# Genetic and hormonal mechanisms of sex differences in immune responses and influenza vaccine efficacy in young and aged mice

> **NIH NIH U54** · JOHNS HOPKINS UNIVERSITY · 2020 · $362,120

## Abstract

SADII RESEARCH PROJECT 3: Genetic and hormonal mechanisms of sex differences in immune responses
and influenza vaccine efficacy in young and aged mice
SUMMARY
 Using C57BL/6 mice and an inactivated 2009 H1N1 vaccine prime and boost strategy, we have shown that
greater antibody in young adult females is sufficient for protection against influenza. Following influenza virus
vaccination, young adult female mice have greater antibody responses and protection against challenge with
an influenza drift variant virus than males. Antibody derived from vaccinated females is better at protecting
both naïve males and females than antibody derived from males, and this protection is associated with
increased antibody specificity and avidity to the influenza virus. We have identified two factors that reduce
female-biased antibody responses and protection following influenza vaccination—old age and deletion of
genes that control somatic hypermutation (activation-induced cytidine deaminase [Aicda]) and antibody class
switching recombination in B cells (toll like receptor 7 [Tlr7]). Because secretion of sex steroids is reduced to a
greater extent in females than males with older age, the age-associated reduction in female-biased immunity
suggests a role for sex steroids. In contrast, because Tlr7 is on the X chromosome and escapes X inactivation
in B cells, female-biased immunity to influenza may also reflect direct effects sex chromosomes. The
overarching goal of SADII Research Project 3 is to analyze and manipulate the biological factors mediating the
sex and age differences in immunity to influenza, through completion of three aims: Aim 1 will systematically
evaluate how sex chromosome complement either directly through imbalanced expression of X and Y genes or
indirectly via sex hormone concentrations cause sex differences in immunity and protection from influenza,
using transgenic mice (i.e., Four Core Genotype); Aim 2 will tease apart the impact of chronological age versus
reproductive senescence on reduced sex differences in humoral immunity and protection from influenza in
aged as compared with young adult mice; and Aim 3 will characterize sex differences in transcriptional activity
and B-cell influenza-specific receptor repertoire following vaccination, focusing initially on activation of
pathways that we have shown to be differentially regulated between the sexes (e.g., TLR7 signaling) in mice,
as well as novel pathways that are uncovered in the analyses of cells from Projects 1 and 2. Together, the
studies in Research Project 3 will provide translational mechanistic insights that can be used test hypotheses
derived from the human data from Research Projects 1 and 2.

## Key facts

- **NIH application ID:** 9939400
- **Project number:** 5U54AG062333-03
- **Recipient organization:** JOHNS HOPKINS UNIVERSITY
- **Principal Investigator:** SABRA L. KLEIN
- **Activity code:** U54 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $362,120
- **Award type:** 5
- **Project period:** — → —

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9939400

## Citation

> US National Institutes of Health, RePORTER application 9939400, Genetic and hormonal mechanisms of sex differences in immune responses and influenza vaccine efficacy in young and aged mice (5U54AG062333-03). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/9939400. Licensed CC0.

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