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SHIV Env-antibody coevolution as a molecular guide to HIV-1 V3 glycan targeted vaccine design

Award Number: P01AI131251
ORGANIZATION: NATIONAL INSTITUTE OF ALLERGY & INFECTIOUS DISEASES
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)

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SHIV Env-antibody coevolution as a molecular guide to HIV-1 V3 glycan targeted vaccine design - PROJECT SUMMARY The development of an effective HIV-1 vaccine has proven to be a daunting scientific challenge. Despite decades of research, there are no examples of immunogens that consistently elicit potent broadly neutralizing antibodies (bNAbs). Our scientific premise is that there are three principal obstacles to inducing bNAbs in primates and humans that prior vaccine approaches have largely failed to overcome. These are: i) efficient and consistent priming of multiple HIV-1 bNAb precursor B cells; ii) immunofocused boosting of B cell responses targeting conserved bNAb epitopes and away from off-target epitopes; and iii) affinity-guided maturation of B cell lineages to select for enhanced neutralization breadth and potency. Here, we address each of these requirements. This application is a competitive renewal of an existing HIVRAD award where we hypothesized that a major roadblock to rational HIV-1 vaccine design is the lack of a suitable primate model in which bNAbs can be commonly induced and the molecular, biological and immunological mechanisms responsible for such responses studied in a reproducible and iterative fashion. Overcoming this roadblock was one of the major goals of that grant, and over the past five years we have made substantial progress in reaching this milestone. We did this by developing a novel design strategy for creating simian-human immunodeficiency viruses (SHIV) that bear clinically-relevant primary HIV-1 Envs and that replicate efficiently in rhesus macaques (RMs). We next hypothesized that SHIV- infected RMs could be used to identify HIV-1 Envs that have a propensity for eliciting bNAbs of predetermined epitope specificity, thus allowing for a detailed and reproducible molecular characterization of the coevolutionary pathways of Env and Ab that lead to affinity maturation and breadth. Again, we obtained strong supporting evidence (Science 371:eabd2638, 2021). Here we propose to build on this foundation and to test the hypothesis that elucidation of the molecular pathways of Env-Ab coevolution leading to neutralization breadth in SHIV- infected RMs, combined with biophysical and immunological analyses of key Env-Ab lineage intermediates, can provide a molecular “blueprint” for successful germline-targeted, B cell lineage-based immunogen design. To test this hypothesis, we propose three highly inter-related research projects and three cores: Project 1 - Env-Ab coevolution in SHIV infected RMs leading to V3 glycan bNAbs (Shaw); Project 2 - Optimizing humoral immunity to HIV-1 Env proteins (Kelsoe); Project 3 - Immunogen design to elicit polyclonal bNAb responses to the V3 glycan supersite (Wiehe). These projects will be enabled by Core A – Administrative (Shaw); Core B – Viral and antibody gene sequencing (Hahn); and Core C – Bioinformatics and statistics (Wagh). The significance of the proposed studies is potentially far-reaching: previous studies of HIV-1 SOSIP Env trimer vaccinations have generally elicited only autologous strain-specific Nab responses in outbred animals. If we can demonstrate consistent induction of bNAbs using germline-targeted, lineage-based SOSIP Env trimers as immunogens in RMs, it would represent a major scientific advance and a new beachhead for HIV-1 vaccine research.


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 = $3,930,527 )
2025	2025	TRUSTEES OF THE UNIVERSITY OF PENNSYLVANIA, THE	3451 WALNUT ST STE 440A	PHILADELPHIA	PA	19104	PHILADELPHIA	USA	Allergy and Infectious Diseases Research	000	9	2/28/2025	NON-COMPETING CONTINUATION	$3,930,527
														Subtotal = $3,930,527

Issue Date FY: 2024 ( Subtotal = $4,076,804 )
2024	2024	TRUSTEES OF THE UNIVERSITY OF PENNSYLVANIA, THE	3451 WALNUT ST STE 440A	PHILADELPHIA	PA	19104	PHILADELPHIA	USA	Allergy and Infectious Diseases Research	000	8	3/26/2024	NON-COMPETING CONTINUATION	$4,076,804
														Subtotal = $4,076,804

Issue Date FY: 2023 ( Subtotal = $4,104,830 )
2023	2023	TRUSTEES OF THE UNIVERSITY OF PENNSYLVANIA, THE	3451 WALNUT ST STE 440A	PHILADELPHIA	PA	19104	PHILADELPHIA	USA	Allergy and Infectious Diseases Research	002	7	3/14/2023	NON-COMPETING CONTINUATION	$4,104,830
2023	2022	TRUSTEES OF THE UNIVERSITY OF PENNSYLVANIA, THE	3451 WALNUT ST STE 440A	PHILADELPHIA	PA	19104	PHILADELPHIA	USA	Allergy and Infectious Diseases Research	001	6	10/13/2022	COMPETING CONTINUATION	$1,324,095
2023	2021	TRUSTEES OF THE UNIVERSITY OF PENNSYLVANIA, THE	3451 WALNUT ST STE 440A	PHILADELPHIA	PA	19104	PHILADELPHIA	USA	Allergy and Infectious Diseases Research	000	5	10/13/2022	NON-COMPETING CONTINUATION	-$1,324,095
														Subtotal = $4,104,830

Issue Date FY: 2022 ( Subtotal = $4,178,808 )
2022	2022	TRUSTEES OF THE UNIVERSITY OF PENNSYLVANIA, THE	3451 WALNUT ST STE 440A	PHILADELPHIA	PA	19104	PHILADELPHIA	USA	Allergy and Infectious Diseases Research	001	6	6/1/2022	COMPETING CONTINUATION	$4,178,808
2022	2021	TRUSTEES OF THE UNIVERSITY OF PENNSYLVANIA, THE	3451 WALNUT ST STE 440A	PHILADELPHIA	PA	19104	PHILADELPHIA	USA	Allergy and Infectious Diseases Research	000	5	5/31/2022	NON-COMPETING CONTINUATION	$0
														Subtotal = $4,178,808

Issue Date FY: 2021 ( Subtotal = $3,218,740 )
2021	2021	TRUSTEES OF THE UNIVERSITY OF PENNSYLVANIA, THE	3451 WALNUT ST STE 440A	PHILADELPHIA	PA	19104	PHILADELPHIA	USA	Allergy and Infectious Diseases Research	000	5	3/22/2021	NON-COMPETING CONTINUATION	$3,218,740
														Subtotal = $3,218,740

Issue Date FY: 2020 ( Subtotal = $3,242,287 )
2020	2020	TRUSTEES OF THE UNIVERSITY OF PENNSYLVANIA, THE	3451 WALNUT ST STE 440A	PHILADELPHIA	PA	19104	PHILADELPHIA	USA	Allergy and Infectious Diseases Research	000	4	3/2/2020	NON-COMPETING CONTINUATION	$3,242,287
														Subtotal = $3,242,287

Issue Date FY: 2019 ( Subtotal = $3,256,887 )
2019	2019	TRUSTEES OF THE UNIVERSITY OF PENNSYLVANIA, THE	3451 WALNUT ST	PHILADELPHIA	PA	19104	PHILADELPHIA	USA	Allergy and Infectious Diseases Research	000	3	2/25/2019	NON-COMPETING CONTINUATION	$3,256,887
														Subtotal = $3,256,887

Issue Date FY: 2018 ( Subtotal = $3,269,168 )
2018	2018	TRUSTEES OF THE UNIVERSITY OF PENNSYLVANIA, THE	3451 WALNUT ST	PHILADELPHIA	PA	19104	PHILADELPHIA	USA	Allergy and Infectious Diseases Research	000	2	3/2/2018	NON-COMPETING CONTINUATION	$3,269,168
														Subtotal = $3,269,168

Issue Date FY: 2017 ( Subtotal = $3,342,300 )
2017	2017	TRUSTEES OF THE UNIVERSITY OF PENNSYLVANIA, THE	3451 WALNUT ST	PHILADELPHIA	PA	19104	PHILADELPHIA	USA	Allergy and Infectious Diseases Research	000	1	3/6/2017	NEW	$3,335,437
2017	2017	TRUSTEES OF THE UNIVERSITY OF PENNSYLVANIA, THE	3451 WALNUT ST	PHILADELPHIA	PA	19104	PHILADELPHIA	USA	Allergy and Infectious Diseases Research	001	1	3/27/2017	NEW	$6,863
														Subtotal = $3,342,300

Grand Total All Awards = $32,620,351

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SHIV Env-antibody coevolution as a molecular guide to HIV-1 V3 glycan targeted vaccine design

Award Number: P01AI131251

ORGANIZATION: NATIONAL INSTITUTE OF ALLERGY & INFECTIOUS DISEASES

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)

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