# mTOR activation as a mechanism for sex differences in vaccine-induced immunity

> **NIH NIH F32** · JOHNS HOPKINS UNIVERSITY · 2024 · $74,764

## Abstract

Project Summary
Biological sex has profound effects on the effectiveness of vaccines that protect against pathogens of pandemic
potential, including influenza A viruses. Following influenza vaccination, females of reproductive ages (18-49
years) produce greater antiviral antibody responses than age-matched males, which correlates with greater
estradiol (E2) concentrations in females. How estrogens drive greater B cell activation and antibody production
after vaccination is not known. Estrogen receptor signaling in B cells might alter metabolic signaling to cause
sex differences in vaccine-induced immunity. Activation of mTOR, in particular, and a switch towards β-oxidation
as a primary energy source has been identified as indispensable for B cell proliferation, differentiation, and
antibody production. Prior studies have demonstrated that females show greater preference for the use β-
oxidation for energy production when under high energy demand. Thus, I hypothesized that differential activation
of mTOR and downstream utilization of lipids for β-oxidation may be a potential mediator of sex differences in
vaccine-induced immunity. My preliminary data show that after H1N1 vaccination in mice, adult females have
greater activation of mTOR and mTOR-related proteins in splenic B cells than age-matched males. I hypothesize
that greater mTOR activation in B cells from females is partially regulated by E2 through an ERα-mTOR feedback
loop. My central hypothesis is that sex steroid signaling causes distinct metabolic signatures in B cells and that
differential regulation of mTOR is the central mechanism governing sex-specific differences in vaccine-mediated
humoral immunity. In Aim 1, I will test whether manipulation of mTOR and selected downstream proteins using
small molecule agonist and antagonist can reverse sex differences in immune responses using a mouse model
of influenza vaccination. I will use immunofluorescence assays and seahorse analysis of mitochondrial
respiration to dissect sex differences in metabolic activation in B cells following vaccination, which will be
correlated with measures of protective immunity. In Aim 2, I will examine the effects of sex chromosome
complement and sex steroid signaling on both mTOR activation and metabolic activation of B cells. Through
these experiments, I seek to define the cellular mechanisms mediating sex differences in vaccine-induced
immunity. These results have significant translational application. As a fellow, the research that I have outlined
is crucial to extend my training in animal models, viral immunology, sex-based biology, and biomedical research
to refine my expertise in using metabolomics-based approaches to gain mechanistic insight into biological
phenomena.

## Key facts

- **NIH application ID:** 10997676
- **Project number:** 1F32AI186453-01
- **Recipient organization:** JOHNS HOPKINS UNIVERSITY
- **Principal Investigator:** Laura Athelle St Clair
- **Activity code:** F32 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $74,764
- **Award type:** 1
- **Project period:** 2024-12-16 → 2025-12-15

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10997676

## Citation

> US National Institutes of Health, RePORTER application 10997676, mTOR activation as a mechanism for sex differences in vaccine-induced immunity (1F32AI186453-01). Retrieved via MORVS 2026-10-25 from https://api.morvs.ai/grant/nih/10997676. Licensed CC0.

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