# Vaccinating at Mucosal Surfaces with Nanoparticle-conjugated Antigen and Adjuvant

> **NIH VA I01** · VETERANS HEALTH ADMINISTRATION · 2024 · —

## Abstract

The incidence of tuberculosis (TB) has increased among Veterans in recent years because global TB burden
has escalated with the emergence of multidrug-resistant and extremely drug resistant Mycobacterium
tuberculosis (Mtb) strains. Further, current vaccines do not elicit long-lasting protective immunity against TB,
especially in adults. Hence, this application addresses a critical unmet need for an effective vaccine against TB
and thereby, significantly improve the quality of life of our Veterans. Herein, we propose pre-clinical studies that
will identify protective CD8+ T cell epitopes and develop intranasal vaccine delivery platforms for the design of
next generation TB vaccines. The global burden of TB caused by Mycobacterium tuberculosis (Mtb) infection is
enormous. A third of the world’s population is currently infected with Mtb, an airborne pathogen that causes ~1.5
million deaths annually. The escalating emergence of multidrug-resistant and extremely drug resistant Mtb
strains for which treatment options are costly and limited, further exacerbates global burden. This problem
persists because current vaccines do not elicit long-lasting protective immunity against TB, especially in adults.
The challenge is multifaceted because Mtb enters the host through the respiratory tract and, therefore, optimal
protection will require installation of lung-resident CD4+ and CD8+ memory T cells positioned at the frontline to
respond immediately to an infection. Traditional vaccines and approved adjuvants typically elicit weak, short-
lived T cell responses, and parenteral vaccination is ineffective at installing protective immunity within the
mucosae. Moreover, most virus-vectored and subunit TB vaccines employ a small subset of Mtb antigens,
resulting in insufficient epitope diversity for optimal protection, partly because the epitopes that are presented
during Mtb infection and confer protective immunity are not fully defined. Hence, our overall objective is to
discover immunogenic, protective Mtb epitopes and to incorporate them in an innovative nanoparticle (NP)-
based intranasal vaccine designed to promote a balanced CD4+ and CD8+ T cell responses in the lungs that are
protective against TB. As a means to accomplish this goal, we discovered >10,000 peptides that bind to HLA-
A*02:01, B*07:02, B*35:01, & B*35:03 in a high-throughput binding assay using ultrahigh-density peptide arrays.
Now the challenge is to identify epitopes recognised by Mtb-reactive CD8+ T cells that can protect against
infection in a preclinical, humanised HLA-Itg mouse models. Moreover, using different infection models, we have
developed multiple nanoparticle platforms for simultaneous delivery of antigens and adjuvants that efficiently
generate protective, tissue resident CD8+ T cells (Trm). Guided by these exciting published and preliminary
results, we will test this central hypothesis: Intranasal immunization with subunit vaccines consisting of novel
Mtb antigens and adjuvant...

## Key facts

- **NIH application ID:** 10873048
- **Project number:** 5I01BX006010-02
- **Recipient organization:** VETERANS HEALTH ADMINISTRATION
- **Principal Investigator:** SEBASTIAN JOYCE
- **Activity code:** I01 (R01, R21, SBIR, etc.)
- **Funding institute:** VA
- **Fiscal year:** 2024
- **Award amount:** —
- **Award type:** 5
- **Project period:** 2023-04-01 → 2027-03-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10873048

## Citation

> US National Institutes of Health, RePORTER application 10873048, Vaccinating at Mucosal Surfaces with Nanoparticle-conjugated Antigen and Adjuvant (5I01BX006010-02). Retrieved via AI Analytics 2026-05-25 from https://api.ai-analytics.org/grant/nih/10873048. Licensed CC0.

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