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Self-amplifying mRNA-based vaccines to elicit VRC01-class bnAbs

Award Number: U19AI174242
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: 01/30/2023
PERIOD OF PERFORMANCE END DATE: 12/31/2027

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Self-amplifying mRNA-based vaccines to elicit VRC01-class bnAbs - ABSTRACT OVERALL The main goal of our IPCAVD Program grant is to evaluate in humans self-amplifying mRNA (saRNA) vaccines that express two HIV-1 Env-derived protein immunogens that activate and initiate the maturation of VRC01-class B cell receptors (BCRs). The first immunogen, 426c.Mod.Core, was specifically designed to bind with high affinity to the unmutated (germline, gl) forms of those BCRs as they are expressed on the surface of naïve B cells. The second immunogen, HxB2.WT.Core, although unable to bind germline VRC01-class BCRs, binds the VRC01-class BCRs that became activated by 426c.Mod.Core and have accumulated some somatic mutations. As a result, the boost immunization with HxB2.WT.Core furthers the maturation of the VRC01-class antibodies elicited by the 426c.Mod.Core. These observations were made with the adjuvanted recombinant (rec) forms of these two immunogens. As mRNA- based vaccines are less costly and more easily GMP-manufactured that rec proteins, we believe that they will accelerate the preclinical and clinical evaluation of HIV-1 Env-derived immunogens. Here, we propose to first compare preclinically the VRC01 B cell and antibody responses elicited by these two Env immunogens when delivered by saRNA vaccines to those elicited by the corresponding adjuvanted rec proteins. And then, if the results are promising, the saRNA vaccines expressing the two immunogens will be GMP-manufactured for clinical evaluation. As the 426c.Mod.Core adjuvanted rec protein will be evaluated clinically (phase I) in the spring of 2022 (HVTN301) and the HxB2.WT.Core rec protein is currently being GMP manufactured for a follow-up phase I clinical evaluation in 2023, we will be in a unique position to compare the VRC01 B cell and antibody responses elicited by humans immunized with these two HIV-1 Env-derived immunogens when delivered as adjuvanted rec proteins and as expressed by saRNA vaccines. To accomplish our goals in this IPCAVD grant we will take advantage of our expertise in immunogen-design and testing, expertise in the analysis of B cell and antibody responses elicited by vaccination and during infection, our ability to rapidly sequence BCR genes using high through put technologies, the availability of appropriate animal models, our expertise in saRNA vaccine technology, our unique expertise in conducting clinical testing of HIV-1 vaccines, the existing collaboration among the participating groups and the documented expertise of the participants to successfully manage complex Programs.


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 = $1,579,320 )
2025	2025	FRED HUTCHINSON CANCER CENTER	1100 FAIRVIEW AVE N	SEATTLE	WA	98109	KING	USA	Allergy and Infectious Diseases Research	005	3	3/24/2025	SUPPLEMENT FOR EXPANSION	$0
2025	2025	FRED HUTCHINSON CANCER CENTER	1100 FAIRVIEW AVE N	SEATTLE	WA	98109	KING	USA	Allergy and Infectious Diseases Research	002	3	12/12/2024	SUPPLEMENT FOR EXPANSION	$163,398
2025	2025	FRED HUTCHINSON CANCER CENTER	1100 FAIRVIEW AVE N	SEATTLE	WA	98109	KING	USA	Allergy and Infectious Diseases Research	001	3	12/6/2024	NON-COMPETING CONTINUATION	$1,415,922
2025	2025	FRED HUTCHINSON CANCER CENTER	1100 FAIRVIEW AVE N	SEATTLE	WA	98109	KING	USA	Allergy and Infectious Diseases Research	004	3	3/24/2025	NON-COMPETING CONTINUATION	$0
2025	2025	FRED HUTCHINSON CANCER CENTER	1100 FAIRVIEW AVE N	SEATTLE	WA	98109	KING	USA	Allergy and Infectious Diseases Research	003	3	1/15/2025	SUPPLEMENT FOR EXPANSION	$0
2025	2024	FRED HUTCHINSON CANCER CENTER	1100 FAIRVIEW AVE N	SEATTLE	WA	98109	KING	USA	Allergy and Infectious Diseases Research	000	2	11/22/2024	NON-COMPETING CONTINUATION	$0
														Subtotal = $1,579,320

Issue Date FY: 2024 ( Subtotal = $2,976,250 )
2024	2024	FRED HUTCHINSON CANCER CENTER	1100 FAIRVIEW AVE N	SEATTLE	WA	98109	KING	USA	Allergy and Infectious Diseases Research	000	2	12/7/2023	NON-COMPETING CONTINUATION	$1,424,249
2024	2024	FRED HUTCHINSON CANCER CENTER	1100 FAIRVIEW AVE N	SEATTLE	WA	98109	KING	USA	Allergy and Infectious Diseases Research	002	2	4/23/2024	NON-COMPETING CONTINUATION	$158,250
2024	2024	FRED HUTCHINSON CANCER CENTER	1100 FAIRVIEW AVE N	SEATTLE	WA	98109	KING	USA	Allergy and Infectious Diseases Research	001	2	4/19/2024	SUPPLEMENT FOR EXPANSION	$1,393,751
														Subtotal = $2,976,250

Issue Date FY: 2023 ( Subtotal = $2,099,783 )
2023	2023	FRED HUTCHINSON CANCER CENTER	1100 FAIRVIEW AVE N	SEATTLE	WA	98109	KING	USA	Allergy and Infectious Diseases Research	001	1	3/17/2023	NEW	$0
2023	2023	FRED HUTCHINSON CANCER CENTER	1100 FAIRVIEW AVE N	SEATTLE	WA	98109	KING	USA	Allergy and Infectious Diseases Research	000	1	1/30/2023	NEW	$2,099,783
														Subtotal = $2,099,783

Grand Total All Awards = $6,655,353

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Self-amplifying mRNA-based vaccines to elicit VRC01-class bnAbs

Award Number: U19AI174242

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: 01/30/2023

PERIOD OF PERFORMANCE END DATE: 12/31/2027

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