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Two days after getting my second dose of the Moderna mRNA vaccine as part of a clinical trial, my body was still mounting a robust immune response when, from the floor of my son’s bathroom, I frantically telephoned the clinical research site at the University of Illinois.

The region of my brain that controls thermoregulation, the hypothalamus, likely detected the flood of vaccine-induced copies of viral proteins in my bloodstream and cranked up my internal thermostat to 104.7 degrees F, a fever high enough to make me feel delirious. The trial’s principal investigator called in a prescription for an anti-nausea medication and two bags of IV fluid, which a mobile service gave me at home to stabilize me.


As a volunteer in Moderna’s Covid-19 vaccine trial, I had received my second dose in early February 2021, before information about side effects was well-known. As I recovered over the following days, I began wondering if my grade 4 fever was typical, or if there was something about my biology that triggered such a dramatic immune response.

Vaccines save lives, and the record time in which scientists developed Covid-19 vaccines is unprecedented. While debilitating side effects from vaccines are rare, vaccine trials and dose recommendations tend to overlook the growing evidence that immune responses differ widely in men and women, both in response to viral infections and following vaccination.

When I dug deeper into vaccine development, I discovered a familiar tug of war in which new scientific recommendations that account for biological sex disparities continue to clash with established practices and beliefs.


A decade before Covid-19 emerged, the world was facing the H1N1 pandemic. As researchers hurried to create a vaccine, infectious disease researcher Sabra L. Klein asked a simple question in an opinion essay in the New York Times: Do women need such big flu shots? She defied vaccine conventions by suggesting that giving a smaller dose of the H1N1 vaccine to women would be effective, while at the same time optimize the limited vaccine supply for the pandemic’s second wave. Klein’s recommendations didn’t prevail, but she is now being joined by a chorus of voices within the scientific community working to reverse the sex blind spot in biomedical research and vaccine development.

Before vaccines and drugs are tested in humans, researchers study their effects on cells and in animals. Tackling sex bias begins in Petri dishes and animal studies. In a February 2022 report, Irene Miguel-Aliega, professor of genetics and physiology at Imperial College London, calls out the perils of sex bias research design: “Whether looking at cells, organs, or animals, a lack of previous evidence of sex differences is not a good reason to exclude either sex in future experiments.”

A now well-known example of sex differences is the sleeping pill Ambien. It was on the market for 20 years before the Food and Drug Administration halved the recommended dosage for women in 2013. It wasn’t until women were “significantly more likely to get into car accidents after a night of Ambien” that experts started to realize the sex differences, Klein told me, referring to the FDA’s notification that it had received about 700 reports linking Ambien and impaired driving ability and/or road traffic accidents. It turns out that women’s livers metabolize the drug slower than men’s.

As the media blitz and outcry from the Ambien fallout targeted regulators at the FDA, federal scientists at the National Institutes of Health had already been working to understand why new drugs failed in human trials after promising preclinical research. Some failures were traced back to the earliest stages of animal research and analysis that didn’t separately account for effects on males and females.

“When investigators consider sex, they often find sex differences,” Chyren Hunter, the associate director of basic and translational research at the NIH’s Office of Research on Women’s Health, explained to me. Hunter and her team are spreading the word about the preclinical treasure trove of data “hidden in plain sight” when early scientific research includes both sexes.

Not all researchers seeking federal funding need to study sex differences, but according to a 6-year-old NIH policy, commonly referred to as SABV (sex as a biological variable), researchers must “consider how biological sex can impact the question they are studying.” SABV is not a mandate, but a criterion, and Hunter tells researchers that it’s “not an obstacle, it’s an opportunity.”

Sexism has deep and twisted roots that have tainted science and medicine for a long time. Hysteria, which comes from the Greek word hystera, meaning uterus, was a medical diagnosis until 1980, when it was removed from the primary reference guide for mental health professionals. Three decades ago, it took an act of Congress to include people of color and women in federally funded clinical trials. A 2001 congressional investigation of FDA-approved drugs found that eight of the 10 that had been withdrawn from the market between 1997 and 2000 posed greater health risks for women than for men.

Men have been dying from Covid-19 at a higher rate than women since the pandemic’s early days. Klein, who studies immunological differences between the sexes, and her team are trying to identify a group of cells, or a protein, in women that protects them from severe disease. Simultaneously understanding female protection and male pathology could lead to sex-specific interventions for men and women.

There is broad recognition that sex is the next frontier in personalized medicine, and including it at all stages will improve scientific rigor. Many signs point to a paradigm shift, with researchers now investigating, observing and measuring the influence of sex on research outcomes.

Toward this worldview, an international set of guidelines was established in 2016 for editors of science and medical journals to explicitly report effects by sex and gender; a growing list of peer-reviewed journals have adopted them. The global leader in biomedical funding, the NIH, is doubling down on the study of sex and sex differences as fundamental variables in research by scaling up training and creating innovation hubs. In March, the national funding body for science and research in the United Kingdom announced that later this year it will “require sex to be specified in the experimental design of grant applications involving animals, and human and animal tissues and cells.”

When I volunteered to participate in Moderna’s Phase 3 vaccine trial, the process wasn’t complicated — though it did take a leap of faith. Aside from the fever incident, I am game to participate in future clinical trials. But before I sign up for the next one, I will ask if the preclinical research included sex as a biological variable. And if it didn’t, I will consider volunteering elsewhere.

Dawn Sinclair Shapiro, a journalist and filmmaker whose credits include “The Edge of Joy” (2011) and “The State of Eugenics” (2017), is currently a master’s degree candidate in science writing at Johns Hopkins University.

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