Why Are Women Bearing the Brunt of Vaccine Side Effects?

Six of the six people who developed a rare blood clotting disorder after being inoculated with the one-shot Johnson & Johnson vaccine were women. Of the 66 cases of anaphylaxis reported after the Moderna and Pfizer vaccines, 63 were women. And of the blood clots that have prompted European countries to suspend the use of the AstraZeneca vaccine, two-thirds occurred in women.

It’s not just these severe and incredibly rare side effects — in the case of Johnson and Johnson, just six people out of more than 6.8 million vaccinated, or 0.00000088% — that are borne disproportionately by women, but a majority of mild and moderate side effects reported from the vaccine as well. (After calling for a “pause” in distribution of the Johnson and Johnson vaccine, the CDC’s Advisory Committee on Immunization Practices will hold an emergency meeting on Wednesday to investigate whether there is a link between the vaccine and the blood clots.)

Dr. Sabra Klein, professor at the Johns Hopkins Bloomberg School of Public Health and co-director of the Center for Women’s Health, Sex, and Gender Research, spoke to Rolling Stone about what researchers do and don’t know about the reasons why women have reported more reactions to the covid vaccines, while men have been effected more severely by the virus itself.

Is it accurate to say that women are experiencing more adverse events from vaccines than men?
Yeah, I think that’s completely accurate. [But], to qualify the accuracy of that statement, a majority of adverse reactions are mild to moderate. “Mild” might be local reactions, like soreness at the site of injection, maybe a little bit of redness, swelling. “Moderate” might start to move into some of those more systemic, like having a headache or some chills, maybe some nausea, fatigue or even a mild fever. Women report that they are more likely to experience side effects from vaccines. And I purposely use that word experience because we can’t ignore [the possibility] that there can be reporting biases.

The Centers for Disease Control, the CDC, implemented the V-safe program so that they can be monitoring these things — it might be that women are more likely to engage with that app. Maybe women are just more likely to be in-touch with their bodies, or to utilize an opportunity made available to them to express how they’re feeling. And then there are issues surrounding masculinity, and perceptions of pain, and reporting of pain.

What about these more severe reactions?

When you start to get into the possibility of more severe adverse reactions, like the anaphylaxis, the severe allergic reaction — again, very, very rare: we’re talking about two to four cases per every million doses given — but 97 percent of them have been in women. Blood clots from the adenovirus vector vaccines — again, unbelievably rare — but for the Johnson and Johnson vaccine, six of the six women; nine out of 11 for AstraZeneca.

When you’re talking about an allergic reaction like what we’ve seen reported and published for the Moderna vaccine… There were pictures of 12 patients who were studied, 10 of the 12 were women. So it is not to say that none of this happens in men, but it’s shocking how many more women it is. And these are things that maybe aren’t so much about just reporting biases. These are visible. These are more serious.

What do we know about the way that women react differently to the vaccines?
One of the things that work from my lab and others have consistently shown is that women often mount greater immune responses to vaccines and than do men. 

One of the common phrases that I used to always hear with the flu vaccine is people reporting that they got the flu from the flu vaccine. You never get the flu from the flu vaccine — the flu shot is inactivated, it can’t replicate, you can’t get the flu. But people will tell you how badly they felt after getting it. And the reason you’re feeling bad isn’t because of the virus — it’s because of your immune response to the vaccine. We don’t attribute feeling sick to an activated immune response, but that’s precisely what causes us to feel sick. It triggers areas of our brain that control our nausea, that control our thermo-regulation, and do things that all of us attribute to being sick. 

Women often mount these types of responses to a greater degree than men. It’s not that men don’t mount them, it’s that women tend to mount them to a greater degree. 

We’re all still trying to fully understand this, but my hypothesis, based on available data, is that greater immunity in females is the double edged sword. Greater immunity can protect you against a replicating virus, it can provide you with protective immunity following vaccination, but it can also contribute to some of these side effects. 

Some women have reported changes to their menstrual cycle after the vaccine — have you seen or heard anything about that?
I have seen that — I haven’t seen an academic study of this. At this moment, I don’t know what to say because I’ve only seen this on Twitter. That’s not to say that anecdotal observations don’t then sometimes form the basis to study something. But I’ve had so many reporters query me, and I’ve turned immediately to the people running trials at Johns Hopkins for each of these different vaccines. And they have no specific data that’s been collected, pertaining, you know, or reporting from the people in their phase three trials about the menstrual cycle. Don’t forget that in the trials, women had to be on birth control. 

Hormonal birth control, or just using any form of birth control?
Using a form of birth control, but they were encouraged to be taking some type of oral contraceptive that could allow them to control and confirm they were not going to get pregnant during the trial. 

Is the fact that there isn’t data available about the impact of the vaccines on women’s periods — is that because researchers didn’t ask about, or because participants didn’t volunteer that information?
I think it’s not asked about. I think aspects of other aspects of women’s health are all too often treated as “bikini science.” I think all too often and we don’t think about the fact that women may respond differently to drugs, as well as things like vaccines. 

I don’t think we think about the bidirectional interactions: it could be that a woman’s hormonal status, even her genetics, can impact how she responds to a virus or to a vaccine.

What, genetically speaking, affords women greater immunity from the virus than men? We’ve seen that men are more severely affected by the virus itself — what’s going on there?
So, biological females have two X chromosomes. Biological males have an X and Y. The X chromosome, it’s large, it’s genetically very rich — there are over 11,000 genes on our X chromosome — and it also turns out to be highly enriched for genes that are very important for our immune responses. And we really don’t understand why. 

And, technically, that shouldn’t matter because there is a genetic process of X-inactivation [in biological [females] where one copy of the genes on our X chromosome get inactivated randomly. You and I should technically not have any greater expression of anything encoded on the X chromosome than a biological male. [But] roughly 15 percent of the genes on the X chromosome escape X-inactivation, and actually have greater expression in cells from biological females than males. So there’s a very good chance that both you and I, [as biological women], have higher expression of some of these immune response genes than a biological male.

What is it about a woman’s hormonal status that could impact the way she responds to a virus or vaccine? Why do hormones matter?

Why does it matter that women will have greater concentrations of estrogen or progesterone, and males have higher concentrations of androgen, and why would that even matter for your immune system? These hormones, when they bind to their receptors inside of our immune cells, they can regulate the activity of those immune cells. They can make those cells make more of certain proteins, they can cause those cells to make less of certain proteins. 

My [research] group and others, we’ve shown that, for example, estrogen tells the cells that make the antibody that gets stimulated following vaccination to make more antibodies. Estrogen causes more antibodies to get made by B cells. And that is great when we’re talking about a vaccination. But other groups have shown that same mechanism contributes to how it is that females are more likely to develop autoimmune diseases. So it’s great when you’re developing all those antibodies and making that response to something foreign. It’s all of a sudden very harmful when it’s being made against yourself.

When you hear that all six of these women who developed the rare blood clot after the Johnson and Johnson vaccination were of reproductive age — 13 to 48 — would that make you think that hormones are somehow at play in this? 

They could be. Absolutely. Absolutely. I would hypothesize. Now, I think, it’s also important, you know, just a little caveat, it’s probably a majority of younger people receiving the Johnson & Johnson vaccine because, in most states, older people were getting vaccinated when only the Pfizer and Moderna vaccines were available. So we may have a sampling bias problem that we can’t ignore. But if it did turn out that even among people of diverse ages receiving the vaccine you only see this in younger age women, then absolutely. [That said,] I’ve seen all over Twitter today just a lot of frustration expressed among women that we care about six cases of blood clots caused by a vaccine, but when blood clots — some of which can be fatal — are caused by oral contraceptives, it does not get this kind of publicity, and the rates of blood clots from oral contraceptives are similar to what this is.

This interview has been edited for clarity and length.

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