The Effects of Sex and Age on Vaccine-Induced Immunity and Protection

Background: Immune responses to vaccines decline with age, but whether this immune senescence occurs similarly for males and females is rarely considered in either preclinical or clinical studies of vaccines. Using both human serum samples and a mouse model of influenza vaccination, this project aims to understand the interaction between sex and age on vaccine-induced immunity and protection against influenza virus challenge. I hypothesized that among both humans and mice, females of reproductive ages would develop higher antibody responses, which in mice would result in better protection upon challenge as compared to young adult males. Further, among aged individuals, sex differences would either wane or be reversed because of the lack of impact of reproductive hormones on immune responses. Methods: To test my hypothesis, I used human serum samples collected prior to and after receipt of an inactivated, monovalent A/Cal/09 H1N1 vaccine, and measured cytokine, neutralizing antibody, and cross-neutralizing antibody responses in young adults (18-41 years of age) and aged adults (65+ years of age). I also compared their neutralizing antibody responses with their hemagglutinin inhibition (HAI) antibody titers. Further, using a mouse model, I vaccinated young (9-10 weeks) and aged (68+ weeks) mice with an inactivated A/Cal/09 H1N1 virus to evaluate their vaccine-induced antibody responses, including HAI, neutralizing antibody, IgG, IgG isotypes, IgG avidity, and cross-neutralizing antibody titers. To correlate antibody responses with protection, we challenged the mice to an H1N1-drift variant virus and monitored their morbidity and mortality. Results: From the human serum analysis, young adult females developed higher IL-6, neutralizing antibody responses against A/Cal/09, and to a lesser extent against A/Mich/15 H1N1, than either young adult males or aged adult females. Overall, aged adults had lower neutralizing antibody responses than young adults. In contrast, neither age nor sex differences in HAI titers were observed, in which all individuals had HAI titers that were more than 4-fold higher post- as compared with pre-vaccination. Consistent with human data, young female mice developed higher vaccine-induced neutralizing antibody, and to a lesser extent cross-neutralizing, responses and were better-protected following influenza virus challenge than either young male or aged female mice. Young adult female mice also had greater IgG class switch recombination and antibody avidity than either young adult male or aged female mice. No sex differences in antibody titers, antibody quality, or morbidity post challenge were observed in aged animals. Conclusions: Taken together, we show robust sex differences among young adults in influenza vaccine responses but such sex differences are not observed among aged adults, pointing to sex-specific changes during immunosenescence