Why Studying Sex Differences in COVID Vaccine Research Matters

As we head into another round of COVID-19 vaccination, researchers are continuing to keep an eye on vaccine safety and effectiveness.

A review of Phase 3 clinical trials of COVID vaccines suggests we could be doing a better job of examining how that safety and effectiveness might differ between men and women.

Authors of the review, published in the journal Contemporary Clinical Trials, found that only 30% of the studies they analyzed reported on significant sex differences regarding vaccine effectiveness and side effects.

The studies that did present sex-disaggregated data—data analyzed by sex—showed there were differences in how well the vaccine worked between men and women. Men were conferred stronger levels of protection than women after receiving their first COVID-19 vaccine dose. And women were more likely to experience more serious and unpleasant vaccine side effects, including blot clots (although blood clotting events occur in less than 1 out of 10,000 people).

The gaps in understanding female and male response to vaccines are nothing new, according to Sabra Klein, PhD, a professor at John Hopkins Bloomberg School of Public Health who researches sex differences and the effects of immune responses to viruses and vaccines. She said that none of the initial trials, including the Phase 3 trials, were designed to test the hypothesis that there might be sex differences.

Understanding the role of biological sex could clear up confusion on booster timing. The Centers for Disease Control and Prevention currently recommends people receive a bivalent booster at least two months since their last booster or primary series. However, Klein said people are unsure on whether they need it now or can afford to delay it for when cases start surging again in the winter.

“Females show stronger immune response than males, and even in people 75 years and older, the durability of immunity is greater in females,” Klein told Verywell. “This is important to consider when you have questions about when you should get your booster.”

Why Is Female Data Often Ignored in Medical Research? 

A lack of data on sex differences has been a recurring problem in research. James Giordano, PhD, MPhil, a professor of neurology and biochemistry and past co-chair for the clinical translational science center at Georgetown University, told Verywell there is even a preference toward using male animals in preclinical studies.

While Giordano, who was not involved with the vaccine review, thinks that while most researchers do understand the importance of having male and female data sets, research tends to skew male because it’s easier.

When studying female animals, researchers have to design studies around their estrous cycle—the reproductive cycle where female animals ovulate to prepare for pregnancy. Like a human menstrual cycle, the estrous cycle causes fluctuations in sex hormones.

“You have the potential to see different responses in female rats at different points across their estrus cycle. So with every female animal you’re testing, you have to [monitor] daily and make sure they’re all in an identical phase of their estrus cycle before getting to the experiment,” Giordano said.

As a result, he said testing on females “takes more time, more planning, more resources, and more money.”

Giordano said this preference for testing on male animals has translated to much of human research being conducted in adult males. This may be the case with the latest Omicron boosters. While the data the Food and Drug Administration (FDA) reviewed before authorizing the shots is not available to the public yet, they did base their decision on mice studies, not human studies.

Even when COVID-19 vaccine trials actively recruited both men and women, Klein said there was no requirement to consider comparing males and females, an analysis that can be quite time-consuming and expensive to unpack.

“Companies will consistently say they didn’t design their study to have the statistical power to see [differences between] men and women and are under no obligation to make those comparisons,” she said.

What Causes These Sex-Based Differences?

One of the biggest differences between males and females differences lies in sex chromosomes. X chromosomes and Y chromosomes are bundles of genes that carry their own set of traits. Females have two X chromosomes; males have one X and one Y chromosome.

According to Klein, your genes can affect both your immunity and how well vaccines work.

The X chromosome has the largest number of immune-related genes. but to make sure genes are equally expressed between both sexes, females undergo a process called “X chromosome inactivation.” One of the two X chromosomes is ‘silenced’ to make sure females don’t have double the number of X-chromosomal genes.

However, Klein explained that roughly 15% of the genes on the second X chromosome in immune cells escape inactivation. Increased gene expression in toll-like receptor 7 (TLR7) gives females a boost in immunity because it increases the diversity of antibody responses. While a strong immune response can mean a more rapid response to infection, it can also mean a stronger reaction to a vaccine—a.k.a., more side effects.

Research suggests increased gene expression of TLR7 could explain why women are less likely to test positive for COVID-19 and tend to have less severe infections. There is also scientific evidence to suggest that women with a stronger expression of TLR7 have better COVID vaccine-induced immunity overall, even though the Contemporary Clinical Trials review saw stronger protection in men after the first shot.

“Greater antibody response contributes to better protection after vaccination in females,” Klein said.

Hormones can also impact your overall immune response.

“The level of estrogen in women is strongly correlated with how much antibody you make from a vaccine,” Klein said, adding that estrogen levels fluctuate throughout the menstrual cycle. “The more estrogen you have, the greater the antibody response to the vaccine.”

A separate 2022 study suggests estrogen protects against severe COVID-19 symptoms and death by inhibiting an overactive immune system, which can cause damage to nearby organs and cells while fighting the virus.

Understanding Sex Differences Will Make for Better Treatment

Based on the limited data found in the study, the researchers of the Contemporary Clinical Trials study advocate for mandated reporting of sex differences in research. Doing so could help doctors make more informed decisions for their patients.

“Women are more likely to report and experience more adverse reactions to vaccines,” Klein said, citing headaches, fever, soreness, and injection site rash as common examples. “Sometimes people misattribute side effects to women being smaller or metabolizing things differently. And that’s not how vaccines work.”

Without acknowledging male-female differences in research, a future of personalized medicine will continue to be out of reach.

“We are missing key research points about what works, what doesn’t, in whom, and why?” Giordano said.

The information in this article is current as of the date listed, which means newer information may be available when you read this. For the most recent updates on COVID-19, visit our coronavirus news page.