Tuesday, July 1, 2025 7/1/2025

Restoring age-dependent vaccine unresponsiveness by a novel ASP-1 adjuvant combination

Award Number: U01AI160421
ORGANIZATION: NATIONAL INSTITUTE OF ALLERGY & INFECTIOUS DISEASES
OPDIV: NIH
AWARD CLASS: COOPERATIVE AGREEMENT
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 08/01/2021
PERIOD OF PERFORMANCE END DATE: 05/31/2026

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Restoring age-dependent vaccine unresponsiveness by a novel ASP-1 adjuvant combination - PROJECT ABSTRACT Infectious diseases are a major cause of morbidity and mortality in the expanding older population. While vaccines are efficient measures to prevent infections, a critical problem is that aging-associated changes in the immune system lead to decreased immunogenicity and clinical efficacy of most currently used vaccines. Novel strategies that increase vaccination efficacy and specifically target the aged immune system are imperative. An essential facet of these efforts is the use of combinatory adjuvants that synergistically potentiate more effective vaccine-induced immune responses against various pathogens. In this project we will define the mechanism of action (MOA) of a combination of a unique parasite protein adjuvant, rASP-1 with each of three well- characterized innate adjuvants: STING, TLR7/8 and RIG-I agonists, known to activate cytoplasmic pattern recognition receptors and Type I IFN signaling, which are specifically dampened in the aged population. We have shown that rASP-1 is a powerful adjuvant as it activates human and mouse dendritic cells to potentiate the differentiation of naïve CD4+ T cells into Th1, Th17 and Tfh-like cells. Transcriptomic analyses of rASP-1- activated hMoDCs revealed upregulation of the MyD88-independent activation pathway and interferon related genes. In mice, rASP-1 elicits a balanced Th1/Th2 antibody response, Th1-biased cellular immunity, and enhanced responses when co-administered with vaccines leading to increased survival following microbial challenge. Importantly, our preliminary data indicate that rASP-1 in combination with 2’3’-cGAMP (STING), R848 (TLR7/8) or 5’3p-hpRNA (RIG-I) in activated adult and aged mouse BMDCs can dramatically synergize beyond merely additive effects; it enhanced secretion of IL-12p40, IP-10 and/or IL-10. The synergy is exceptionally evident when it activates aged mouse BMDCs with the STING ligand. Therefore, we hypothesize that combining rASP-1 with STING, TLR7/8 or RIG-I agonists will synergistically activate early innate immune signaling that critically contributes to the establishment and nature of immune responses, and the duration and intensity of immune activation. We posit that this will help restore the aging-associated deficits in the critical regulatory pathways of the antiviral responses. Through comprehensive immunologic and transcriptomic analyses, the MOA through which rASP-1 in combination with these three PRR agonists leads to optimal activation of helper T cells driving humoral and cellular antiviral responses will be established in both mouse (Aim 1) and human (Aim 2) DCs (adult and aged), to establish that they are conserved, and then test their efficacy in vivo in adult and aged mice using the trivalent inactivated influenza vaccine (IIV3) as a model antigen (Aim 3). This project brings together a dynamic team with a history of collaboration and complementary expertise in vaccinology, immunology, biochemistry, innate cell receptor biology, adjuvants, and bioinformatics. We will deliver a novel, efficacious combination of innate cytoplasmic PRR adjuvants with rASP-1 that promotes protective long-lived adaptive responses and boosts efficacy of vaccines in aged populations.


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 = $719,415 )
2025	2025	NEW YORK BLOOD CENTER, INC	310 E 67TH ST	NEW YORK	NY	10065	NEW YORK	USA	Allergy and Infectious Diseases Research	000	5	5/20/2025	NON-COMPETING CONTINUATION	$719,415
														Subtotal = $719,415

Issue Date FY: 2024 ( Subtotal = $853,735 )
2024	2024	NEW YORK BLOOD CENTER, INC	310 E 67TH ST	NEW YORK	NY	10065	NEW YORK	USA	Allergy and Infectious Diseases Research	001	4	7/16/2024	SUPPLEMENT FOR EXPANSION	$134,320
2024	2024	NEW YORK BLOOD CENTER, INC	310 E 67TH ST	NEW YORK	NY	10065	NEW YORK	USA	Allergy and Infectious Diseases Research	000	4	5/13/2024	NON-COMPETING CONTINUATION	$719,415
														Subtotal = $853,735

Issue Date FY: 2023 ( Subtotal = $719,415 )
2023	2023	NEW YORK BLOOD CENTER, INC.	310 E 67TH ST	NEW YORK	NY	10065	NEW YORK	USA	Allergy and Infectious Diseases Research	000	3	5/3/2023	NON-COMPETING CONTINUATION	$719,415
														Subtotal = $719,415

Issue Date FY: 2022 ( Subtotal = $719,415 )
2022	2022	NEW YORK BLOOD CENTER, INC.	310 E 67TH ST	NEW YORK	NY	10065	NEW YORK	USA	Allergy and Infectious Diseases Research	001	2	5/11/2022	NON-COMPETING CONTINUATION	$719,415
2022	2021	NEW YORK BLOOD CENTER, INC.	310 E 67TH ST	NEW YORK	NY	10065	NEW YORK	USA	Allergy and Infectious Diseases Research	000	1	5/10/2022	NEW	$0
														Subtotal = $719,415

Issue Date FY: 2021 ( Subtotal = $737,115 )
2021	2021	NEW YORK BLOOD CENTER, INC.	310 E 67TH ST	NEW YORK	NY	10065	NEW YORK	USA	Allergy and Infectious Diseases Research	000	1	7/29/2021	NEW	$737,115
														Subtotal = $737,115

Grand Total All Awards = $3,749,095

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Restoring age-dependent vaccine unresponsiveness by a novel ASP-1 adjuvant combination

Award Number: U01AI160421

ORGANIZATION: NATIONAL INSTITUTE OF ALLERGY & INFECTIOUS DISEASES

OPDIV: NIH

AWARD CLASS: COOPERATIVE AGREEMENT

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

PERIOD OF PERFORMANCE START DATE: 08/01/2021

PERIOD OF PERFORMANCE END DATE: 05/31/2026

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