​The Flu Shot Is Less Effective in Men With High Testosterone

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For years, Sabra Klein has been trying to start a conversation about sex. The Johns Hopkins immunologist studies why women have stronger immune systems than men—a phenomenon that underlies the fact that women are three times more likely to develop autoimmune diseases—but are also better protected by vaccines. The latter, however, has gotten very little attention from vaccine makers or doctors.

A flu vaccine paper published today argues that it really should. Testosterone suppresses the immune system, and that, of course, disproportionately concerns men. The study in PNAS from Mark Davis's lab at Stanford also identifies a cluster of genes affected by testosterone and somehow involved in immunity. Davis wasn't looking for sex differences in his initial flu vaccine study, but that's what he found. And that's when he got in touch with Klein.

Davis's study appears in a major journal, with a press office that chose to send his paper out to journalists in advance. This may just kick up enough fuss about sex differences in vaccine response to get pharmaceutical companies to pay attention. Klein calls the new study, "amazingly exciting." "I hope this does continue to generate greater discussions," she says.


Why does it matter?

Clinical trials usually treat sex as a confounding variable to be factored out, rather than a variable to be studied. Vaccines that protect women but not men may not look effective when the two sexes are lumped together, prematurely ending a promising vaccine for the half the population. That's on top of another problem: women are often underrepresented in clinical trials in the first place.


Another issue is dosing: Men may need larger doses. The flip side is also that vaccines have side effects—a virus, weakened or dead, is still being injected into your body, after all—and a stronger immune system in women can mean stronger side effects like fever, headache, and fatigue. The flu vaccine is a voluntary, and one crummy experience can keep women from coming back. By the way, PSA: If you haven't yet, you should go get your flu shot.

What does testosterone have to do with it?

At Stanford, Davis started out looking for reasons the flu vaccine worked better in some people than others, as measured by the antibody response. A vaccine teaches your body to create antibodies, or molecules that identify and neutralize a specific pathogen. A big factor in antibody response, he found, was sex.


But then he dug deeper, analyzing the testosterone levels to find that even within men, those with high testosterone levels had a lower antibody response to the flu vaccine. His lab also identified a new set of genes involved in the synthesis of fats that are also correlated with testosterone levels and antibody response to vaccines. The exact functions of those genes are fodder for future research.

"I think absolutely that vaccine makers need to give a think about these are very real male-female differences," said Davis. "This hasn't really been on the front burner, but now I think it should."


What now?

When I first spoke to Klein months ago, she said her research had been gaining more mainstream attention. She was being invited to more talks. The HPV vaccine, which primarily protects against cervical cancer, had paved the way for thinking about gender with respect to vaccines. (Though the vaccine is now approved for both young men and women.) She hopes the FDA will incorporate sex into clinical trials and vaccine design.


A whole host of drugs from sleeping pills to blood pressure medications have been found to be metabolized differently in men and women in recent years. Earlier this year, the FDA reduced the recommended dose of Ambien for women by half. It'll take more research to figure out exactly how and why the immune systems of men and women are different, but at this point, it's clear they are.

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