Age-associated changes in the impact of sex steroids on influenza vaccine responses in males and females

Abstract

Vaccine-induced immunity declines with age, which may differ between males and females. Using human sera collected before and 21 days after receipt of the monovalent A/Cal/09 H1N1 vaccine, we evaluated cytokine and antibody responses in adult (18–45 years) and aged (65+ years) individuals. After vaccination, adult females developed greater IL-6 and antibody responses than either adult males or aged females, with female antibody responses being positively associated with concentrations of estradiol. To test whether protection against influenza virus challenge was greater in females than males, we primed and boosted adult (8–10 weeks) and aged (68–70 weeks) male and female mice with an inactivated A/Cal/09 H1N1 vaccine or no vaccine and challenged with a drift variant A/Cal/09 virus. As compared with unvaccinated mice, vaccinated adult, but not aged, mice experienced less morbidity and better pulmonary viral clearance following challenge, regardless of sex. Vaccinated adult female mice developed antibody responses that were of greater quantity and quality and more protective than vaccinated adult males. Sex differences in vaccine efficacy diminished with age in mice. To determine the role of sex steroids in vaccine-induced immune responses, adult mice were gonadectomized and hormones (estradiol in females and testosterone in males) were replaced in subsets of animals before vaccination. Vaccine-induced antibody responses were increased in females by estradiol and decreased in males by testosterone. The benefit of elevated estradiol on antibody responses and protection against influenza in females is diminished with age in both mice and humans.Influenza vaccines: Sex differences in responses lost with ageMales and females show pronounced differences in their immune responses. Sabra L. Klein and colleagues at Johns Hopkins University examine how sex differences in immune responses to influenza vaccination are affected by aging. Using both human volunteers and mouse models (adults vs. aged) they find that adult females have more robust interleukin-6 production and greater titers and quality of influenza-specific antibodies. Vaccination was also more protective in adult female mice. These sex differences in influenza responses are however lost in aged individuals. Gonadectomy and hormone replacement demonstrate that sex steroids exert a key influence, with estradiol positively- and testosterone negatively-correlating with influenza vaccine responses. The diminished production of estradiol in aged females and testosterone in aged males likely contributes to the equalization of influenza vaccine responses in the aged.