Dissecting Sex Differences in the Immune Response to Vaccines

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Vaccines represent one of the most impactful public health interventions with the prevention of millions of infections and deaths annually worldwide. As illustrated by recent epidemic or pandemic outbreaks caused by emerging viruses such as Ebola Virus, MERS-CoV and more recently SARS-CoV-2, the need for rapid and strategic vaccine development remains paramount. A growing body of data have demonstrated sex differences in immune responses following vaccination. 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. This effect is not only observed post-puberty, but also in children of all ages, suggesting that factors beyond mere hormonal influences, such as chromosomal factors and epigenetics may contribute to this phenomenon. Yet the exact mechanisms and signaling pathways involved in the differential vaccine outcomes between the sexes remain incompletely understood. We hypothesize that: a) sex hormones regulate critical innate signaling pathways resulting in differential outcomes in vaccine reactogenicity and immunogenicity and b) gene-dosage effects resulting from escape from X-chromosome inactivation (XCI) contribute to sex-specific differences in vaccine responses. These hypotheses will be explored using data and biomaterial from two unique Phase 1 clinical trials investigating novel emergency vaccines. We propose to prospectively investigate and dissect sex-specificity in immunity to viral vector vaccines against two important emerging respiratory pathogens with pandemic potential and high global significance: MERS-CoV and SARS-CoV-2, two recently discovered novel coronaviruses. Specifically we propose to prospectively investigate sex-differences in the overall reactogenicity, antibody and T cell response to the two novel coronavirus vaccines, MVA-MERS-S-DF1 and MVA-SARS-2 (Objective 1), to comprehensively analyze sex-differences in innate immune response profiles following vaccination using a systems vaccinology approach (Objective 2) and to investigate whether differences in the expression of genes encoded by the X chromosome in dendritic cells and B cells are associated with the magnitude of vaccine-induced antibody responses (Objective 3). A detailed understanding of the molecular factors associated with sex-differences in vaccine-induced immune responses may ultimately allow for strategic modulation of vaccine immunity and foster individualized vaccine design.