Dissecting Sex Differences in the Immune Response to Vaccines

• Applicant: Professorin Dr. Marylyn Martina Addo
• Subject Area: Immunology
• Term: since 2021
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 429191104

Vaccines are among the most impactful public health interventions, preventing millions of new infections and deaths annually worldwide. Recent outbreaks caused by emerging viruses, such as Ebola Virus, MERS-CoV and SARS-CoV-2, additionally highlight the continued need for rapid and strategic vaccine development. Cisgender men and women differ in the immune response to vaccination with females typically developing higher antibody responses, but also experiencing more adverse reactions following vaccination than males for most licensed vaccines. Sex hormones regulate critical innate signalling pathways, potentially contributing to differential outcomes in vaccine responses in cisgender females and males in terms of reactogenicity and immunogenicity. Additionally, escape from X chromosome inactivation (XCI) in genes critical for immune regulation may have a robust impact on vaccine-induced immune responses. Yet the exact mechanisms and signalling pathways involved in the differential vaccine outcomes between the sexes remain incompletely understood. While sex differences in Ig-binding and neutralizing antibodies have been regularly investigated in the context of vaccination, the contribution of non-neutralizing Fc-mediated antibodies to differential vaccine immunogenicity has not been systematically explored. We therefore hypothesize that sex differences in Fc-mediated antibody functions, Ig isotypes and antibody glycosylation contribute to differential outcomes in vaccine immunogenicity and that gene-dosage effects resulting from escape from X-chromosome inactivation lead to differences in vaccine responses between the sexes. These hypotheses will be explored using data and biomaterial from longitudinal human vaccine cohorts. We specifically propose to investigate two vaccines against the respiratory pathogens MERS-Coronavirus and Influenza Virus, for which opposite vaccine response effects between the sexes have been reported: In the first funding period, we demonstrated that the recombinant MVA-based viral vector vaccine MVA-MERS elicited higher antibody responses in cisgender males compared to females. In contrast for licensed influenza vaccines, influenza-specific immune responses have shown to be higher in females. We will complement the ex vivo studies with detailed analyses of sex-specific differences in induction of B cells, plasmablasts and T follicular helper cells using tonsil organoid systems. Taken together dissecting the molecular factors related to sex differences in vaccine-induced immune responses may enable strategic modulation of vaccine-induced immunity and promote individualized approaches to vaccine design.

• DFG Programme: Research Units
• Subproject of: FOR 5068: Sex differences in immunity