Sex hormones more than sex chromosomal complement predict sex differences in influenza vaccine-induced immunity and protection in mice

Abstract Following influenza vaccination, adult female mice have greater quantity and quality of antiviral antibodies than males, which is a correlate of protection against live influenza virus challenge. Whether sex steroid hormone concentrations, sex chromosome complement, or both underlie greater immunity and protection following vaccination has not been determined. To dissect the relative contribution of steroid hormones and chromosome complement, we used the Four Core Genotype (FCG) mouse model on a C57BL/6 background to evaluate how gonadal sex (i.e., testes or ovaries) and sex chromosome complement (i.e., XX or XY) can independently or together contribute to sex differences in influenza immunity. Adult FCG mice were vaccinated intramuscularly with inactivated mouse-adapted A/California/04/09 (ma2009 H1N1). Blood samples were collected at several time points post vaccination to measure total IgG and neutralizing antibodies. All mice were challenged intranasally with live ma2009 H1N1 drift variant virus and used to either measure lung virus replication kinetics or disease pathogenesis. Gonadal females (i.e., XXF and XYF), regardless of chromosome complement, produced greater antibody responses and had less pulmonary virus replication than gonadal males (i.e., XYM and XXM). Gonadal sex and sex chromosomal complement intersected to impact disease severity following challenge, in which among gonadal females, XX females experienced less morbidity than XY females. In contrast, there was no effect of chromosome complement among gonadal males. Our data suggests that sex steroid hormones more than sex chromosome complement underlie sex differences in influenza vaccine-induced immunity and protection. Financial support provided by NIH/OWRH/NIA U54AG062333