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Mechanisms of Nanomaterials-based Combination Adjuvants

Award Number: R01AI168918
ORGANIZATION: NATIONAL INSTITUTE OF ALLERGY & INFECTIOUS DISEASES
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 12/05/2022
PERIOD OF PERFORMANCE END DATE: 11/30/2026

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Mechanisms of Nanomaterials-based Combination Adjuvants - PROJECT SUMMARY The discovery of pattern recognition receptors (PRRs), including toll-like receptors (TLRs) and NOD-like receptors (NLRs) has led to the investigation of molecular agonists of innate immunity in adjuvant formulations. An emerging paradigm is that careful selection of adjuvant combinations can result in complementary and even synergistic enhancement of vaccine-induced immune responses. Most combination adjuvants under investigation are chemically heterogeneous mixtures of depot adjuvants mixed with PRR agonists and suffer from batch-to-batch variability and poor chemical definition making investigation of mechanisms and safety a challenge. Our lab investigates self-assembling peptide nanofibers (PNFs) as vaccine adjuvants. A key advantage of PNFs over emulsion adjuvants is that the primary sequence of the self-associating peptide can be designed to control the physicochemical features of PNFs such as morphology, charge, chirality, or hydrophobicity, which are key contributors to adjuvant activity. Mechanistic insights into the mode of action indicates that unlike PAMPs, PNFs do not cause DC maturation but facilitate the release of DAMPs related to osmotic/oxidative stress. In this application, we propose to develop combination adjuvants composed of chemically defined DAMP-inducing peptide nanofibers (PNFs) and TLR2/NOD2 agonists. Our objectives are to understand how molecular mechanisms of DAMP-inducing PNFs and PRR agonists orchestrate innate immune signaling and induce responses that are complimentary, synergistic, or inhibitory for balancing immunogenicity with safety. In aim 1, we will examine the effect of PNFs with varying physicochemical properties and TLR2 or NOD2 agonist combinations on DC activation, DAMP release, and antigen presentation. In aim 2, using a design of experiments (DOE) approach, we will develop an optimal formulation with precisely controlled PNF-TLR2 and PNF-NOD2 combinations and determine the molecular mechanisms of innate immunity in DCs using various KO mouse models. In aim 3, we will validate the efficacy of PNF-TLR2-NOD2 combination adjuvants and investigate translational potential using human DCs. Outcomes of the proposed studies will advance our understanding of the molecular mechanisms that mediate innate immune responses to PNF-PRR agonist adjuvant combinations and will lead to new combinatorial- adjuvant platforms for combating infectious and non-infectious diseases with high translational potential.


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: 2026 ( Subtotal = $477,960 )
2026	2026	WASHINGTON UNIVERSITY, THE	1 BROOKINGS DR	SAINT LOUIS	MO	63130	SAINT LOUIS	USA	Allergy and Infectious Diseases Research	000	4	12/3/2025	NON-COMPETING CONTINUATION	$477,960
														Subtotal = $477,960

Issue Date FY: 2025 ( Subtotal = $475,300 )
2025	2025	WASHINGTON UNIVERSITY, THE	1 BROOKINGS DR	SAINT LOUIS	MO	63130	SAINT LOUIS	USA	Allergy and Infectious Diseases Research	000	3	1/14/2025	NON-COMPETING CONTINUATION	$475,300
														Subtotal = $475,300

Issue Date FY: 2024 ( Subtotal = $498,707 )
2024	2024	WASHINGTON UNIVERSITY, THE	ONE BROOKINGS DR	SAINT LOUIS	MO	63110	SAINT LOUIS CITY	USA	Allergy and Infectious Diseases Research	001	2	5/14/2024	NON-COMPETING CONTINUATION	$49,870
2024	2024	WASHINGTON UNIVERSITY, THE	ONE BROOKINGS DR	SAINT LOUIS	MO	63110	SAINT LOUIS CITY	USA	Allergy and Infectious Diseases Research	000	2	11/29/2023	NON-COMPETING CONTINUATION	$448,837
														Subtotal = $498,707

Issue Date FY: 2023 ( Subtotal = $511,628 )
2023	2023	WASHINGTON UNIVERSITY, THE	ONE BROOKINGS DR	SAINT LOUIS	MO	63130	SAINT LOUIS	USA	Allergy and Infectious Diseases Research	000	1	12/5/2022	NEW	$511,628
														Subtotal = $511,628

Grand Total All Awards = $1,963,595

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Mechanisms of Nanomaterials-based Combination Adjuvants

Award Number: R01AI168918

ORGANIZATION: NATIONAL INSTITUTE OF ALLERGY & INFECTIOUS DISEASES

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

PERIOD OF PERFORMANCE START DATE: 12/05/2022

PERIOD OF PERFORMANCE END DATE: 11/30/2026

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