# Mechanisms of vaccine immunity against coccidioidomycosis

> **NIH NIH R01** · UNIVERSITY OF WISCONSIN-MADISON · 2024 · $577,624

## Abstract

ABSTRACT
Coccidioidomycosis is a re-emerging infection that NIH has prioritized for vaccine prevention. An experimental
vaccine of live attenuated spores is highly protective after intranasal delivery. We propose to study this vaccine
to define mechanisms by which lung epithelium regulates durable mucosal T cell immunity. Resistance against
inhaled microbes is thought to reside within tissue-resident memory (TRM) cells, but little is known about how this
intranasal vaccine induces lung TRM. Our preliminary data reveal that the vaccine elicits protective, Coccidioides
endoglucanase 2 (C-Eng2) specific CD4+ T cells and that bronchiolar club cells and Ca++ calcineurin signaling in
the cells are needed to mobilize inflammatory and T cells in response to vaccine. We also find that Microfold (M)
cells descend from the bronchiolar club cells and facilitate T cell priming in response to the vaccine.
 From these preliminary data, we hypothesize that bronchiolar club cells and M cells regulate mucosal
cellular immunity in response to intranasal vaccine. To test this hypothesis, we have created innovative tools: (i)
transgenic mice to deplete epithelial cell subsets or their products to further define their role in inducing immunity;
(ii) C-Eng2 specific tetramers to track and analyze protective CD4+ T cells and TRM in C57BL6 mice; and (iii)
methods to isolate and culture human lung epithelial cells to translate results from mice to humans. We propose
three aims to test our hypothesis. In Aim 1, we will elucidate early stages of the inflammatory response to
intranasal vaccine regulated by bronchiolar club cells and M cells; in Aim 2, we will identify lung epithelial cell
receptors - dectin-1, DUOX1 and DUOXA1 - and downstream PLCG2 that may sense intranasal vaccine and
signal via Ca++ and calcineurin to mobilize mucosal immunity; and in Aim 3, we will define mechanisms of
vaccine-induced durable mucosal immunity by studying lung TRM and the regulatory role of lung epithelium.
 In sum, we address the unmet need of vaccination against coccidioidomycosis. Our work is significant as
it will define mechanisms by which a promising vaccine establishes T cell immunity at the lung mucosa. Results
will identify tactics useful for other vaccine immunogens given intranasally, including subunit vaccines. The work
will define correlates of immunity needed to advance this attenuated vaccine or next generation subunit vaccines
against this high priority pathogen. The work will be done with state-of-the-art, cutting-edge tools. Our team of
PI and Co-I’s will let us translate results from mouse to human, with tools and reagents for human lung epithelium.

## Key facts

- **NIH application ID:** 10773122
- **Project number:** 5R01AI168370-02
- **Recipient organization:** UNIVERSITY OF WISCONSIN-MADISON
- **Principal Investigator:** BRUCE Steven KLEIN
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $577,624
- **Award type:** 5
- **Project period:** 2023-02-01 → 2028-01-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10773122

## Citation

> US National Institutes of Health, RePORTER application 10773122, Mechanisms of vaccine immunity against coccidioidomycosis (5R01AI168370-02). Retrieved via AI Analytics 2026-05-26 from https://api.ai-analytics.org/grant/nih/10773122. Licensed CC0.

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