# Combination Adjuvants to Program Durable Immunity to Respiratory Viral and Fungal Pathogens

> **NIH NIH U01** · UNIVERSITY OF WISCONSIN-MADISON · 2021 · $599,483

## Abstract

ABSTRACT: Respiratory infections with viruses and fungi constitute major public health problems globally.
Except for influenza virus, there are no licensed vaccines against viruses or fungi. It is generally agreed that
induction of T-cell memory is critical for defense against viruses and fungi in the respiratory tract. We and others
have shown that induction of tissue-resident memory (TRM) CD8 and CD4 T cells and systemic migratory memory
CD4 T cells are essential for protection against influenza A virus (IAV) and inhaled fungi, respectively. However,
both TRM cells and systemic memory CD4 T cells undergo attrition, leading to short-lived immunity, which is
especially true for TC1/TH1 cells. Therefore, induction of durable T-cell immunity poses major challenges for
vaccinologists. As compared to TH1 cells, TH17 cells display sought-after attributes of stem-ness, durability and
functional plasticity. We propose to tailor combination adjuvants to harness T17 programming and induce durable
and protective lung TRM cells and migratory memory CD4 T cells against viruses and fungi.
 We find that Adjuplex, a nano-emulsion adjuvant, when combined with the TLR4 agonist glucopyranosyl
lipid A (GLA), evokes antigen-specific CD8 and CD4 T-cell responses in the lung that are: (i) durable and
multifaceted (TC1/TC17/TH1/TH17), and (ii) confer heterosubtypic immunity against IAV that persists >400 days.
We further find that combining those adjuvants with fungal CLR ligands Blastomyces endoglucanase 2 (Bl-Eng2;
Dectin-2 agonist) and b-glucan particles (Dectin-1 agonist) augments antiviral TC17/TH17/TC1/TH1 and elicits
migratory memory T cells that protect against fungal pneumonia. By single-cell RNAseq, we found that our
combined adjuvants induce memory antiviral and antifungal CD8 and CD4 T-cell clusters that express ICOS
(Inducible T Cell Co-stimulator), the transcription factor c-Maf, and a transcriptome that fosters tissue residency,
stem cell-ness and non-pathogenic T17 programming. Cyclic dinucleotides also promote T17 programming in
lungs. This, we postulate that programming stem cell-like, functionally plastic, non-pathogenic TC17/TH17
memory cells with our combination adjuvants (that engage TLR-4, Dectin-1/2 and STING pathways) will foster
durable protective immunity to viral and fungal pathogens in the lung. Our specific aims will test three
hypotheses: Aim 1: Combination adjuvants that evoke TC17/TH17 stem cell-like functionally-plastic TRM or
systemic migratory memory will engender durable immunity to respiratory viral and fungal pathogens; Aim 2:
Functional plasticity of TC17/TH17 memory is important for protective immunity to viruses and fungi; Aim 3: The
ICOS/c-Maf pathway is integral to establishment and/or maintenance of durable vaccine-induced protective
immunity to respiratory viral and fungal infections. The proposed work is significant and of high impact because
it has the potential to create a tractable adjuvant system/tool kit that will adv...

## Key facts

- **NIH application ID:** 10224468
- **Project number:** 2U01AI124299-06
- **Recipient organization:** UNIVERSITY OF WISCONSIN-MADISON
- **Principal Investigator:** BRUCE Steven KLEIN
- **Activity code:** U01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $599,483
- **Award type:** 2
- **Project period:** 2016-02-17 → 2026-04-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10224468

## Citation

> US National Institutes of Health, RePORTER application 10224468, Combination Adjuvants to Program Durable Immunity to Respiratory Viral and Fungal Pathogens (2U01AI124299-06). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10224468. Licensed CC0.

---

*[NIH grants dataset](/datasets/nih-grants) · CC0 1.0*