Program Director/Principal Investigator (Last, First, Middle): Klein, Sabra L. PROJECT II: Sex differences in immune responses to vaccine and circulating strains of influenza in healthcare workers Summary Seasonal epidemics of influenza pose important public health threats to humans despite the availability of vaccines and antivirals. Influenza vaccine efficacy can vary significantly from year to year and the immunogenicity of the vaccine or the antigenic match between the vaccine and circulating influenza strains are most often blamed for the low efficacy. However, host factors, including the sex and age of the vaccine, may also be contributing to poor influenza vaccine efficacy but these have not been explored extensively. Adult females often have stronger antibody responses to a number of antigens – including influenza vaccines - when compared to males. These differences are often most pronounced during their reproductive years when sex hormone levels are highest. Our preliminary data illustrate that females (18-45 years of age) develop higher neutralizing antibody titers to a vaccine antigen, but not to a antigenic variant virus, which may reflect the greater specificity of the female’s antibody response. The SADII Research Project 2 will investigate sex differences in response to influenza vaccination in a human cohort of individuals between the ages of 18-45. We will quantify sex differences in pre-existing immunity to influenza, as this may contribute to the magnitude of the sex differences after vaccination. We will characterize sex-specific differences, with consideration of hormonal and genetic mediators, in a number of different antibody responses, including virus neutralizing activity, antibody avidity, and IgG class switch recombination. The number of total and antigen-specific B cells will be determined and the transcriptional activity and B cell receptor utilization of the antibody producing B cells will be quantified. Together, the studies in the SADII Research Project 2 will enhance our understanding of the role of sex in modulating the immune response to influenza vaccination and identify sex-specific mechanisms mediating those differences in adults. If females of reproductive ages develop antibody and memory B cell responses that are of greater titer and specificity than males, then this should inform the formulation, dosing, and predicted protection following vaccination, in a manner similar to our consideration of age in vaccination guidelines. OMB No. 0925-0001/0002 (Rev. 01/18 Approved Through 03/31/2020) Page Continuation Format Page