Sex differences in influenza virus infection, vaccination, and therapies

Males and females differ in the likely outcome of influenza virus infection and vaccination. Following infection with pandemic and outbreak strains of influenza viruses, females of reproductive ages (15-49 years of age) experience a worse outcome than their male counterparts. Among females of reproductive ages, pregnancy is one factor linked to an increased risk of severe outcome of influenza, although it is not the sole factor explaining the female preponderance of severe disease. The sex bias in disease outcome is reversed in children under the age of 10 years and adults over the age of 65 years, where males appear to be more likely to be hospitalized or die from influenza. Small animal models of influenza virus infection illustrate that inflammatory immune responses also differ between the sexes and impact the outcome of infection. Males and females also generally respond differently to influenza vaccines and antiviral treatments, with females on average initiating higher humoral immune responses following vaccination and experiencing more adverse reactions to vaccines and drug treatments than males. Small animal models further show that elevated immunity following vaccination in females compared with males leads to greater cross protection against novel influenza viruses. We hypothesize that sex steroid hormones, including estrogens, progesterone, and androgens, as well as genetic differences between the sexes, may play roles in modulating sex differences in immune responses to influenza virus infection and vaccination.