Women have a worse reaction to the Covid-19 vaccine than men—is that right?

By Madeline Keleher

Apr 13, 2021

You may have heard anecdotally from your Covid-19 vaccinated friends and family that those with the worst side effects have been women—particularly younger women. Or perhaps you’ve encountered a newspaper article about this phenomenon, like this excellent piece by The New York Times. Is this trend real? And is it unique to the Covid-19 vaccine? This calls for an investigation of the immune system.

In considering if younger women have more side effects, let’s first examine the age aspect of the question. Compared to younger people, those 65 and older have a 62 times higher chance of dying from Covid-19. As we age, our immune systems progressively weaken. Skin cells are replaced less, macrophages produce fewer cytokines, our bone marrow produces fewer stem cells, we make fewer immune cells, and we develop constant low-grade inflammation. These changes make us more likely to get sick and less responsive to vaccines.

Because older people make fewer and less potent antibodies after vaccination, a high-dose flu shot has been developed for people 65 and older, with a 4 times more potent dose. Older people have fewer side effects from the Covid-19 vaccine, likely because of an overall dampened immune response (although fortunately the vaccine is still highly effective in the elderly).

So that accounts for seeing more vaccine side effects in younger people. Let’s find out if their sex matters too.

Do men and women have different immune systems? They do. Women produce stronger immune responses than men, making more antibodies and clearing pathogens faster. Fewer women are infected by viruses than men, and when women are infected, their viral loads are lower. Women have a vastly lower Covid-19 death rate than men. Women also mount a greater immune response to vaccines for the flu, hepatitis B, and yellow fever. This difference is evident early in life, with baby girls mounting a greater immune response to vaccines for measles, diphtheria, and pertussis than baby boys, and girls in childhood having a greater response to vaccines for hepatitis B, rabies, pneumococcal pneumonia, and HPV than boys. This is true in mice, as well.

If you’d like to know why these differences exist on a cellular level, pardon my jargon when I say that compared to men, women have higher expression of toll-like receptor immune pathways, more efficient antigen-presenting cells, higher macrophage and T cell activation, and more B cells and CD4+ T cells. If the immune system is an army, women have stronger, more alert armies, with far more soldiers and ammo. Humans are not unique in this: female lizards, fruit flies, and birds also have stronger immune responses than males.

So how do women get these stronger immune systems? A lot of this has to do with sex chromosomes. Men have one X and one Y chromosome (XY), whereas women have two X chromosomes (XX). The tiny Y chromosome has only about 100 genes, whereas the much larger X chromosome has about 1,000, including many immune system genes.

Men have just one copy of X chromosome genes, but women have two. That means women have the potential to produce double the level of X chromosome proteins. To avoid having a potentially lethal double dose of all the X chromosome genes, female embryos randomly turn off one of the X chromosomes in each cell as they develop in the womb.

But here’s the catch: this system only works on about 85% of genes—the other 15% of X genes escape silencing and end up turned on much higher in women than in men. One of the genes that can escape silencing is Toll-like receptor 7 (TLR7). Its job is to find viruses and activate an immune response. It is, however, a double-edged sword. TLR7 is also linked to the autoimmune disorder lupus, which primarily afflicts women (90% of cases).

The role of the X chromosome in the immune system is evident in people with an unusual number of chromosomes. Men with Klinefelter syndrome, who have an extra X chromosome (XXY), have immune systems more like women’s, with higher numbers of B cells and CD4+ T cells. Likewise, women with Turner Syndrome (just one functioning X chromosome) have fewer T cells and B cells than typical XX women.

Sex hormones also play a role. Our immune cells have receptors for both estrogen and testosterone. Testosterone constrains inflammation, suppressing the immune system and worsening the severity of diseases like malaria and tuberculosis. Meanwhile, estrogen boosts immune activity in response to viruses. The responsiveness of the immune systems of transgender individuals changes with hormone treatment: those taking estrogens to transition from male to female start making more white blood cells and chemokine receptors, and those taking androgens to transition from female to male reduce the levels of antibodies in their blood.

I’m all about girl-power, but are there any costs to having a stronger immune system? Unfortunately, yes. Women are vastly more prone to autoimmune diseases, where one’s immune system is too active and attacks itself. Women also die of the flu more often than men, potentially due to creating a “cytokine storm,” when the immune system goes into life-threatening overdrive.

And because women mount a greater immune response to vaccines, they also have more adverse reactions. 80% of adults who develop life-threatening anaphylaxis from vaccines are women. When it comes to the Covid-19 vaccines, women report more side effects and comprise the vast majority of anaphylaxis cases (94% of Pfizer’s anaphylaxis cases and 100% of Moderna’s from December to January). All 6 people in the United States who developed blood clots after receiving the Johnson & Johnson vaccine are women under the age of 50. The majority of those who have developed blood clots after the AstraZeneca vaccine are women and younger than 55.

My little sister, feverish after her second dose of the Moderna vaccine, texted asking why a petite woman gets the same dose of mRNA in a vaccine as a 250-pound man. After all, she noted, Moderna is testing their vaccine in babies at a lower dose than is given to adults. My answer was that sex-specific vaccine dosing should be considered, but women have been excluded from biomedical research for a long time, and most clinical trials don’t analyze their results in men and women separately. If you don’t look, you won’t see.

But this is 2021, are women really still underrepresented in biomedical research?

Basic biomedical research has long left out females (some scientists claimed hormonal cycles were too complicated while others figured whatever happens in males is no different in females). Phase 3 clinical trials for new medicines weren’t even required to enroll any women until 1993. And it wasn’t until 2014, when I was halfway through graduate school, that the NIH finally mandated the inclusion of both males and females in research on animals and cells. However, the field has been slow to change. Heart disease is the top killer of women worldwide, but merely 38% of participants in cardiovascular clinical trials are women. In 2019, only 49% of all biomedical studies included both males and females. This is up from 28% in 2009, but a far cry from equality. Of those studies that did include both sexes, less than half actually analyzed the data by sex—the rest just lumped the males and females together and didn’t check if the treatments affected them differently (even though it is well-known that medications affect men and women differently, with adverse reactions such as liver toxicity, gastrointestinal problems, and allergic skin rashes more common in women). Women are hospitalized at a greater rate for adverse reactions to medications; by not having enough women in clinical trials, researchers underestimate the risk their drug may pose to women, and are free to unleash it into the unsuspecting public. In the last three years when I have served as a peer reviewer of other scientists’ manuscripts being considered for publication in research journals, I have encountered multiple studies that used only male mice, with no apparent rationale for excluding females nor an acknowledgment of the limitations of such an approach.

There are serious consequences to ignoring women. From coronary artery disease to neck pain, women with the same severity of symptoms as men receive less treatment. Doctors are less likely to refer women for diagnostic tests for cardiovascular disease, despite their having similar risk as men. In identical clinical circumstances, we perceive boys as being in more pain than girls. The healthcare system spends less money on treatments for women and is more likely to interpret men’s symptoms as “real” and physical, and women’s symptoms as psychological. For hundreds of diseases, women are diagnosed later than men. A woman having a heart attack in public is less likely to receive CPR from a bystander than a man is. When arriving at the hospital for chest pain, a woman with acute coronary syndrome is more likely to be misdiagnosed than a man—and she’s more likely to die of a heart attack if her doctor is male.

These new coronavirus vaccines are powerful, life-saving shots. I’ve already had my first dose and am eagerly awaiting my second. But it is high time to study Covid-19 vaccine side effects by sex, to test different dosing for women, and to give women appropriate information of the risks involved. Blood clots after vaccination are exceedingly rare, but they do happen, and everyone—particularly, young women—must know the danger signs. Seek medical attention if 1-3 weeks after your vaccine, you experience any of the following: severe headaches, shortness of breath, blurred vision, fainting, or pain in your abdomen or leg, as they may be symptoms of a blood clot.

A study of flu vaccine dosing found that women produced the same immune response with just a half dose as men did with a full dose. Giving sex-specific vaccine doses could potentially reduce side effects in women, as well as leave more vaccine doses to go around. But of nearly 2,500 ongoing Covid-19 trials, just 4% plan to analyze their data for differences based on sex. While Pfizer and Moderna did check if their vaccines were as effective in males and females (they are), they didn’t present analyses on side effects broken down by sex.

Men and women have immune systems that respond differently to infections, medications, and vaccines; studies that analyze the effects by sex will save lives.