Monday, October 13, 2025 10/13/2025

Immunological mechanism of muscle-localizing self-replicating RNA vaccines

Award Number: R01AI180195
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: 09/13/2024
PERIOD OF PERFORMANCE END DATE: 07/31/2029

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Immunological mechanism of muscle-localizing self-replicating RNA vaccines - PROJECT SUMMARY/ABSTRACT As evident in the ongoing “tripledemic” of severe acute respiratory syndrome-Coronavirus-2, Respiratory Syncytial virus, and Influenza virus, as well as re-emergence of enterovirus D68, virus infection is an important health threat and a huge economic burden. Multivalent RNA vaccination is an effective measure for counteracting virus infections and cancerous threats. However, multivalent vaccines need to inject relatively larger doses of RNA than monovalent vaccines, which can trigger a potent innate immune response in vivo, causing reduced transgene expression and unwanted reactogenicity. We have recently found that high dose RNA vaccination can be safely achieved in mice by delivering self-amplifying replicon RNA (repRNA) with a family of muscle-localizing cationic nanocarriers, LIONTM. In vivo delivery of repRNA by LION restricted the formulation to the muscle and local lymph nodes without inducing unwanted systemic cytokine responses. Systemic blockade of type I IFN signaling increased transgene expression and the subsequent antibody and T cell responses. Notably, we also found that CD11b+ cells [mostly monocyte dendritic cells (DC)] expand over time after intramuscular injection of repRNA/LION. However, the role of the muscle-infiltrating cells in immunogenicity is unknown. Consequently, many questions remain about how repRNA/LION vaccines induce adaptive immune responses and how transgene expression and adaptive immune responses are inhibited by the type I IFN system. So, Aim 1 looks at skeletal muscle DC (SMDC) and characterizes their immunological function both in vitro and in vivo. Aim 2 focuses on type I IFN signaling and seeks to identify how type I IFN signaling limits transgene expression and adaptive immune responses to repRNA vaccines. Aim 3 spotlights the inflammatory responses to muscle damage and their role in inducing adaptive immune responses to repRNA/LION vaccines. The proposed studies will test the following hypotheses that (1) the muscle plays a critical role in eliciting the immune response to intramuscular-based RNA vaccines, and (2) muscle-restricted activation of the immune system is a novel strategy for RNA vaccines to achieve high efficacy with reduced reactogenicity.


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 = $1,300,587 )
2025	2025	HDT BIO CORP	1150 EASTLAKE AVE E STE 200A	SEATTLE	WA	98109	KING	USA	Allergy and Infectious Diseases Research	003	2	8/1/2025	NON-COMPETING CONTINUATION	$1,090,789
2025	2024	HDT BIO CORP	1150 EASTLAKE AVE E STE 200A	SEATTLE	WA	98109	KING	USA	Allergy and Infectious Diseases Research	002	1	5/2/2025	NEW	$0
2025	2024	HDT BIO CORP	1150 EASTLAKE AVE E STE 200A	SEATTLE	WA	98109	KING	USA	Allergy and Infectious Diseases Research	001	1	1/2/2025	NEW	$209,798
2025	2024	HDT BIO CORP	1150 EASTLAKE AVE E STE 200A	SEATTLE	WA	98109	KING	USA	Allergy and Infectious Diseases Research	000	1	11/14/2024	NEW	$0
														Subtotal = $1,300,587

Issue Date FY: 2024 ( Subtotal = $864,721 )
2024	2024	HDT BIO CORP	1150 EASTLAKE AVE E STE 200A	SEATTLE	WA	98109	KING	USA	Allergy and Infectious Diseases Research	001	1	9/19/2024	NEW	$86,473
2024	2024	HDT BIO CORP	1150 EASTLAKE AVE E STE 200A	SEATTLE	WA	98109	KING	USA	Allergy and Infectious Diseases Research	000	1	9/13/2024	NEW	$778,248
														Subtotal = $864,721

Grand Total All Awards = $2,165,308

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Immunological mechanism of muscle-localizing self-replicating RNA vaccines

Award Number: R01AI180195

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: 09/13/2024

PERIOD OF PERFORMANCE END DATE: 07/31/2029

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