women, even though only 61.2% of the vaccines had been administered to women.
Nearly all of the rare anaphylactic reactions to COVID-19 vaccines have occurred among women, too. CDC researchers reported that all 19 of the individuals who had experienced such a reaction to the Moderna vaccine have been female, and that women made up 44 of the 47 who have had anaphylactic reactions to the Pfizer vaccine.
“I am not at all surprised,” said Sabra Klein, a microbiologist and immunologist at the Johns Hopkins Bloomberg School of Public Health. “This sex difference is completely consistent with past reports of other vaccines.”
In a 2013 study, scientists with the CDC and other institutions found that four times as many women as men between ages 20 and 59 reported allergic reactions after receiving the 2009 pandemic flu vaccine, even though more men than women got those shots. 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 medical officer in the CDC’s Immunization Safety Office. That includes influenza vaccines given to adults, as well as some given in infancy, such as the hepatitis B and measles, mumps and rubella (MMR) vaccines.
The news isn’t all bad for women, though. Side effects are usually mild and short-lived. And these physical reactions are a sign that a vaccine is working — that “you are mounting a very robust immune response, and you will likely be protected as a result,” Klein said.
But why do these sex differences happen? 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, an international health researcher at the Johns Hopkins Bloomberg School of Public Health. There’s no vaccine-specific research to support this claim, but men are less likely than women to see doctors when they are sick, so they may also be less likely to report side effects, she said.
Still, there’s no question 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 with their male counterparts, women and girls produce more — sometimes twice as many — infection-fighting antibodies in response to the vaccines for influenza, MMR, yellow fever, rabies, and hepatitis A and B. They often mount stronger responses from immune fighters called T cells, too, Gee noted. These differences are often most robust among younger 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 produce more antibodies in response to the flu vaccine, for example.
And testosterone, Klein said, “is kind of beautifully immunosuppressive.” The flu vaccine tends to be less protective in men with lots of testosterone compared with men with less of the sex hormone. Among other things, testosterone suppresses the body’s production of immune chemicals known as cytokines.
Genetic differences between men and women may also influence immunity. Many immune-related genes are 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 turned on, and that 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 to explain why 80% of autoimmune diseases afflict women. “Women have greater immunity, whether it’s to ourselves, whether it’s to a vaccine antigen, whether it’s to a virus,” Klein said.
The size of a vaccine dose may also be important. Studies have shown that women absorb and metabolize drugs differently than men do, often needing lower doses for the same effect. But until the 1990s, drug and vaccine clinical trials largely excluded women. “The drug dosages that are recommended are historically based on clinical trials that involve male participants,” Morgan said.
Clinical trials today do include women. But in the trials for the new COVID vaccines, side effects were not sufficiently separated and analyzed by sex, Klein said. And they did not test whether lower doses might be just as effective for women but cause fewer side effects.
Until they do, Klein said, health care providers should talk to women about vaccine side effects so they are not scared by them. “I think that there is value to preparing women that they may experience more adverse reactions,” she said. “That is normal, and likely reflective of their immune system working.”