Sunday, May 18, 2025 5/18/2025

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

Award Number: U01AI124299
ORGANIZATION: NATIONAL INSTITUTE OF ALLERGY & INFECTIOUS DISEASES
OPDIV: NIH
AWARD CLASS: COOPERATIVE AGREEMENT
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)

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Combination Adjuvants to Program Durable Immunity to Respiratory Viral and Fungal Pathogens - 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 advance the formulation of vaccines: (i) targeted for mucosal or parenteral administration; (ii) designed to induce TRM or systemic T-cell memory; and (iii) tailored to elicit CD8 and CD4 T cells that protect against diverse pathogens such as viruses and fungi.


Issue Date FY	Funding FY	Legal Entity Name	Legal Entity Address	Legal Entity City	Legal Entity State	Legal Entity Zip Code	Legal Entity COUNTY	Legal Entity COUNTRY	Assistance Listing	Award Code	Budget Year	Action Date	Action Type	Action Amount

Issue Date FY: 2025 ( Subtotal = $606,473 )
2025	2025	UNIVERSITY OF WISCONSIN SYSTEM	21 N PARK ST STE 6301	MADISON	WI	53715	DANE	USA	Allergy and Infectious Diseases Research	000	10	4/29/2025	NON-COMPETING CONTINUATION	$606,473
														Subtotal = $606,473

Issue Date FY: 2024 ( Subtotal = $895,197 )
2024	2024	UNIVERSITY OF WISCONSIN SYSTEM	21 N PARK ST STE 6301	MADISON	WI	53715	DANE	USA	Allergy and Infectious Diseases Research	001	9	8/27/2024	SUPPLEMENT FOR EXPANSION	$285,674
2024	2024	UNIVERSITY OF WISCONSIN SYSTEM	21 N PARK ST STE 6301	MADISON	WI	53715	DANE	USA	Allergy and Infectious Diseases Research	000	9	5/3/2024	NON-COMPETING CONTINUATION	$609,523
														Subtotal = $895,197

Issue Date FY: 2023 ( Subtotal = $612,573 )
2023	2023	UNIVERSITY OF WISCONSIN SYSTEM	21 N PARK ST STE 6301	MADISON	WI	53715	DANE	USA	Allergy and Infectious Diseases Research	002	8	4/12/2023	NON-COMPETING CONTINUATION	$612,573
2023	2022	UNIVERSITY OF WISCONSIN SYSTEM	21 N PARK ST STE 6301	MADISON	WI	53715	DANE	USA	Allergy and Infectious Diseases Research	001	7	3/1/2023	NON-COMPETING CONTINUATION	$0
2023	2021	UNIVERSITY OF WISCONSIN SYSTEM	21 N PARK ST STE 6301	MADISON	WI	53715	DANE	USA	Allergy and Infectious Diseases Research	000	6	12/12/2022	COMPETING CONTINUATION	$0
														Subtotal = $612,573

Issue Date FY: 2022 ( Subtotal = $765,438 )
2022	2022	UNIVERSITY OF WISCONSIN SYSTEM	21 N PARK ST STE 6301	MADISON	WI	53715	DANE	USA	Allergy and Infectious Diseases Research	000	6	1/12/2022	SUPPLEMENT FOR EXPANSION	$117,939
2022	2022	UNIVERSITY OF WISCONSIN SYSTEM	21 N PARK ST STE 6301	MADISON	WI	53715	DANE	USA	Allergy and Infectious Diseases Research	004	7	7/26/2022	NON-COMPETING CONTINUATION	$31,878
2022	2022	UNIVERSITY OF WISCONSIN SYSTEM	21 N PARK ST STE 6301	MADISON	WI	53715	DANE	USA	Allergy and Infectious Diseases Research	003	7	4/27/2022	NON-COMPETING CONTINUATION	$615,621
2022	2021	UNIVERSITY OF WISCONSIN SYSTEM	21 N PARK ST STE 6301	MADISON	WI	53715	DANE	USA	Allergy and Infectious Diseases Research	002	6	3/17/2022	COMPETING CONTINUATION	$99,698
2022	2020	UNIVERSITY OF WISCONSIN SYSTEM	21 N PARK ST STE 6301	MADISON	WI	53715	DANE	USA	Allergy and Infectious Diseases Research	001	5	3/17/2022	NON-COMPETING CONTINUATION	-$99,698
														Subtotal = $765,438

Issue Date FY: 2021 ( Subtotal = $599,483 )
2021	2021	UNIVERSITY OF WISCONSIN SYSTEM	21 N PARK ST STE 6401	MADISON	WI	53715	DANE	USA	Allergy and Infectious Diseases Research	001	6	7/9/2021	COMPETING CONTINUATION	$599,483
2021	2020	UNIVERSITY OF WISCONSIN SYSTEM	21 N PARK ST STE 6401	MADISON	WI	53715	DANE	USA	Allergy and Infectious Diseases Research	000	5	7/9/2021	NON-COMPETING CONTINUATION	$0
														Subtotal = $599,483

Issue Date FY: 2020 ( Subtotal = $689,030 )
2020	2020	UNIVERSITY OF WISCONSIN SYSTEM	21 N PARK ST STE 6401	MADISON	WI	53715	DANE	USA	Allergy and Infectious Diseases Research	001	5	12/27/2019	NON-COMPETING CONTINUATION	$451,192
2020	2020	UNIVERSITY OF WISCONSIN SYSTEM	21 N PARK ST STE 6401	MADISON	WI	53715	DANE	USA	Allergy and Infectious Diseases Research	002	5	2/14/2020	NON-COMPETING CONTINUATION	$237,837
2020	2020	UNIVERSITY OF WISCONSIN SYSTEM	21 N PARK ST STE 6401	MADISON	WI	53715	DANE	USA	Allergy and Infectious Diseases Research	003	5	8/26/2020	NON-COMPETING CONTINUATION	$0
2020	2019	UNIVERSITY OF WISCONSIN SYSTEM	21 N PARK ST STE 6401	MADISON	WI	53715	DANE	USA	Allergy and Infectious Diseases Research	000	4	11/21/2019	NON-COMPETING CONTINUATION	$1
														Subtotal = $689,030

Issue Date FY: 2019 ( Subtotal = $417,999 )
2019	2019	UNIVERSITY OF WISCONSIN SYSTEM	21 N PARK ST STE 6401	MADISON	WI	53715	DANE	USA	Allergy and Infectious Diseases Research	000	4	1/25/2019	NON-COMPETING CONTINUATION	$376,140
2019	2019	UNIVERSITY OF WISCONSIN SYSTEM	21 N PARK ST STE 6401	MADISON	WI	53715	DANE	USA	Allergy and Infectious Diseases Research	001	4	7/23/2019	SUPPLEMENT FOR EXPANSION	$41,859
														Subtotal = $417,999

Issue Date FY: 2018 ( Subtotal = $646,335 )
2018	2018	UNIVERSITY OF WISCONSIN SYSTEM	21 N PARK ST STE 6401	MADISON	WI	53715	DANE	USA	Allergy and Infectious Diseases Research	001	3	6/28/2018	NON-COMPETING CONTINUATION	$270,195
2018	2018	UNIVERSITY OF WISCONSIN SYSTEM	21 N PARK ST STE 6401	MADISON	WI	53715	DANE	USA	Allergy and Infectious Diseases Research	002	3	8/30/2018	NON-COMPETING CONTINUATION	$0
2018	2018	UNIVERSITY OF WISCONSIN SYSTEM	21 N PARK ST STE 6401	MADISON	WI	53715	DANE	USA	Allergy and Infectious Diseases Research	000	3	1/8/2018	NON-COMPETING CONTINUATION	$376,140
														Subtotal = $646,335

Issue Date FY: 2017 ( Subtotal = $576,140 )
2017	2017	UNIVERSITY OF WISCONSIN SYSTEM	21 N PARK ST STE 6401	MADISON	WI	53715	DANE	USA	Allergy and Infectious Diseases Research	001	2	8/9/2017	NON-COMPETING CONTINUATION	$200,000
2017	2017	UNIVERSITY OF WISCONSIN SYSTEM	21 N PARK ST STE 6401	MADISON	WI	53715	DANE	USA	Allergy and Infectious Diseases Research	000	2	1/13/2017	NON-COMPETING CONTINUATION	$376,140
														Subtotal = $576,140

Issue Date FY: 2016 ( Subtotal = $376,670 )
2016	2016	UNIVERSITY OF WISCONSIN SYSTEM/BOARD OF REGENTS	21 N PARK ST	MADISON	WI	53715	DANE	USA	Allergy and Infectious Diseases Research	000	1	2/17/2016	NEW	$376,670
														Subtotal = $376,670

Grand Total All Awards = $6,185,338

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

Award Number: U01AI124299

ORGANIZATION: NATIONAL INSTITUTE OF ALLERGY & INFECTIOUS DISEASES

OPDIV: NIH

AWARD CLASS: COOPERATIVE AGREEMENT

AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)

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