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Improving phage-based medicine with immunoengineering

Award Number: R00AI173544
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: 07/01/2023
PERIOD OF PERFORMANCE END DATE: 07/31/2027

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Improving phage-based medicine with immunoengineering - PROJECT SUMMARY/ABSTRACT A resurgence of research interest in bacteriophages, viruses that infect bacteria, is driving the development of engineered phages for biomedical applications, including antimicrobial therapy and phage-based vaccination. As antimicrobial agents, phages have significant advantages over conventional antibiotics: they are well- tolerated, pathogen-specific, and replicate at the site of infection. Phages are also promising as vaccine platforms because they can be precisely engineered to deliver multiple foreign antigens. However, phages are immunogenic and both applications are susceptible to interfering immune responses. Antimicrobial phages, for example, can elicit neutralizing antibodies that prevent infection of the bacterial target. This immunogenic nature is advantageous for vaccine development, since the phage acts as its own adjuvant, but it comes at a price: off-target responses to immunodominant phage antigens can distract from intended protective responses to foreign antigens. Unfortunately, data on phage immunology are limited, confounding routine biomedical applications of phage. This proposal outlines basic experiments to elucidate the basis of phage immunogenicity and evaluate methods of modulating it. Aim 1 will develop a structural map of antibody binding to three therapeutic mycobacteriophages. Structure- guided engineering and directed evolution will be used to generate mutant phages that escape antibody binding. The ability of these mutants to evade established immune responses to their wild-type counterparts in vivo will be evaluated in a mouse model. In Aim 2 the same phages will be used as platforms for a therapeutic bacterial vaccine. Leveraging both phage display and phage DNA vector technologies, the vaccine candidates will defend and protect against bacteria with three mechanisms: 1) phage infection and killing, 2) generation of bacterium-binding antibodies, and 3) activation of helper and cytotoxic T cells. Aim 3 will evaluate a method to suppress interfering immune responses: co-administration of phage with rapamycin-loaded nanoparticles. This will down-regulate phage-specific helper T cells and upregulate regulatory T cells, training the immune system to recognize phage as ‘self’. These Aims will expand our understanding of phage immunogenicity and assess the potential to improve phage-based medicine with principles from immunoengineering. Furthermore, Aim 1 is a training vehicle for the candidate, who has developed immunology experience in the lab but requires mentored training and formal education to establish independence in this field. Aim 1 also provides additional mentored training in structural biology, specifically asymmetric reconstructions of phage-antibody complexes. With the planned scientific training, practice in publishing and grant writing, and the support of her mentors throughout an academic job search, the candidate is expected to establish and sustain an independent research career focused on immunoengineering phage to improve their biomedical applications.


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 = $248,998 )
2025	2025	CASE WESTERN RESERVE UNIVERSITY	10900 EUCLID AVE	CLEVELAND	OH	44106	CUYAHOGA	USA	Allergy and Infectious Diseases Research	000	3	8/20/2025	EXTENSION WITH OR WITHOUT FUNDS	$248,998
														Subtotal = $248,998

Grand Total All Awards = $248,998

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Improving phage-based medicine with immunoengineering

Award Number: R00AI173544

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: 07/01/2023

PERIOD OF PERFORMANCE END DATE: 07/31/2027

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