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Broadly neutralizing antibody combinations with single virions in HIV+ plasma

Award Number: R01AI172487
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: 01/23/2023
PERIOD OF PERFORMANCE END DATE: 12/31/2026

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Broadly neutralizing antibody combinations with single virions in HIV+ plasma - Certain broadly HIV-neutralizing antibodies (bnAbs) are being actively investigated as agents for HIV/AIDS treatment, functional cure and/or prevention. These bnAbs are classified according to cognate epitopes clusters on the HIV envelope (Env). Rigorous preclinical studies evince several potential advantages of bnAbs over currently used antiretroviral drugs (ARVs) in various settings. Currently, optimization of breadth, potency, and virus escape resistance are primary goals for clinical development. A major issue is that all single bnAbs exhibit limited coverage of epitope variability/mutability among HIV strains, allowing virus escape. A lead mitigation strategy proposes triple combinations of bnAb classes for clinical intervention under the premise that polyspecific reactivity will boost potency and breadth. However, the identification of promising combinations is challenging. Screening through all possible triple combinations; bnAb class members; and engineered class members via clinical trials or animal models is an expensive and lengthy process. Therefore, the advancement of bnAb combinations requires a rational, preclinical selection process based on in vitro analytical systems that inform prospects for efficacy. Standardized neutralization assays will continue to play an important role; however, the data can overestimate in vivo potency and escape resistance, fail to capture important determinants of combination bnAb action, and appear incongruous with clinical outcomes in bnAb prevention or therapy trials. Past trials of mono or dual bnAb therapy did not achieve sustained virus suppression of viremia; in some cases, viral rebound occurred via resistance to only one bnAb. This experience reinforces the need for new analytical techniques that capture additional determinants of potency and escape resistance more thoroughly. Such efforts should focus on bnAb interactions with wild type virus swarms in plasma, as these are targets for infused bnAbs and mediate transmission and disease. The development of combination ARV therapies points to instantaneous inhibition and concurrent bnAb class action as highly relevant measures of potency, breadth, and escape resistance. The goal of this project is to introduce new capacities to take these measures for various bnAb combination and test settings, including wild type virus populations in plasma. In ongoing studies, we developed novel quantitative single molecule and fluorescence correlation spectroscopy (FCS) detection methods that can directly measure qualitative and quantitative aspects of triple bnAb class binding to virus populations in plasma. We hypothesize that our goals will be met by innovative applications of these techniques toward analyses of bnAb combinations and plasma viruses. Two Specific Aims are: 1) Establish and interpret the interactions of bnAb combinations with single virions or Env trimers measured by FCS techniques. 2) Characterize interactions of bnAbs and bnAb combinations with single virions in HIV+ plasma. This project will yield innovative new tools for evaluating the potency, breadth, and escape resistance of bnAb combination in highly relevant settings of wild type viruses in plasma that are not efficiently explored by current methods.


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 = $386,250 )
2026	2026	UNIVERSITY OF MARYLAND, BALTIMORE	220 ARCH ST OFC LEVEL2	BALTIMORE	MD	21201	BALTIMORE CITY	USA	Allergy and Infectious Diseases Research	000	4	12/19/2025	NON-COMPETING CONTINUATION	$386,250
														Subtotal = $386,250

Issue Date FY: 2025 ( Subtotal = $374,663 )
2025	2025	UNIVERSITY OF MARYLAND, BALTIMORE	220 ARCH ST OFC LEVEL2	BALTIMORE	MD	21201	BALTIMORE CITY	USA	Allergy and Infectious Diseases Research	000	3	12/11/2024	NON-COMPETING CONTINUATION	$374,663
														Subtotal = $374,663

Issue Date FY: 2024 ( Subtotal = $619,177 )
2024	2024	UNIVERSITY OF MARYLAND, BALTIMORE	220 ARCH ST OFC LEVEL2	BALTIMORE	MD	21201	BALTIMORE CITY	USA	Allergy and Infectious Diseases Research	002	2	5/30/2024	NON-COMPETING CONTINUATION	$38,625
2024	2024	UNIVERSITY OF MARYLAND, BALTIMORE	220 ARCH ST OFC LEVEL2	BALTIMORE	MD	21201	BALTIMORE CITY	USA	Allergy and Infectious Diseases Research	000	2	12/5/2023	NON-COMPETING CONTINUATION	$347,625
2024	2023	UNIVERSITY OF MARYLAND, BALTIMORE	220 ARCH ST OFC LEVEL2	BALTIMORE	MD	21201	BALTIMORE CITY	USA	Allergy and Infectious Diseases Research	001	1	12/12/2023	NEW	$232,927
														Subtotal = $619,177

Issue Date FY: 2023 ( Subtotal = $160,938 )
2023	2023	UNIVERSITY OF MARYLAND	220 ARCH ST RM 02148	BALTIMORE	MD	21201	BALTIMORE CITY	USA	Allergy and Infectious Diseases Research	000	1	1/23/2023	NEW	$160,938
														Subtotal = $160,938

Grand Total All Awards = $1,541,028

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Broadly neutralizing antibody combinations with single virions in HIV+ plasma

Award Number: R01AI172487

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: 01/23/2023

PERIOD OF PERFORMANCE END DATE: 12/31/2026

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