The morning Shelly Kendeffy received her second dose of the Moderna Covid-19 vaccine, she felt fine. In the afternoon she noticed aching arms and body pain, and in the evening it felt like the flu.
“My teeth were chattering, but I was sweating – drenched but frozen,” said Ms. Kendeffy, 44, a medical technician at State College in Pennsylvania.
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 one woman who had no symptoms of the flu vomited most of the night.
The eight men gave drastically different reports. One had mild arm pain, headaches, and body aches. Two described slight fatigue and a little pain. You got a headache. And four had no symptoms at all.
“I work with some very tough women,” said Ms. Kendeffy. But “of course, we women suffered from the severity of the side effects.” After 24 hours she felt better and is thrilled that she got the vaccine. “I wouldn’t change anything because it sure beats the alternative,” she said. “But I also didn’t know what to expect.”
The differences that Ms. Kendeffy has observed between her employees play 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 percent were women, even though only 61.2 percent of the vaccines had been given to women.
Almost all rare anaphylactic reactions to Covid-19 vaccines have also occurred in women. CDC researchers reported that all 19 people who had such a reaction to the Moderna vaccine were female and that 44 of the 47 women 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 gender difference is completely in line with previous reports on other vaccines.”
In a 2013 study, scientists from the CDC and other institutions found that four times as many women as men between the ages of 20 and 59 reported allergic reactions after receiving the 2009 pandemic flu vaccine, even though more men than women received these shots . Another study found that between 1990 and 2016, 80 percent of all anaphylactic reactions in adults to vaccines occurred in women.
In general, “women are more responsive to a variety of vaccines,” said Julianne Gee, a doctor with the CDC’s Immunization Safety Bureau. These include influenza vaccines for adults, as well as some vaccines given in infancy such as hepatitis B and measles, mumps, and rubella (MMR) vaccines.
The news is not all bad for women, however. Side effects are usually mild and short-lived. And those physical responses are a sign that a vaccine is working – that “you are developing a very robust immune response and will likely be protected by it,” said Dr. Small.
But why do these gender differences happen? Part of the answer might be behavior. 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’re sick, so they may also be less likely to report side effects, she said.
However, there is no question that biology plays an important role. “The female immune response differs from the male immune response in a number of ways,” said Eleanor Fish, an immunologist at the University of Toronto.
Research has shown that women and girls produce more – sometimes twice as many – anti-infection antibodies in response to vaccines for influenza, MMR, yellow fever, rabies, and hepatitis A and B compared to their male counterparts. They take it too often. Ms. Gee noted that immune fighters, called T cells, also reacted more strongly. These differences are often most pronounced in younger adults, suggesting “a biological effect that may be linked to reproductive hormones,” she said.
Sex hormones such as estrogen, progesterone and testosterone can bind to the surface of immune cells and affect their functioning. For example, exposure to estrogen causes immune cells to produce more antibodies in response to the flu vaccine.
And testosterone, said Dr. Klein, “is kind of wonderfully immunosuppressive.” The flu vaccine tends to be less protective in men with high levels of testosterone than in men with fewer sex hormones. Among other things, testosterone suppresses the body’s own production of immune chemicals known as cytokines.
Genetic differences between men and women can also affect immunity. Many immune-related genes are on the X chromosome, of which women have two copies and men only one. In the past, immunologists believed that only one X chromosome was turned on and the other was inactivated in women. However, studies show that 15 percent of genes escape this inactivation and are more strongly expressed in women.
These robust immune responses explain why 80 percent of autoimmune diseases affect women. “Women have greater immunity, whether it’s ourselves, whether it’s a vaccine antigen, whether it’s a virus,” said Dr. Small.
The size of a vaccine dose can also be important. Studies have shown that women absorb and metabolize drugs differently than men and often require lower doses for the same effect. Until the 1990s, clinical trials of drugs and vaccines largely excluded women. “The recommended drug dosages are historically based on clinical studies involving male participants,” said Dr. Morgan.
Clinical trials today include women. However, in the studies for the new Covid vaccines, the side effects were not sufficiently segregated and analyzed by gender, said Dr. Small. And they didn’t test whether lower doses might be as effective for women but cause fewer side effects.
Until then, says Dr. Klein, health care providers should talk to women about vaccine side effects so they don’t fear them. “I think it makes sense to prepare women to have more side effects,” she said. “This is normal and probably a reflection of how your immune system is working.”