Anna Kern, a 33-year-old nurse practitioner in Ferndale, Michigan, didn’t expect to get COVID-19 after being vaccinated. She got her shots in January, but then in April, she tested positive after being exposed to the virus through an unvaccinated coworker. She has had chills, fatigue, and a racing heart ever since.
“You feel lots of guilt — like, what did I do wrong? How could I have been more cautious?” Kern told Insider, adding, “It feels weird to be a statistical anomaly.”
Breakthrough infections — cases of COVID-19 diagnosed at least two weeks after someone is fully vaccinated — are indeed rare. Just 0.01% of vaccinated Americans had developed breakthrough infections as of April 30, according to a recent report from the Centers for Disease Control and Prevention. But the CDC data suggests that women represent a majority of these cases: 63%.
That’s consistent with clinical trial data, which suggests that coronavirus vaccines are slightly less effective among women. Pfizer’s COVID-19 vaccine was found to have a 96.4% efficacy rate in men, but 93.7% in women. Its widely cited 95% efficacy rate is an average of those two results.
Moderna’s vaccine, meanwhile, was found to have a 95.4% efficacy rate in men, but 93.1% in women. And Johnson & Johnson’s shot reduced the risk of moderate to severe COVID-19 by 68.8% in men, but 63.4% in women.
Together, these results are “a bit perplexing,” Sabra Klein, co-director of the Johns Hopkins Center for Women’s Health, Sex, and Gender Research, told Insider.
Normally, women mount stronger immune responses to vaccines than men do, which often leads to greater protection. Scientists suspect that higher levels of estrogen play a role in this, since estrogen stimulates the immune system.
Klein has a theory as to why that same pattern isn’t playing out for the coronavirus vaccines: It’s possible the shots might be less effective against coronavirus variants for women than for men. Five “variants of concern” have caused the majority of breakthrough infections in the US.
Vaccines train the body to recognize the original coronavirus identified in Wuhan, so they might still work well against that strain in women.
“The whole basis of vaccination is to have some memory cells so that, should you get infected with the virus, if it’s even possible to get for you to get infected, you would be asymptomatic as opposed to being symptomatic because your immune system’s already been trained,” Klein said. “So it might be that some of that training and the specificity of that training is greater for females than males.”
There are, of course, other possible explanations. More women than men have been vaccinated so far, and women could be more inclined to seek out COVID-19 tests or report their illness if they’re experiencing breakthrough symptoms. Women also represent the majority of healthcare workers, who are regularly screened for coronavirus infections at work. So it’s possible that the vaccines won’t turn out to be less effective among women after all.
But it’s hard to determine the answer, Klein said, without more data on how each sex is responding to vaccines.
“The biological differences between males and females and how this could be playing out in response to these vaccines has really not received adequate attention,” she said. “I definitely don’t think these kinds of things should be ruled out — and that’s often what happens because it’s easier to think this is reporting bias than something real.”
Age could also influence vaccine efficacy in women
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Few real-world studies have examined the effectiveness of coronavirus vaccines among men versus women in great detail, so scientists are hesitant to say whether women are more likely to develop breakthrough infections.
“While the overall percent of reported breakthrough infections was higher in women, we do not know the sex-disaggregated numbers for the severity of these infections,” Vaishali Moulton, an assistant professor of medicine at Beth Israel Deaconess Medical Center, told Insider.
Researchers also don’t know whether vaccine effectiveness is particularly low for women in a certain age bracket.
On average, people who have experienced breakthrough infections are between 40 and 74 years old, the CDC report found. Most women undergo menopause between 40 and 60 — so that could partly explain why vaccine efficacy was lower in that group.
“We know that some of the female immunity definitely declines post-menopausally and is associated with a reduction in estrogen,” Klein said.
Since no mRNA vaccine had been authorized before last year, scientists are also considering whether the platform itself might stimulate different immune responses in each sex.
A new study suggests that men and women may respond differently to the lipid molecules that mRNA vaccines use to deliver coded messages to the body. The researchers found that natural killer cells — a type of immune cell that helps fight off infection — absorbed fewer lipid molecules in female blood samples than in male samples.
Klein said it’s important to explore these sex-based differences quickly, since more breakthrough infections could allow the pandemic to stretch on.
“If we don’t have good efficacy of this vaccine in all people, two things are going to happen,” Klein said. “You’re going to have these breakthrough cases and we are not going to be able to really stop the spread as much as we hope we will. You’re also going to start to lose public trust.”
Vaccine trials have a history of focusing on men
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Vaccine trials have a long history of focusing on male participants. US trials weren’t legally required to enroll women until 1993, when Congress passed the National Institutes of Health Revitalization Act.
Prior to that, women were often left out of medical research because doctors and scientists were concerned that experimental drugs could pose a health risk to babies if a woman became pregnant during a study. Researchers also worried that women’s fluctuating hormone levels could complicate trial results. In 1997, the Food and Drug Administration even recommended excluding women of reproductive age — as well as women who were single, used contraception, or whose husbands had gotten a vasectomy — from early-stage drug trials.
In general, today’s clinical trials often prefer to enroll women taking
birth control
due to similar concerns about pregnancy, Klein said. Many early-stage vaccine trials also default to using exclusively male mice to avoid having to factor in hormonal differences between the sexes. But even when female participants are included in trials, Klein said, there’s no requirement that the results be analyzed separately for men and women.
That often means that women don’t receive the ideal vaccine dose: Women only need half the standard dose of the seasonal flu vaccine, for instance, to generate the same amount of protective immunity as men do. As a result, women are more prone to adverse reactions from drugs or vaccines. A report last year found that women experience adverse drug reactions nearly twice as often as men do.
Some of these issues could be playing out now with coronavirus vaccines.
The vaccines’ early-stage trials included female animals, and human trials enrolled a relatively equal share of men and women. But the trials didn’t separate data for the sexes when it came to side effects, and pregnant women were excluded.
“Whether you’re talking about male-female differences, or you’re talking about pregnancy, a lot of this could have started in preclinical studies in order to just test some of these things,” Klein said. “All too often, the dogma is that biological sex isn’t important in this context.”
Real-life data has also revealed that women tend have more severe side effects after their coronavirus shots than men do. A February report found that roughly 79% of instances of vaccine side effects reported to the CDC came from women, though just 61% of doses were administered to women overall.
Women also represent the majority of people who experience adverse reactions to coronavirus vaccines, including rare blood clots and anaphylaxis (a severe allergic reaction).
Still, biologists like Klein are hopeful that vaccine researchers will begin studying female subjects more closely in the near future.
“If there’s one silver lining of the pandemic for people like myself who work in the broader area of women’s health, it’s that it’s finally making it very clear that women’s health extends beyond our reproductive tract and that we really should be studied and compared with men,” she said.
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