What Your Sex Has To Do With COVID-19 Vaccine Side Effects

You probably know that there's a risk of developing minor side effects after getting any of the COVID-19 vaccines authorized for use. But what you likely don't know is that if your sex is female, you may be more likely to have side effects from the vaccines.

A study published by the Centers for Disease Control and Prevention (CDC) in February 2021 crunched data from the first month of administering the COVID-19 vaccine in the United States and found a clear sex divide.

People who were given the 13.7 million doses of the vaccine were encouraged to report any side effects they might experience through V-safe, the CDC's after-vaccine health checker. Of the 6,994 people that actually reported side effects, 79.1% of them were women. Just 61.2% of those who were vaccinated were women.

Another study from CDC researchers published in JAMA in February 2021 found that all 19 people who experienced the severe and potentially life-threatening allergic reaction anaphylaxis after receiving the Moderna vaccine were women. So were 44 of the 47 people who experienced the reaction after receiving the Pfizer-BioNTech vaccine.

More evidence followed. An August 2021 meta-analysis appearing in Vaccines concluded that data available on COVID-19 vaccines indicate "potential sex-related differences in efficacy and safety." Specifically, the vaccines appeared to show more efficacy in men and increased toxicity in women.

The study authors note that a total of 30,350 subjects treated with mRNA-1273-Moderna vaccine were evaluated for safety. Of the non-fatal serious adverse events described, 85.7% were reported in females. However, the study notes, there were a total of seven non-fatal serious adverse events, six of which occurred in females.

An April 2022 study published in Contemporary Clinical Trials reviewed data from multiple COVID-19 vaccine safety trials as well as peer-reviewed studies on sex differences seen with the vaccines. Authors found that peer-reviewed studies looking at vaccine safety in the general population reported higher rates of adverse reactions to the vaccines in females compared to males.

One study the authors highlighted was a Swissmedic evaluation of nearly 2000 reports of adverse reactions to the Moderna and Pfizer-BioNTech vaccines (out of approximately 2.8 million doses administered in Switzerland). The Swissmedic evaluation reported that 69.2% of adverse side effects were experienced by females, whereas only 27.8% were experienced by males, with severity ranging from mild (e.g., redness at the injection site) to serious (e.g., death).

Possible COVID-19 Vaccine Side Effects

According to the CDC, side effects after a COVID-19 vaccination tend to be mild, temporary, and like those experienced after routine vaccinations. They can vary across different age groups and will vary from person to person. They generally go away in a few days.

Possible side effects of the COVID-19 shot, per the CDC, include:

• Pain in the arm where you got the shot
• Redness around the area where you were vaccinated
• Swelling in the arm where you got the shot
• Tiredness
• Headache
• Muscle pain
• Chills
• Fever
• Nausea

The most commonly reported side effects after a COVID-19 booster shot were:

• Fever
• Headache
• Fatigue (tiredness)
• Pain at the injection site

Why Might the Vaccine Affect One Gender More Than the Other?

"I don't think there's enough information to be able to draw any strong conclusions about why this may be occurring more in females than males," infectious disease expert Amesh A. Adalja, MD, senior scholar at the Johns Hopkins Center for Health Security, told Health. It's entirely possible that women are just more likely than men to report their symptoms, Dr. Adalja said.

But, while women are more likely to report symptoms, that's not the only thing that's going on, William Schaffner, MD, an infectious disease specialist and professor at the Vanderbilt University School of Medicine, told Health.

Women have more autoimmune diseases than men and "it seems to be because their immune system is more reactive," Dr. Schaffer said.

The Contemporary Clinical Trials study authors write that, historically, males and females have shown different reactions to vaccines of many kinds, which have become apparent with the arrival of COVID-19 vaccines. Compared to males, females develop higher antibody responses and report more adverse reactions following vaccination.

A 2013 study published in the journal Vaccine analyzed reports of side effects after the 2009 H1N1 vaccine and found that women between the ages of 20 and 59 years reported much higher rates of allergic reactions than men, even though more men than women received that vaccine. (The rates were equal in other age groups.)

And a 2019 study published in the Journal of Allergy and Clinical Immunology that analyzed cases of anaphylaxis after vaccination from 1990 and 2016 found that women made up 80% of all anaphylactic reactions to vaccines in adults.

While the exact reason for this is unclear, Dr. Schaffner said, hormonal differences may be at play. Estrogen "jazzes up" the immune system, while testosterone seems to dampen it a little. In fact, higher concentrations of estrogen are associated with a heightened vaccine response, while testosterone has been associated with a milder vaccine response, write the Contemporary Clinical Trials study authors.

In addition, explain the Contemporary Clinical Trials study authors, genetics may play a role. There are approximately 10 times more genes on the X chromosome than on the Y chromosome, including a large proportion of genes that code for immune-related proteins. Females, who carry two X chromosomes, therefore have a higher expression of these immune-related genes and proteins, which may interact with sex hormones to strengthen the immune response.

"There is a real difference between immune reactions between men and women," Dr. Schaffner said. "We in the medical community haven't studied that as thoroughly as we ought to."

Men and women also metabolize drugs differently, women's health expert Jennifer Wider, MD, told Health. "Clinical trials often do not take into account this difference and the vaccine dose may be on the higher side for female recipients," Dr. Wider said.

Overall, the link is "something that needs to be studied in more detail to be able to be fully unraveled," Dr. Adalja said. But it's also not anything terribly new. "This has been happening for years," Rajeev Fernando, MD, an infectious disease expert working in field hospitals around the world, told Health. "I would just tell women to be aware of it."

What To Do if You Have Side Effects From the COVID-19 Vaccine

It's important to understand that it's actually a good thing to have side effects from the vaccine. "This means the vaccine is working," Jamie Alan, PhD, associate professor of pharmacology at Michigan State University, told Health.

Dr. Fernando also stressed that women—and everyone—should still absolutely get the vaccine when they can, regardless of potential side effects. "It's very straightforward: Vaccination saves lives," Dr. Fernando said. "The benefit of getting the vaccine and not dying from COVID-19 far outweighs the risks."

The CDC says it's OK to take over-the-counter medication like ibuprofen, acetaminophen, aspirin, or antihistamines, for any pain and discomfort you may have after getting vaccinated. But the CDC advises against taking any of those medications before you get vaccinated, noting that it's not known at this point how they may impact how well the vaccines work.

For arm soreness, the CDC suggests putting a clean, cool, wet washcloth over the area where you received your shot or trying to move your arm more. And, if you have a fever, the CDC says you should drink plenty of fluids and dress lightly.

If you develop severe side effects or you're not getting relief from the above methods, Dr. Adalja recommended calling your healthcare provider about next steps.

The information in this story is accurate as of press time. However, as the situation surrounding COVID-19 continues to evolve, it's possible that some data have changed since publication. While Health is trying to keep our stories as up-to-date as possible, we also encourage readers to stay informed on news and recommendations for their own communities by using the CDC, WHO, and their local public health department as resources.