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Why Do Mostly Women Report "COVID Vaccine Arm"?

Out of 396 people with COVID vaccine arm, 378 were women, and only 18 were men.

Key points

  • An 8th-day delayed skin reaction at the vaccine injection site, allergic shock, and blood clots are being reported by women more than men.
  • Researchers hypothesize that this difference is probably multifactorial: Genetics, hormones, and fat/muscle ratio all play a role.
  • Research shows women tend to have a stronger immune reaction and more side effects to many vaccines than men. Is personalized vaccinology needed?

After writing about my unexpected 8th day “COVID vaccine arm” rash, I had 396 people email me saying they were having the same reaction: redness and itchiness (which all resolved) around the injection site starting at day 8 or even later after the first COVID vaccine shot, most of them after the Moderna vaccine. Out of those 396 people, 378 (95.4 percent) were women, and only 18 (4.6 percent) were men.

The huge ratio of women versus men really surprised me.

I was not the only one who noticed that mostly women self-reported delayed skin reactions near the injection site after the first Moderna COVID vaccine shot.

Dr. Kimberly Blumenthal, allergist and researcher at Massachusetts General Hospital and author of a letter to the editor published in the New England Journal of Medicine, reports that her first study on delayed skin reaction to the Moderna vaccine was on 12 people (10 women and 2 men), but since she opened her website recently for patients to self-report, a lot more women contacted her than men.

Dr. Samarakoon, who works with Dr. Blumenthal, told me yesterday: “186 patients reported a delayed, large, local skin reaction with onset of symptoms at or after 8 days after vaccination. Of these cases, 95 percent are females. Eighty-eight percent of these delayed reactions are reported for the Moderna Vaccine.”

This 95 percent female/male ratio is very similar to my 95.4 percent female/male ratio.

Why such a large gender difference?

Could it be because in December 2020 and February 2021, health care workers got vaccinated first? And we know that there is a higher percentage (nearly 80 percent) of female health care workers versus male health care workers. But I witnessed a 95.4 percent female to male ratio that was much higher than the 80 percent ratio of female to male health care workers. Moreover, the disproportionate incidence of skin reaction in women versus men continues as people other than health care workers are now getting vaccines.

What other reason could create a 95.4 percent female-to-male ratio in this 8th-day skin reaction?

Could it be that women, in general, are more likely than men to report and seek help when experiencing adverse reactions? Possibly.

But I had several women (including myself) reporting that they got the vaccine at the same time as their husband, and the husband didn’t get any side effects from the vaccine, whereas the women got an 8th-day rash. That seemed to indicate a sex difference.

I even had one woman who emailed me that she got the Moderna vaccine at the same time as her mother and her father and that both she and her mother got COVID vaccine arm, whereas her father didn’t have any side effects.

Another woman got the Moderna vaccine at the same time as her mother, her mother’s sister, and the mother’s sister’s husband. The three women got COVID vaccine arm, whereas the husband didn’t have any 8th-day reaction.

All this made me wonder whether there could be an additional genetic factor in this delayed 8th-day skin reaction.

I also questioned if a sex difference was seen with vaccines other than the Moderna vaccine.

Curious, I looked at the reported cases of anaphylactic reactions to all the mRNA vaccines (Moderna and Pfizer-BioNTech) from December 14th, 2020, to January 18th, 2021. The results of the Vaccine Adverse Effect Reporting System published in the last Journal of the American Medical Association showed that—in close to 10 million vaccine recipients—there were 44 anaphylactic reactions (within 30 minutes after the vaccine) in women versus only three in men for the Pfizer-BioNTech vaccine. Further, in a population of 7.6 million receiving the Moderna vaccine, all of the 19 anaphylactic reactions were in women.

The Pfizer-BioNTech and Moderna vaccines aren’t the only ones affecting women: Recently, another COVID vaccine, the Johnson & Johnson, has possibly triggered an abnormally low platelet count and blood clots in the brain vessels within three weeks after the vaccine injection in six women in the United States. This blood clot problem associated with a low platelet count is prompting a pause in the J&J vaccine administration. One case is described in the recent New England Journal of Medicine .

To learn more, I contacted Sabra Klein, Ph.D., a professor in the Department of Molecular Microbiology and Immunology, and co-director of the John Hopkins Center for Women’s Health, Sex and Gender research. Dr. Klein put me in contact with Janna Shapiro, a Ph.D. candidate working with her at John Hopkins Blomberg School of Public Health. Janna explained that she was studying sex and age differences in the immune response to the influenza vaccine.

Janna hypothesized that the reason why most women contacted me for their COVID vaccine arm was probably multifactorial, including a gender factor (more women got vaccinated in the first wave due to profession, and women are more likely to report), a genetic factor (people in the same family), and also a pure biological sex factor since women have very different biology than men, including different genetic makeup (i.e., XX vs XY chromosomes), different hormones, and different fat/muscle ratio.

Janna mentioned two studies:

Ian Cook wrote in Human Vaccines that female children and adult women have more adverse effects from vaccines than male children and adult men; this gender difference manifests for all kinds of vaccines (the diphtheria tetanus pertussis, measles, flu vaccine, and many more).

Ian Cook also mentioned that if the vaccine is injected intradermally (under the skin) instead of in the muscle, there is a stronger local reaction, which is more likely to happen in females due to their thicker adipose (fat) layer over their muscles.

Flanagan, Fink, Plebanski, and Klein wrote in The Annual Review of Cell and Developmental Biology that, for most vaccines, studies show that women have a stronger immune response than men, with more inflammation and more antibodies than men.

According to Flanagan and colleagues, estradiol (the female hormone) may stimulate antibody production, whereas testosterone (the male hormone) may decrease the same antibody production.

Flanagan mentions that genes that are linked to the extra X chromosome in females could code for more immune proteins than the Y chromosome in males.

Flanagan adds that people’s diet (women eat differently than men) influences the microbiome and the gut microbiota, which seems to have an effect on reactions to infections and to vaccines. For example, probiotics may enhance immunity.

In an additional study , Stephane Fishinger and colleagues from MIT and Harvard (Seminars in Immunopathology ) confirmed that female children and adult women have a greater immune response to vaccines than do men. The authors went on to suggest that females’ greater immune response could make them less prone to infections, but conversely more prone to develop an autoimmune disease than men.

So, if studies show that when males and females get the same vaccine, women have a stronger immune response and more adverse effects than men, wouldn’t it make sense to give a smaller dose of vaccine to women? Logically, a smaller dose would decrease adverse effects while still giving an adequate immune response.

Indeed, Dr. Sabra Klein published an article titled “Personalized vaccinology: One size and dose might not fit both sexes” in which she describes how females and males react differently to vaccinations and how males and females might benefit from receiving different vaccines.

Her student, Janna, confirmed:

“Since women generally have stronger immune responses and more adverse effects than men, it would make sense to study a precision vaccinology approach, where men and women get a different dose of the same vaccine. We need to start analyzing data from clinical trials based on sex (Is there a difference between men and women’s immune response and adverse reactions?) and age (Is there a difference for women between before menopause and after menopause?).”

Janna’s last sentence was: “If we don’t look for sex differences, we’ll never know if they exist.”

References

https://link.springer.com/article/10.1007/s00281-018-0726-5

https://www.tandfonline.com/doi/abs/10.4161/hv.8476

https://www.sciencedirect.com/science/article/pii/S0264410X13003666?via%3Dihub

https://www.cdc.gov/mmwr/volumes/70/wr/mm7004e1.htm

https://jamanetwork.com/journals/jama/fullarticle/2777417

https://jamanetwork.com/journals/jama/fullarticle/2776557

https://www.nejm.org/doi/full/10.1056/NEJMc2102131?query=featured_home

https://www.annualreviews.org/doi/10.1146/annurev-cellbio-100616-060718?url_ver=Z39.88-2003&rfr_id=ori%3Arid%3Acrossref.org&rfr_dat=cr_pub++0pubmed

https://www.nejm.org/doi/full/10.1056/NEJMc2105869?query=pfw&jwd=000020107919&jspc=GP

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