Sex and Gender and COVID-19 Vaccine Side Effects

A couple of weeks ago, I received an emoji-laden text from one of my friends, giddy with the news that Connecticut Gov. Ned Lamont announced plans to expand vaccine eligibility to everyone over the age of 16 on April 1. Now, I finally can make an appointment to get the vaccine!

In case it wasn’t already apparent, I was, and am still very excited about this opportunity to protect myself and my community. The currently available vaccines have all proven highly safe and effective, offering complete protection against severe disease and death. But after a few of my female friends and acquaintances became fatigued and achy after their second doses, I did wonder if I might experience any side effects. As I soon discovered after some research, women generally are reporting worse side effects from vaccination.

Preliminary data from the earliest vaccinations in December suggest that women are reporting more severe vaccine side effects than men. In February, the CDC released data on adverse effects during the first month of the COVID-19 vaccine rollout, finding that while women received 61 percent of vaccine doses, 72 percent of the side effects reported to the agency were from women.

Should I be worried about this apparent trend? While the possibility of side effects will not affect my decision to get a life-saving and society-restoring vaccine when I can, understanding what effects I might experience and why they are happening would help to ease any anxiety.

To start, I found it reassuring to learn that side effects or adverse events following vaccinations affect a relatively small number of people. Early data from the Centers for Disease Control and Prevention (CDC) and the Food and Drug Administration’s (FDA) Vaccine Adverse Event Reporting System (VAERS) indicate that for every 1 million doses of vaccine administered, there were only 45 reports of serious adverse events (.0045 percent) and 372 reports of non-serious adverse events (.0375 percent).

Should we be concerned? According to medical experts, the short answer to that question is no. Most medicines, including vaccines, produce side effects in some people, usually a very small percentage. The most common COVID-19 vaccine side effects are usually mild and last for a short amount of time. These mild effects include soreness, headache, fatigue, dizziness, chills, and nausea. It is true that, like with any other vaccination, severe allergic reactions such as anaphylaxis may occur. However, the CDC suggests that this type of reaction only occurs in between two to five people per million vaccinated. Furthermore, of the extremely rare cases of death following vaccination (0.0017 percent of people vaccinated with more than 145 million doses between December 14, 2020 and March 29, 2021), CDC and FDA investigations have revealed no evidence that the vaccination contributed to these deaths.

For comparison, the National Safety Council recently reported that over the course of a lifetime in the United States, an individual has a one in 138,849 chance (.00072 percent) of dying from a lightning strike, a one in 8,248 chance (.012 percent) of dying from sunstroke, and a one in 2,535 chance (.039 percent) of choking to death on food.

But again, the overwhelming number of reactions to the COVID-19 vaccines have been mild. And I was reassured to learn that mild physical effects following any vaccination are a sign that the vaccine is working. For example, some people experience swollen lymph nodes after receiving their shot. Lymph nodes are small bumps of tissue with disease-fighting white blood cells.

“The COVID-19 vaccination is given in the arm and the closest lymph nodes are the ones under your arm, so that is where the reaction is occurring,” said Dr. Brita Roy, an internal medicine physician and Director of Population Health for Yale Medicine, in a recent YM article. “It’s completely normal. It’s your immune system reacting to the vaccine, as it should.”

But why might there be a sex or gender difference? Well, I was also interested to discover that gender disparity in vaccine side effects is not a new phenomenon. A 2019 study looking at vaccine adverse events reported to the CDC from 1990 to 2016 found that 80 percent of the reports of severe allergic reactions (anaphylaxis) involving adults came from women. Following the 2009-10 H1N1 (swine flu) pandemic vaccine distribution, researchers found that four times as many women than men who were between 20 and 59 years old reported an allergic response to the H1N1 vaccine.

Do we know why women report adverse reactions to vaccines more often than men? The answer to this question is not simple, as a variety of factors may contribute to this phenomenon. It is possible that women might simply be more likely to report adverse effects after a vaccine than men, based on evidence showing that women are more likely than men to seek out medical treatment when ill. But that has not yet been studied, and we might also look toward the important biological associations between sex and immune responses.

For example, estrogens, hormones responsible for the female reproductive system and secondary sex characteristics in women, may be related to larger immune response. A 2019 study of immune response to the H1N1 vaccine found that in both humans and mice, presence of the major female sex hormone estradiol in adult females led to more robust antibody responses following vaccination in comparison with males and older females without high levels of estradiol. This indicates that while women might actually have more side effects as well as report them more often, they also may benefit more from the protective effects of a vaccine.

The observations concerning sex, gender, and vaccine response highlight a larger issue concerning how women process and are physiologically affected by medications. The historical gap in research into the possible effects of sex or gender on a drug’s efficacy and safety has too often left women in the dark and sometimes at risk. In fact, as described in a 2001 report, from 1997 to 2000, eight of the 10 drugs removed from the U.S. market posed greater health risks for women than for men. However, more researchers are examining and understanding the factors that confer sex-and-gender differences in drug efficacy and safety during the trial process.

One such researcher, and COVID-19 science all-star, is Dr. Akiko Iwasaki. In a January New York Times op-ed written with Alice Lu-Culligan, a Yale M.D.-Ph.D. student, Dr. Iwasaki described false rumors about the approved vaccines’ effects that have scared some women. Yet, all three FDA-authorized COVID-19 vaccines have demonstrated safety and effectiveness in both clinical trials and now widespread inoculation. With regard to people who are pregnant, the CDC says the vaccines are unlikely to represent an increased risk, and more data are currently being collected. So, remember, it is crucial to look to reputable sources such as the CDC COVID-19 vaccine website with up-to-date information on vaccine safety/efficacy, as well as what to expect during and after your appointment.

Let’s educate ourselves but not give in to unfounded fears. When you are ready to schedule your vaccination, this is a handy guide for appointments in Connecticut. For residents of other states, here is the CDC’s vaccine finder, which may assist you in scheduling appointments in your area.

Let’s get vaccinated! And get back to living our lives.

Ke'ala Akau is a fellow with Women's Health Research at Yale and a junior in Branford College majoring in the History of Science, Medicine, and Public Health. Read more on her blog: "Why Didn't I Know This?"