COVID vaccine trials must weigh effects on both men, women, researchers say

When the National Institutes of Health and biotechnology company Moderna released initial promising results of a vaccine for COVID-19, biochemist Nicole Woitowich read the study with disappointment.

The research, published in the New England Journal of Medicine in mid-July, had a glaring oversight, she said. While both men and women participated in the trial, the data related to adverse drug effects were not analyzed by sex. This means the clinical community right now has no way of knowing if men or women responded differently to various vaccine dosages. The adverse effects from the experimental vaccine were mild or moderate and included chills, nausea and fever.

The NIH along with HHS’ Office of Biomedical Advanced Research and Development Authority are funding the Moderna trial. The other major vaccine trial underway in the U.S. from drugmaker Pfizer and biotechnology company BioNTech also hasn’t analyzed data by sex in their published results, although the findings haven’t been peer-reviewed yet.

Woitowich, associate director of the Women’s Health Research Institute at Northwestern University in Chicago, said the absence of analysis by sex in the COVID-19 vaccine trials thus far is concerning as there are high hopes for an effective vaccine that can be brought to market quickly.

“If we are going to be developing treatments and vaccines that will be given to the global population, then it’s important that these experiments driving these treatments and vaccines are rigorous, and they are analyzing and reporting the data by sex. We know there are sex differences,”  Woitowich said.

Men are more likely to die from coronavirus-related symptoms and suffer negative outcomes compared with women. There are also studies finding women respond better to influenza vaccines and have a stronger immune response. Understanding how men and women respond to the COVID-19 vaccine will be critical to determining the appropriate dosages and ways to avoid adverse effects.

“I don’t want to make this a women’s health issue—it benefits all people if we analyze data by sex,” Woitowich said.

In an email, the NIH’s National Institute of Allergy and Infectious Diseases said the initial results released in the New England Journal of Medicine represent phase one of the trial, which had only 45 participants, and “was not designed to understand differences among sexes” but rather how the participants who met the inclusion criteria responded to the vaccine.

The NIH added that analysis by sex, as well as race and age, would more likely happen in phase three when the vaccine is administered to more participants. The NIH and Moderna are currently recruiting for phase three, aiming to get 30,000 enrolled.

While there have been recent improvements in recruiting women to participate in clinical trials after a long history of being left out, researchers and clinicians still rarely consider how men and women are impacted differently by a drug or intervention.

The same is true for race and gender. Furthermore, medical schools and residency programs rarely integrate sex differences into education beyond courses about reproductive health.

“Medical training is taught within male-centric literature, and rarely do lectures uncover what’s the difference” between men and women, said Dr. Deborah Bartz, associate gynecologist at Brigham and Women’s Hospital.

Infectious disease specialists with expertise in vaccine development argue that analysis by sex scarcely happens because researchers likely don’t find any differences worth noting. Researchers should and would provide those differences if they come up, said Dr. William Schaffner, medical director of the National Foundation for Infectious Diseases.

Furthermore, even if the data isn’t analyzed by sex, it can be done quite easily for those interested because all the primary data is available, added Dr. Paul Offit, director of the Vaccine Education Center at Children’s Hospital of Philadelphia.

Although sex-based differences haven’t historically been observed during vaccine trials, studies on influenza vaccines do show women respond differently than men. A 2005 study found women had higher immune response rates to both half and full doses compared with men. Reactions from the vaccine like headache and fatigue were significantly higher for women than men. Right now, women and men get the same dose for the flu shot.

But even if the COVID-19 vaccine trials don’t uncover significant differences between men and women, the data should still be analyzed and published, said Brian Prendergast, professor of psychology at the University of Chicago.

“We have inclusion now, but it’s almost like the minimum compliance” is being done, he said. “Perhaps there is a reason to collapse the data together—show me there is no sex difference.”

He also said similar data should always be available for medications. Prendergast along with colleagues recently published a study finding women were more likely to have adverse reactions from FDA-approved drugs when data showed they had differing responses to the drug than men. Drugmakers however aren’t required to put such information on drug labels, so women and men usually receive the same dosage.

Prendergast recommends clinicians prescribe women a lower dose of a drug to be on the safe side and then gradually increase it if symptoms persist.

Sex-based analyses likely still don’t happen because of biases and lack of awareness, said Rosemary Morgan, an assistant scientist at Johns Hopkins Bloomberg School of Public Health.

“Caucasian men have been the ones predominantly in power positions and they have been using themselves as the norm, meaning the male body was given the norm,” she said.

Furthermore, research that does examine differences between men and women is usually done by female researchers, said Dr. Kim Templeton, professor of orthopedic surgery at the University of Kansas and past-president of the American Medical Women’s Association. “We need to bring more male researchers on board,” she said.

Congress and the NIH have made moves to improve diversity in research.

A 1993 law requires the inclusion of women and people of color in NIH-funded clinical trials. And because the continued use of only male mice and other animals during preclinical research persisted, the NIH in 2016 created a policy requiring researchers to consider sex in studies. This means not only using both male and female animals but reporting whether sex differences are detected in the findings.

A recent study by Woitowich evaluating the impact of the 2016 NIH policy shows that although parity has improved—more female participants are involved in studies—the data is still often not analyzed by sex and an explanation for the exclusion is rarely given. Indeed, of the 356 studies analyzed that used both sexes, 42% included analysis by sex and only two studies specified that the authors didn’t find any differences between the sexes.

“The biomedical research enterprise is working together at an unprecedented pace to develop therapies and treatments to combat the COVID-19 pandemic,” Woitowich said. “If these data analyses aren’t happening on a good day in science, what happens if we are rushing to get this data out?”

Woitowich recently received a grant from the not-for-profit organization Women’s Health Access Matters to study COVID-19 research thus far for analysis by sex. She expects it’ll take about six months to complete.

Even with more women participating in clinical trials, pregnant women are almost always excluded. Bartz said this is alarming because women often take some medications, such as those for depression or seizures, that haven’t been studied in pregnant women.

Journals and grant funders should require greater study based on sex and also require a justification if such an analysis isn’t done, Woitowich argued, adding, “This would ultimately change the way scientists conduct their research in order to meet publication standards.”

Morgan said she’s hopeful COVID-19 may signal a turning point in sex-based research given the heightened awareness about how the disease is affecting men at higher rates. She said she’s receiving more calls from researchers asking about sex and gender research.

“I do think there is a lot more attention because of COVID,” she said.