# Vaccinating at Mucosal Surfaces with Nanoparticle Conjugated Antigen and Adjuvant

> **NIH VA I01** · VETERANS HEALTH ADMINISTRATION · 2020 · —

## Abstract

The incidence of tuberculosis (TB) has increased among the Veterans in recent years because the global burden
of TB is enormous. This burden has escalated with the emergence of multidrug-resistant and extremely drug
resistant Mycobacterium tuberculosis (Mtb) strains and because current vaccines do not elicit long-lasting
protective immunity against TB especially in adults. Hence, the development of new generations of vaccines that
will confer durable protection against TB will significantly improve the quality of life of our Veterans. Our plan
proposes pre-clinical studies that will identify protective CD8+ T cell epitopes and develop mucosal vaccine
delivery platforms for the design of next generation TB vaccines. Mtb enters the host through the respiratory
tract. Hence, optimal protection will require lung-resident CD4+ and CD8+ memory T cells to be positioned at
the frontline to respond immediately to infection. Traditional vaccines and approved adjuvants typically elicit
weak, short-lived T cell responses, and parenteral vaccination is ineffective at installing protective immunity
within tissue 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 have not been explored. Hence, our overall
objective is to discover immunogenic Mtb epitopes generated during infection and to incorporate them in an
innovative nanoparticle (NP)-based intranasal vaccine that is designed to promote a balanced pulmonary CD4+
and CD8+ T cell responses that will protect against TB. In preliminary experiments, we have identified 41 novel
peptides from Mtb H37Rv-infected primary macrophages using a proteomics approach. Among these, 17 are
putative HLA-B*07;02-binding epitopes, which we will characterize to advance anti-TB vaccine design. Eliciting
CD8+ T cells that complement a CD4+ T cell response requires that subunit antigens be presented by HLA class
I molecules for CD8+ T cell cross-priming in the context of appropriate inflammatory cues that drive both CD8+
T cell and CD4 differentiation. Our team has recently pioneered a “pathogen-mimicking” vaccine that is based
on pH-responsive, endosome-rupturing NP chemistry. Such NPs promote delivery of antigens and nucleic acid
adjuvant cargoes into the cytooplasm. Preliminary studies demonstrated that a single intranasal administration
of NPs loaded with ovalbumin in conjunction with a structurally optimized 5'ppp-RNA hairpin adjuvant, that
activates cytoplasmic retinoic acid-inducible gene-I, elicits a robust, durable and protective antigen-specific T
cell response in the lungs. Based on these exciting new findings, we hypothesize that intranasal immunization
with NP vaccines co-loaded with naturally processed class I-restricted Mtb-derived epitopes and 5'ppp-RNA
adjuvant will significantly enhance tissue reside...

## Key facts

- **NIH application ID:** 9898281
- **Project number:** 5I01BX001444-07
- **Recipient organization:** VETERANS HEALTH ADMINISTRATION
- **Principal Investigator:** SEBASTIAN JOYCE
- **Activity code:** I01 (R01, R21, SBIR, etc.)
- **Funding institute:** VA
- **Fiscal year:** 2020
- **Award amount:** —
- **Award type:** 5
- **Project period:** 2014-01-01 → 2022-03-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9898281

## Citation

> US National Institutes of Health, RePORTER application 9898281, Vaccinating at Mucosal Surfaces with Nanoparticle Conjugated Antigen and Adjuvant (5I01BX001444-07). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/9898281. Licensed CC0.

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