A Clearer View of Vaccines for Women and Men

One factor rarely gets mentioned in discussions about vaccines: the differences in how males and females react to them. Yet Sabra Klein, assistant professor in the W. Harry Feinstone Department of Molecular Microbiology and Immunology (MMI), says understanding those differences can improve vaccine distribution. In the May issue of The Lancet Infectious Diseases, Klein, PhD, MS, MA, Andrew Pekosz, PhD, and others examine the impact of male-female differences in responding to viral vaccines, from yellow fever and measles to hepatitis.

One example is herpes simplex virus type 2 (HSV-2). Despite extensive clinical trials, there is still no successful vaccine for HSV-2 because no overall protection was observed with all participants included. Disaggregating those trial results by sex, however, showed the vaccines offered significant protection for women. Phase 1 and 2 studies of one vaccine revealed efficacy in females of 73 percent vs. 11 percent in males. A closer look at the female response to that vaccine could provide important clues about what type of immune responses a successful vaccine should produce.

What's more, pregnant women have strikingly different immune responses than women who aren't pregnant, the Lancet Infectious Diseases study notes. During pregnancy, progesterone levels are substantially higher, and activity of regulatory T cells increases at the maternal-fetal interface; these and other hormone changes may affect vaccination response.

Last fall, amid the H1N1 pandemic, Klein pointed out that women's bodies provide a stronger antibody response to the seasonal flu vaccine than men's. As a result, reducing the dosage for women could make more vaccine available, for example, to vulnerable populations in poor countries.

"In all likelihood, we'd have a better H1N1 vaccine—and more of it—if in our preparations we had accounted for the biological differences between men and women," suggested Klein and colleague Phyllis Greenberger in a New York Times op-ed last October.

Still, clinical studies typically don't look at those differences. "A lot of vaccine trials aren't designed to answer that question," says Klein, and so they perpetuate the blind spot. A trial may not have an equal proportion of males and females, for example, making it difficult to analyze differences adequately. "My goal is to show that this matters."

In her current work, Klein uses animal models to explore how hormones affect immune response. By manipulating hormones, she can see which ones mediate immune response to viruses and vaccines. Her collaboration with Pekosz, an MMI associate professor, looks at sex differences in protective immunity following vaccination.

"Andy is a virologist," she explains. "He comes at it from the perspective of the virus. I'm coming at it from the perspective of the host response and sex differences in that response."

"Most research scientists who study or develop vaccines do not consider sex as a variable," says Pekosz, "so they don't really know if sex has an effect in their experiments. I was among that group until I started to collaborate with Sabra and see the data coming from her laboratory."

Klein first encountered differences in immune responses during her master's degree research. Her thesis was on prenatal stress, especially the impact of maternal stress on offspring. She continued to explore the topic in her doctoral research.

One reason for a lack of sex-specific research, says Klein, is that "society has conditioned us to believe that the sexes are equal when in fact we are biologically different."

The tide may be turning. After her New York Times article, Klein caught the attention of WHO officials. This spring, WHO will publish Sex, Gender and Influenza, a report that looks at the 2009 H1N1 pandemic through the prism of sex differences in immunology. Such attention can help get these ideas into practice. Says Klein, "Clinicians look to policies and procedures from places like the WHO and CDC."

"I hope our review will stimulate research scientists to ask whether they know if sex is a variable that might be important in their research," says Pekosz. "If they don't, hopefully they will be motivated to design experiments to answer that question."