# Project 3 Determinants of Vaccine Efficacy

> **NIH NIH P01** · UNIV OF MASSACHUSETTS MED SCH WORCESTER · 2024 · $594,375

## Abstract

Project 3: Determinants of Vaccine Efficacy (Project Leader: Behar)
Abstract
The bacterium Mycobacterium tuberculosis (Mtb) causes tuberculosis (TB), which is a leading cause of
global morbidity and mortality. Given the rapid spread of drug resistant Mtb strains, the long-term solution
must be a safe and effective vaccine. Much well-deserved attention has been devoted to developing new
vaccines against TB during the past twenty years, but without notable success yet. Key knowledge gaps
include the role of human genetics in vaccine-induced protection, the nature of protective immunity itself,
and the identification of clinically useful correlate measures. Moreover, given the challenges in testing
vaccines in NHPs, improved small animal models are of strong interest. To study how variation in genetics
and immunity affect TB vaccine efficacy, we have comprehensively analyzed BCG-elicited protection in
genetically diverse Collaborative Cross (CC) and Diversity Outbred (DO) mice. CC / DO mice have vaccine
responses that differ quantitatively and qualitatively from B6 mice, and more closely resemble the variable
outcomes observed in natural human populations. Our data provide a rigorous basis for correlative and
mechanistic studies to identify pathways associated with vaccine-induced immunity. In Aim 1, we will
analyze BCG-induced immunity in CC strains that vary in their ability to be protected by BCG. We expect to
distinguish a subset of transcriptional signatures and immunological features that correlate with BCG-
induced protection from the pool of immune perturbations triggered by BCG but not associated with
protection. In Aim 2, we will identify alternative vaccine strategies that protect diverse CC/DO mice from TB.
Three novel vaccine strategies will be compared with the goal to identify CoP and to evaluate the use of
CC/DO mice as preclinical models for vaccine testing. In Aim 3, the features identified in vaccinated CC/DO
mice will be used to discover human immunological and transcriptional pathways that are associated with
different TB outcomes, using prospectively collected clinical samples from RePORT South Africa, and BCG
and M72 vaccination trials. Finally, Aim 4 will evaluate novel mechanisms of vaccine-induced immunity. For
example, BCG-protected CC strains have distinct immune responses after vaccination and Mtb challenge.
One of these, Th17-skewed responses, are associated with protection in mice, NHP, and humans, but the
mechanisms are largely unknown. In several CC strains, but not B6 mice, BCG elicits Th1/17 responses
that are associated with protection. Moreover, we identified a genetic locus that controls vaccine-induced
protection in DO mice and Th1/17 cytokine production in CC strains. We will evaluate engineered mouse
strains to define mechanisms of Th1/17-mediated protection and search for the causative variants
underlying these quantitative trait loci (QTL). Thus, in close collaboration with all projects and cores in this
pr...

## Key facts

- **NIH application ID:** 10861334
- **Project number:** 1P01AI181898-01
- **Recipient organization:** UNIV OF MASSACHUSETTS MED SCH WORCESTER
- **Principal Investigator:** SAMUEL M BEHAR
- **Activity code:** P01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $594,375
- **Award type:** 1
- **Project period:** 2024-08-20 → 2029-05-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10861334

## Citation

> US National Institutes of Health, RePORTER application 10861334, Project 3 Determinants of Vaccine Efficacy (1P01AI181898-01). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10861334. Licensed CC0.

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