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Inducing HIV-1 NAb Breadth by Native Trimer Prime-Boost Vaccination

Award Number: R01AI093278
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: 03/01/2011
PERIOD OF PERFORMANCE END DATE: 05/31/2025

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Inducing HIV-1 NAb Breadth by Native Trimer Prime-Boost Vaccination - Although leading HIV-1 vaccines now routinely elicit potent NAbs, 2 problems are 1) NAbs usually target strain- specific "glycan holes", limiting breadth, 2) NAbs are inconsistent among vaccinees. Regarding the latter point, we have found that eliminating glycan head group clashes reveals consistent tier 2 NAbs in all vaccinated animals, suggesting that NAbs often fail to navigate glycans. In stark contrast, broad NAbs (bNAbs) from HIV- 1+ donors frequently contact glycans rather than avoid them. Therefore, we hypothesize that, by promoting NAb-glycan contacts, we might improve vaccine breadth & consistency. Here, we propose sequential heterologous prime-boost (SHPB) immunizations to try to elicit bNAbs to 2 conserved protein/glycan epitopes (V2 & fusion peptide; FP). Both sites accommodate multiple NAb binding modes, facilitating epitope focused approaches. In Aim 1, we will identify a panel of 5 diverse, multi-V2 bNAb-sensitive, well-expressed trimers. Although high trimer expression is essential, such Envs are uncommon. 2 ways to obtain useful trimers will be: 1) to test various V2-sensitive "special" strains & 2) KI V2-sensitivity into high-expressing strains. Selected Envs will be modified to: 1) Plug glycan holes, 2) KI the common FP variant 1 (FP8var1) sequence/KO the N611 glycan (regulates FP exposure). In Aim 2, we will try to improve vaccine NAbs, using virus-like particles (VLPs) expressing trimers from Aim 1. CH01 HC KI BL6 mice express the UCA of the CH01 NAb heavy chain (HC) amid a mouse HC repertoire that can combine with diverse mouse LCs. These mice can potentially generate NAbs to additional targets like FP. Since early events shape NAb responses, following initial KLH-FP8v1 priming a variety of concepts will be tested in 3 subsequent VLP shots, including glycosidase-digested VLPs to minimize clashes or immunogenic foreign glycans to promote early NAb-glycan contacts. Later VLP shots will be kept consistent to expand NAbs arising from earlier shots. 5 mice will be sacrificed at an intermediate timepoint & the rest after the final shot, allowing us to study NAb ontogeny. The best priming regimen will be determined primarily from neutralization kinetics, potency, breadth & consistency, & from molecular genetics criteria. This regimen will be re-tested in mice where CH01 precursors are reduced to physiologic frequency by adoptive transfer & in CH01 HC x Balb/c F1 mice that also exhibit reduced CH01 HC frequency & a more robust genetic background to potentiate NAb development. Having identified effective priming shots, assembled SHPB regimens will be tested in the same F1 mice to try to improve breadth. Variables will include overlapping or non-overlapping sequential shots, increasing strain diversity, & increasing epitope stringency. Finally, we will test leading regimens in Trianni mice expressing polyclonal human IgG. Serum neutralization of vaccine & non-vaccine strains will be monitored. MAbs will be rescued using VLP probes & analyzed for SHM, V gene use, & H/L pairings. NAb titers, breadth, effects of glycan changes, specificity, glycan array activity & ontogeny will be investigated. Overall, we hope to advance HIV vaccines by identifying regimens that induce glycan-dependent, V2 & FP-targeted NAb breadth.


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: 2024 ( Subtotal = $926,870 )
2024	2024	SAN DIEGO BIOMEDICAL RESEARCH INSTITUTE	3525 JOHN HOPKINS CT STE 200	SAN DIEGO	CA	92121	SAN DIEGO	USA	Allergy and Infectious Diseases Research	000	15	5/22/2024	NON-COMPETING CONTINUATION	$926,870
														Subtotal = $926,870

Issue Date FY: 2023 ( Subtotal = $946,370 )
2023	2023	SAN DIEGO BIOMEDICAL RESEARCH INSTITUTE	3525 JOHN HOPKINS CT	SAN DIEGO	CA	92121	SAN DIEGO	USA	Allergy and Infectious Diseases Research	000	14	5/11/2023	NON-COMPETING CONTINUATION	$946,370
														Subtotal = $946,370

Issue Date FY: 2022 ( Subtotal = $1,309,318 )
2022	2022	SAN DIEGO BIOMEDICAL RESEARCH INSTITUTE	3525 JOHN HOPKINS CT	SAN DIEGO	CA	92121	SAN DIEGO	USA	Allergy and Infectious Diseases Research	001	13	7/12/2022	NON-COMPETING CONTINUATION	$367,331
2022	2022	SAN DIEGO BIOMEDICAL RESEARCH INSTITUTE	3525 JOHN HOPKINS CT	SAN DIEGO	CA	92121	SAN DIEGO	USA	Allergy and Infectious Diseases Research	000	13	5/18/2022	NON-COMPETING CONTINUATION	$941,987
														Subtotal = $1,309,318

Issue Date FY: 2021 ( Subtotal = $950,504 )
2021	2021	SAN DIEGO BIOMEDICAL RESEARCH INSTITUTE	10865 ROAD TO THE CURE STE 100	SAN DIEGO	CA	92121	SAN DIEGO	USA	Allergy and Infectious Diseases Research	002	12	5/17/2021	NON-COMPETING CONTINUATION	$950,504
2021	2020	SAN DIEGO BIOMEDICAL RESEARCH INSTITUTE	3525 JOHN HOPKINS CT	SAN DIEGO	CA	92121	SAN DIEGO	USA	Allergy and Infectious Diseases Research	001	11	4/30/2021	COMPETING CONTINUATION	$96,792
2021	2019	SAN DIEGO BIOMEDICAL RESEARCH INSTITUTE	3525 JOHN HOPKINS CT	SAN DIEGO	CA	92121	SAN DIEGO	USA	Allergy and Infectious Diseases Research	000	10	4/30/2021	NON-COMPETING CONTINUATION	-$96,792
														Subtotal = $950,504

Issue Date FY: 2020 ( Subtotal = $959,144 )
2020	2020	SAN DIEGO BIOMEDICAL RESEARCH INSTITUTE	10865 ROAD TO THE CURE STE 100	SAN DIEGO	CA	92121	SAN DIEGO	USA	Allergy and Infectious Diseases Research	000	11	1/23/2020	COMPETING CONTINUATION	$959,144
														Subtotal = $959,144

Issue Date FY: 2019 ( Subtotal = $914,216 )
2019	2019	SAN DIEGO BIOMEDICAL RESEARCH INSTITUTE	10865 ROAD TO THE CURE STE 100	SAN DIEGO	CA	92121	SAN DIEGO	USA	Allergy and Infectious Diseases Research	000	10	5/22/2019	NON-COMPETING CONTINUATION	$914,216
														Subtotal = $914,216

Issue Date FY: 2018 ( Subtotal = $914,216 )
2018	2018	SAN DIEGO BIOMEDICAL RESEARCH INSTITUTE	10865 ROAD TO THE CURE STE 100	SAN DIEGO	CA	92121	SAN DIEGO	USA	Allergy and Infectious Diseases Research	000	9	5/2/2018	NON-COMPETING CONTINUATION	$914,216
														Subtotal = $914,216

Issue Date FY: 2017 ( Subtotal = $914,216 )
2017	2017	SAN DIEGO BIOMEDICAL RESEARCH INSTITUTE	10865 ROAD TO THE CURE STE 100	SAN DIEGO	CA	92121	SAN DIEGO	USA	Allergy and Infectious Diseases Research	000	8	5/5/2017	NON-COMPETING CONTINUATION	$914,216
														Subtotal = $914,216

Issue Date FY: 2016 ( Subtotal = $914,216 )
2016	2016	SAN DIEGO BIOMEDICAL RESEARCH INSTITUTE	3550 GENERAL ATOMICS COURT	SAN DIEGO	CA	92121	SAN DIEGO	USA	Allergy and Infectious Diseases Research	000	7	5/5/2016	NON-COMPETING CONTINUATION	$914,216
														Subtotal = $914,216

Issue Date FY: 2015 ( Subtotal = $914,216 )
2015	2015	SAN DIEGO BIOMEDICAL RESEARCH INSTITUTE	3550 GENERAL ATOMICS COURT	SAN DIEGO	CA	92121	SAN DIEGO	USA	Allergy and Infectious Diseases Research	001	6	6/26/2015	COMPETING CONTINUATION	$914,216
2015	2014	SAN DIEGO BIOMEDICAL RESEARCH INSTITUTE	3550 GENERAL ATOMICS COURT	SAN DIEGO	CA	92121	SAN DIEGO	USA	Allergy and Infectious Diseases Research	000	5	6/25/2015	CHANGE OF GRANTEE / TRAINING INSTITUTION / AWARDING INSTITUTION	$0
														Subtotal = $914,216

Issue Date FY: 2014 ( Subtotal = $480,000 )
2014	2014	SAN DIEGO BIOMEDICAL RESEARCH INSTITUTE	3550 GENERAL ATOMICS COURT	SAN DIEGO	CA	92121	SAN DIEGO	USA	Allergy and Infectious Diseases Research	004	5	7/17/2014	CHANGE OF GRANTEE / TRAINING INSTITUTION / AWARDING INSTITUTION	$215,995
2014	2014	SAN DIEGO BIOMEDICAL RESEARCH INSTITUTE	3550 GENERAL ATOMICS COURT	SAN DIEGO	CA	92121	SAN DIEGO	USA	Allergy and Infectious Diseases Research	003	5	7/3/2014	CHANGE OF GRANTEE / TRAINING INSTITUTION / AWARDING INSTITUTION	$264,005
2014	2014	TORREY PINES INSTITUTE FOR MOLECULAR STUDIES	3550 GENERAL ATOMICS COURT	SAN DIEGO	CA	92121	SAN DIEGO	USA	Allergy and Infectious Diseases Research	002	4	7/2/2014	NON-COMPETING CONTINUATION	-$455,000
2014	2014	TORREY PINES INSTITUTE FOR MOLECULAR STUDIES	3550 GENERAL ATOMICS COURT	SAN DIEGO	CA	92121	SAN DIEGO	USA	Allergy and Infectious Diseases Research	001	4	5/29/2014	NON-COMPETING CONTINUATION	$455,000
2014	2013	TORREY PINES INSTITUTE FOR MOLECULAR STUDIES	3550 GENERAL ATOMICS COURT	SAN DIEGO	CA	92121	SAN DIEGO	USA	Allergy and Infectious Diseases Research	000	3	2/25/2014	NON-COMPETING CONTINUATION	$0
														Subtotal = $480,000

Issue Date FY: 2013 ( Subtotal = $427,700 )
2013	2013	TORREY PINES INSTITUTE FOR MOLECULAR STUDIES	3550 GENERAL ATOMICS COURT	SAN DIEGO	CA	92121	SAN DIEGO	USA	Allergy and Infectious Diseases Research	000	3	1/29/2013	NON-COMPETING CONTINUATION	$409,500
2013	2013	TORREY PINES INSTITUTE FOR MOLECULAR STUDIES	3550 GENERAL ATOMICS COURT	SAN DIEGO	CA	92121	SAN DIEGO	USA	Allergy and Infectious Diseases Research	001	3	5/31/2013	NON-COMPETING CONTINUATION	$18,200
2013	2013	TORREY PINES INSTITUTE FOR MOLECULAR STUDIES	3550 GENERAL ATOMICS COURT	SAN DIEGO	CA	92121	SAN DIEGO	USA	Allergy and Infectious Diseases Research	002	3	2/25/2014	NON-COMPETING CONTINUATION	$0
														Subtotal = $427,700

Issue Date FY: 2012 ( Subtotal = $562,213 )
2012	2012	TORREY PINES INSTITUTE FOR MOLECULAR STUDIES	3550 GENERAL ATOMICS COURT	SAN DIEGO	CA	92121	SAN DIEGO	USA	Allergy and Infectious Diseases Research	001	2	7/31/2012	NON-COMPETING CONTINUATION	$107,213
2012	2012	TORREY PINES INSTITUTE FOR MOLECULAR STUDIES	3550 GENERAL ATOMICS COURT	SAN DIEGO	CA	92121	SAN DIEGO	USA	Allergy and Infectious Diseases Research	000	2	2/15/2012	NON-COMPETING CONTINUATION	$455,000
														Subtotal = $562,213

Issue Date FY: 2011 ( Subtotal = $455,000 )
2011	2011	TORREY PINES INSTITUTE FOR MOLECULAR STUDIES	3550 GENERAL ATOMICS COURT	SAN DIEGO	CA	92121	SAN DIEGO	USA	Allergy and Infectious Diseases Research	000	1	2/28/2011	NEW	$455,000
														Subtotal = $455,000

Grand Total All Awards = $11,588,199

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Inducing HIV-1 NAb Breadth by Native Trimer Prime-Boost Vaccination

Award Number: R01AI093278

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: 03/01/2011

PERIOD OF PERFORMANCE END DATE: 05/31/2025

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