The Danger of a ‘Dudes Only’ Vaccine

The Johnson & Johnson shot is teetering on the precipice of becoming America’s “dudes only” vaccine. On Tuesday, the CDC and FDA advised halting the vaccine’s nationwide rollout to investigate six cases of a rare blood-clotting disorder that’s occurred in people within about two weeks of receiving the vaccine—all of them women under the age of 50. In an emergency meeting convened Wednesday by the CDC, experts raised the possibility of limiting its future use to males, reserving Johnson & Johnson’s vaccine, as some have unfortunately put it, for johnsons alone.

That idea, crude though it may be, has something to it. The demographic pattern that’s emerged is striking, and many of the experts I talked with this week told me they suspect that, if the vaccine is ultimately linked to these clots, the relationship will come with a clear-cut sex or gender difference too. (These questions are also being debated with regard to the AstraZeneca vaccine, which contains comparable ingredients and might very rarely cause a similar or identical type of clotting disorder.)

But health officials have strongly cautioned that it’s too early to tell for certain whether a specific subset of the population is at increased risk of this clotting disorder; scientists haven’t even definitively pinpointed the J&J shot as its cause. Prematurely masculinizing the J&J vaccine could not only reinforce biases that compromise health care, but also run counter to one of the most important goals of the ongoing pause: identifying what factors, if any, do contribute to these unusual clots, and protecting the people they affect.

Read: The blood-clot problem is multiplying

The post-vaccination clots under investigation belong to a class called cerebral venous sinus thrombosis (CVST), and they seem to manifest when antibodies, perhaps produced in response to the shots, inadvertently rile up platelets in the blood. Platelets exist to keep wounds from bleeding indefinitely: They clump blood cells and proteins together to plug up leaks. But in CVST, they seem to spark a clotting cascade that can clog veins in dangerous places, including the brain, and lead platelet levels to plunge. The disorder is a collision between a powerful immune response and a naturally clot-prone environment; a potentially simple explanation for why they might show up more in women is that the hormone estrogen can amp up both of these factors.

Estrogen has many jobs in the body, and in a lot of contexts, it’s an instigator: It can boost a person’s propensity to clot, and it can goad immune cells into responding more vigorously to pathogens and vaccines. (There’s also some evidence that having two X chromosomes can make immune systems more reactive.) CVSTs are rare among the general population, but are more common in women. Menaka Pai, a hematologist who specializes in blood clots at McMaster University, in Ontario, likens clotting to falling off a cliff; estrogen, among other things, “pushes us closer to the edge.”

Estrogen and chromosomes aren’t the only variables here, though. Physiology undoubtedly influences a person’s responses to diseases, treatments, and vaccines, but behavior and social factors can, too. In recent weeks, dozens of similar CVST cases have cropped up amid millions of doses of the AstraZeneca shot (which hasn’t yet been green-lit in the United States). As with the J&J effect, most of these cases involved younger women. But in certain countries, women also made up the majority of people who were inoculated early on, weakening the clots’ link with gender. Some experts I talked with also noted that women tend to stay in more frequent contact with their health-care providers than do men, and might feel less wary about reporting unusual side effects or symptoms after getting a vaccine.

Read: The rural pandemic isn’t ending

If researchers confirm that these two vaccines are operating in similar ways, “being older, being a man—that’s not going to protect you,” Pai told me. In addition to the six cases in women, researchers are now reevaluating a potentially similar CVST case that was identified in a young man who had received J&J’s vaccine during the company’s late-stage clinical trials. Still, the extreme gender trend in the early J&J reports has been hard to ignore. Prior to the pause, roughly equal numbers of men and women had received the company’s shot, according to the CDC. I asked Alfred Lee, a hematologist at Yale New Haven Hospital, how often his discussions with colleagues about the clotting disorder had turned to the topic of sex or gender since Tuesday’s news broke. “Literally almost every single one,” he told me. Lee and his team are now being particularly vigilant about monitoring their recently vaccinated female patients, especially those taking estrogen-containing oral contraceptive pills—the group of people they’ve deemed to be “high-risk right now,” he said.

It’s heartening, several people told me, to see the possibility of sex and gender differences in vaccine side effects being openly acknowledged and addressed. For years, gender norms have influenced health-care providers in ways that haven’t served patients well—by dismissing women’s “hysterical” complaints of pain, for instance, or accusing them of falsifying their symptoms. But grabbing onto a still-tenuous link between sex and certain side effects could create problems, too. The seemingly obvious culprit of estrogen, for example, could end up obscuring some more obtuse cause. Sarah Richardson, the director of the Harvard GenderSci Lab, pointed me to the case of the sleep aid zolpidem, also known by its brand name Ambien. In 2013, the FDA recommended that women should receive a lower dose of the drug than men. The agency claimed that women’s bodies were more sluggish at clearing Ambien, leaving female users more cognitively impaired eight hours after ingesting it. That analysis later turned out to be flawed and incomplete, in part because the agency hadn’t properly accounted for differences in body weight; the drug wasn’t leaving all women worse off. “There isn’t any scientific evidence supporting sex-based dosage for zolpidem,” Richardson wrote in a 2019 op-ed for The Washington Post. Ambien, once hailed as a “flagship example of how sex differences can influence health,” she wrote, has morphed into a cautionary tale.

To truly home in on what’s at play with the Johnson & Johnson vaccine, Richardson told me, researchers will need to consider factors such as age, sex, gender, race, ethnicity, medical history, even social norms around how unusual symptoms are reported to health-care providers, and figure out how these variables intersect. That work is extraordinarily hard to do with just a handful of people, a likely reason the vaccine’s pause has been prolonged—so more data could be collected and analyzed. “People are really interested in the gender thing,” Lee, of Yale, told me. “But we can’t prove it yet.” That’s in part why a universal halt—one that didn’t segregate by gender, age, or any other demographic—was probably “the right approach” for now, Janna Shapiro, who studies sex differences in immune responses at Johns Hopkins University, told me.

Categorizing these clotting events incorrectly or too early also comes with dangers. The repetitive association of women and clots could stoke vaccine hesitancy in skewed ways. One recent poll showed that public confidence in the safety of the J&J vaccine plunged after the pause, and Elaine Hernandez, a medical sociologist at Indiana University, told me she’s concerned that reluctance about vaccines might concentrate among certain subgroups of women. She and her colleagues have found that young women who are Black and Latinx—groups that already have more limited access to vaccines—are more wary of getting immunized than their white peers.

Pushing this association too hard and too quickly could also skew data collection. Health workers could narrow their clinical lens; women might scour themselves for symptoms, while men and other people who don’t identify as women “may not take the symptoms [of CVST] seriously,” Krutika Kuppalli, an infectious-disease physician and vaccine expert at the Medical University of South Carolina, told me. That bell could be especially tough to un-ring in a culture where masculinity is so often considered incompatible with sickness. “People want to appear strong and tough, men in particular,” Hernandez told me. “There are already social pressures to not complain.” Casting the clotting condition as a “female problem” too early means donning blinders. “That’s troubling for the objectivity of the investigation going forward,” Richardson, of Harvard, said. (There’s still a paucity of data on whether transgender, intersex, or nonbinary people, especially those who are on hormonal therapies, might be vulnerable to unique vaccine side effects.)

Read: The pandemic broke America’s health-care workers

If a clear sex or gender difference does emerge, nuanced messaging will be necessary. As coronavirus cases surge, the risk of taking the vaccine might still be relatively low, especially in parts of the country where the fragile Pfizer and Moderna vaccines are harder to store and administer. Restricting the vaccine to certain age or gender groups could seed equity issues, both in the U.S. and internationally, or trigger repeated rounds of sociopolitical fallout. Shapiro pointed to the HPV vaccine, which was initially targeted to adolescent girls. The shots are now recommended for children of all genders, but misperceptions of the early rollout stigmatized the mostly female preteens who signed up for the shots as promiscuous, and the sole bearers of disease.

The goal in the coming days and weeks, Pai told me, is to appropriately titrate expectations of risk—to address concerns, but also avoid sensationalizing them. Our understanding of the clots’ danger could shift quickly as more data are collected. The dangers implied by six cases of a rare clotting disorder out of the roughly 7 million Americans who have received the J&J shot is much lower than the risk implied by six cases within the smaller population of the 1.4 million vaccinees who are women under 50. But now that physicians know what to look for, the numerator in that ratio will likely change as well. More cases will certainly appear, spanning a wider range of genders, ages, races, and ethnicities. These shifting odds will be easier to communicate if our lens isn’t unnecessarily narrowed: Expanding the definition of an at-risk population is harder than paring it down.

The suspension might already seem frustratingly long to some; plenty of people have called it out as cowardly and unwise, and questioned why federal officials prolonged it. But nearly everyone I’ve spoken with this week has praised the move as prudent, during a time of great uncertainty about who’s most at risk. “Ideally, we find out over time which vaccines are best for which groups, and why,” Leana Wen, an emergency physician affiliated with George Washington University, told me. “That’s the positive way of seeing this—this is in part the kind of information we’re getting here.”