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Eliciting neutralizing antibodies and B cell responses using novel HIV Env immunogens in non-human primates

Award Number: P01AI157299
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: 02/04/2021
PERIOD OF PERFORMANCE END DATE: 01/31/2026

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Eliciting neutralizing antibodies and B cell responses using novel HIV Env immunogens in non-human primates - Neutralizing antibodies are likely to be required for an effective HIV-1 vaccine. However, few candidate vaccines efficiently elicit broadly neutralizing antibodies (bNAbs) following vaccination. Recently, the VRC working group has elicited fusion peptide-directed bNAbs in guinea pigs and non-human primates (NHPs). Similarly, we recently elicited bNAbs in rabbits following heterologous NFL (uncleaved) trimer-liposome prime:boosting at Scripps where we activated B cell responses with targeted N-glycan deletions in the priming immunizations (Dubrovskaya et al, Immunity 2019). We isolated two rabbit bNAbs that recapitulate the serum activity. These bNAbs are directed against two distinct sites of Env vulnerability. The elicitation of neutralizing responses was enhanced by targeted N-glycan deletion, high-density liposomal array and heterologous trimer restorative boosting Env. In independent experiments in guinea pigs, we have elicited bNAbs in multiple animals also using a N-glycan deletion, heterologous Env NFL prime:boost approach. These recent outcomes are encouraging inroads toward the successful solution of a 3-decade-long problem. The new era of near-native trimeric spike mimics, coupled with particulate array, structure-informed design and high-resolution analysis of Env-specific B cell and lymph node responses, afford new opportunities to more efficiently elicit bNAbs. We propose an integrated, multi-faceted approach blending the expertise of world leaders in HIV Env trimer design, analysis of B cell responses and Abs following vaccination, NHP immune tissue analysis and EM-based analysis of ongoing immune responses and high-resolution Ab:trimer interactions. We will use well-ordered trimer prime:boosting that elicited bNAbs in rabbits and guinea pigs to elicit such responses in NHPs, translating success in small animals to NHPs using novel immunogen design and presentation in Project 1 (Wyatt) and immunization of NFL trimers into NHPs via Core B (Silvestri). We will use “real-time” serum Fab-to-trimer binding evaluated by EM polyclonal IgG epitope mapping (EMPEM) in Core C (Ward) in complement with rapid mAb NGS-based mAb cloning, sequencing and functional expression in Project 2 (Karlsson Hedestam). In collaboration with the VRC (Mascola) we will define either non-neutralizing mAbs to mask unwanted non-neutralizing epitopes or to better display the epitopes of cross-neutralizing mAbs. We will compare NFL trimer-liposomes to cell surface NFL trimer array expressed from the exciting mRNA lipid encapsulation technology. We will assess if immunization in the juvenile NHP B cell repertoire compared to adult macaques will better generate bNAbs as is observed during human infection. To follow our discovery of a tier 2 CD4bs-directed bNAb following trimer-liposome vaccination, termed E70, we will target the CD4bs by directed NFL trimer deglycosylation in the NHPs. Based on our recent discovery of the very broadly neutralizing vaccine-induced mAb, 1C2, we will also focus on the gp41:120 trimer interface. Leveraging these initial leads, we will undertake a multifaceted, cross-component integrated approach to guide the elicitation of bNAbs in NHPs following vaccination with near-native, uncleaved NFL Env trimers.


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 = $2,794,109 )
2025	2025	SCRIPPS RESEARCH INSTITUTE	10550 N TORREY PINES RD	LA JOLLA	CA	92037	SAN DIEGO	USA	Allergy and Infectious Diseases Research	000	5	4/25/2025	NON-COMPETING CONTINUATION	$2,794,109
														Subtotal = $2,794,109

Issue Date FY: 2024 ( Subtotal = $4,419,128 )
2024	2024	SCRIPPS RESEARCH INSTITUTE	10550 N TORREY PINES RD	LA JOLLA	CA	92037	SAN DIEGO	USA	Allergy and Infectious Diseases Research	002	4	8/13/2024	SUPPLEMENT FOR EXPANSION	$976,445
2024	2024	SCRIPPS RESEARCH INSTITUTE	10550 N TORREY PINES RD	LA JOLLA	CA	92037	SAN DIEGO	USA	Allergy and Infectious Diseases Research	001	4	4/17/2024	NON-COMPETING CONTINUATION	$344,265
2024	2024	SCRIPPS RESEARCH INSTITUTE	10550 N TORREY PINES RD	LA JOLLA	CA	92037	SAN DIEGO	USA	Allergy and Infectious Diseases Research	003	4	9/4/2024	NON-COMPETING CONTINUATION	$0
2024	2024	SCRIPPS RESEARCH INSTITUTE	10550 N TORREY PINES RD	LA JOLLA	CA	92037	SAN DIEGO	USA	Allergy and Infectious Diseases Research	000	4	1/18/2024	NON-COMPETING CONTINUATION	$3,098,418
														Subtotal = $4,419,128

Issue Date FY: 2023 ( Subtotal = $3,402,658 )
2023	2023	SCRIPPS RESEARCH INSTITUTE, THE	10550 NORTH TORREY PINES RD	LA JOLLA	CA	92037	SAN DIEGO	USA	Allergy and Infectious Diseases Research	000	3	3/3/2023	NON-COMPETING CONTINUATION	$3,402,658
														Subtotal = $3,402,658

Issue Date FY: 2022 ( Subtotal = $3,420,035 )
2022	2022	SCRIPPS RESEARCH INSTITUTE, THE	10550 NORTH TORREY PINES RD	LA JOLLA	CA	92037	SAN DIEGO	USA	Allergy and Infectious Diseases Research	000	2	1/12/2022	NON-COMPETING CONTINUATION	$3,420,035
														Subtotal = $3,420,035

Issue Date FY: 2021 ( Subtotal = $3,242,006 )
2021	2021	SCRIPPS RESEARCH INSTITUTE, THE	10550 NORTH TORREY PINES RD	LA JOLLA	CA	92037	SAN DIEGO	USA	Allergy and Infectious Diseases Research	000	1	2/3/2021	NEW	$3,242,006
														Subtotal = $3,242,006

Grand Total All Awards = $17,277,936

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Eliciting neutralizing antibodies and B cell responses using novel HIV Env immunogens in non-human primates

Award Number: P01AI157299

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: 02/04/2021

PERIOD OF PERFORMANCE END DATE: 01/31/2026

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