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A versatile structure-based therapeutic platform for development of VHH-based antitoxin and antiviral agents

Award Number: R01AI173059
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: 08/04/2023
PERIOD OF PERFORMANCE END DATE: 07/31/2025

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A versatile structure-based therapeutic platform for development of VHH-based antitoxin and antiviral agents - ABSTRACT In previous NIH sponsored research we successfully tested the hypothesis that integrating structural and mechanistic information into heteromultimeric VHH-based neutralizing agent (VNA) design facilitated development of antitoxins with even greater efficacy and versatility. In this renewal proposal, we will apply these findings to test the hypothesis that our designer VNA platform, which is rapidly responsive to new threats, will permit development of highly practical, next-generation antitoxin and antiviral products that possess excellent potencies in treating intoxications or viral infections and are effective against a broad range of natural pathogen variants. Our research will focus on two pathogens that are major current threats which could benefit from next- generation therapeutics: botulinum neurotoxin (BoNT) and SARS-CoV-2. We propose two Specific Aims which will be underway simultaneously throughout the five years of research. In Aim 1, we will develop a small pool of antitoxin VNAs that protect against all subtypes of the three prevalent BoNT serotypes (A, B and E). BoNTs are CDC Tier 1 select agents. However, the few available antitoxin treatments against BoNTs primarily derive from large animal polyclonal antisera, such as the equine botulism antitoxin HBAT, which suffer from multiple manufacturing and storage challenges. Our goal is to test the platform’s ability to produce highly practical VNAs as a next-generation BoNT antitoxin product, likely delivered as RNA nanoparticles, which improves on the potencies and natural variant specificities of the current HBAT antitoxin product and is rapidly responsive to potential new BoNT threats. In Aim 2 we will develop a single VNA antiviral agent that protects against known variants of SARS-CoV-1 and SARS-CoV-2. SARS-CoV-2 is the viral cause of the ongoing COVID-19 pandemic. A promising strategy for rapid development of a therapy is development of SARS-CoV-2 neutralizing antibodies, especially antibodies targeting the spike protein, for prophylactic or passive immunotherapies. However, novel variants of SARS-CoV-2, which cause enhanced infection and transmission, have emerged, and more dangerous variants are expected to evolve. Of immediate concern are variants that partially escape neutralization by current Ab-based therapies and in vaccinated or previously-infected COVID-19 patients, leading to reduced vaccine efficacy in certain areas with a high prevalence of these variants. We propose an mRNA- based antiviral product that, once administered, elicits expression of a VNA with extremely high virus neutralizing potency. The VNA will contain multiple covalently linked VHHs binding to conserved epitopes of the spike protein. This approach will test the platform’s ability to develop a product that minimizes the risks of immune escape through evolution and selection of clinical strains of SARS-CoV-2 and SARS-CoV-1. If successful, this technology platform could have broad applications in creating practical therapeutics for a wide variety of emerging and potential pandemic viral infections, bioterror threat agents, and other infectious diseases.


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 = $0 )
2026	2024	TRUSTEES OF TUFTS COLLEGE	136 HARRISON AVE	BOSTON	MA	02111	SUFFOLK	USA	Allergy and Infectious Diseases Research	000	2	2/13/2026	NON-COMPETING CONTINUATION	$0
														Subtotal = $0

Issue Date FY: 2025 ( Subtotal = $1,549,397 )
2025	2025	TRUSTEES OF TUFTS COLLEGE	136 HARRISON AVE	BOSTON	MA	02111	SUFFOLK	USA	Allergy and Infectious Diseases Research	001	3	9/5/2025	EXTENSION WITH OR WITHOUT FUNDS	$1,549,397
2025	2024	TRUSTEES OF TUFTS COLLEGE	136 HARRISON AVE	BOSTON	MA	02111	SUFFOLK	USA	Allergy and Infectious Diseases Research	000	2	9/5/2025	NON-COMPETING CONTINUATION	$0
														Subtotal = $1,549,397

Issue Date FY: 2024 ( Subtotal = $802,815 )
2024	2024	TRUSTEES OF TUFTS COLLEGE	136 HARRISON AVE	BOSTON	MA	02111	SUFFOLK	USA	Allergy and Infectious Diseases Research	000	2	7/19/2024	NON-COMPETING CONTINUATION	$802,815
														Subtotal = $802,815

Issue Date FY: 2023 ( Subtotal = $865,682 )
2023	2023	TRUSTEES OF TUFTS COLLEGE	136 HARRISON AVE	BOSTON	MA	02111	SUFFOLK	USA	Allergy and Infectious Diseases Research	000	1	8/4/2023	NEW	$865,682
														Subtotal = $865,682

Grand Total All Awards = $3,217,894

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A versatile structure-based therapeutic platform for development of VHH-based antitoxin and antiviral agents

Award Number: R01AI173059

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: 08/04/2023

PERIOD OF PERFORMANCE END DATE: 07/31/2025

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