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Maximizing germinal centers and somatic hypermutation to HIV Env immunogens

Award Number: R37AI125068
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: 02/01/2016
PERIOD OF PERFORMANCE END DATE: 01/31/2026

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Maximizing germinal centers and somatic hypermutation to HIV Env immunogens - Abstract We propose that the features of germinal center biology important for developing high affinity B cells to a very difficult epitope, such as a tier 2 nAb epitope on HIV Env trimer, are very different than the well characterized features of GC biology for conventional antigens, such as haptens. We have demonstrated that slow delivery immunization changes fundamental aspects of the immune response, which can result in dramatic improvements in nAb responses (Cell 2019). Conventional immunization strategies will likely be insufficient for the development of a bnAb vaccine to HIV or other difficult pathogens due to the immunological hurdles posed, including B cell immunodominance and GC quantity and quality. We found that two independent methods of slow delivery immunization of RMs resulted in more robust Tfh cells and more GC B cells with Env-binding, tracked by longitudinal lymph node (LN) fine needle aspirates (FNA) 1. Improved GCs correlated with the development of > 20-fold higher titers of autologous tier 2 neutralizing Abs (nAbs). BCR sequencing and Ab mapping demonstrated targeting of immunodominant non-neutralizing (nnAb) epitopes by conventional bolus immunized animals, while slow delivery immunized animals targeted a more diverse set of epitopes, including multiple tier 2 nAb epitopes. We will continue these groundbreaking studies to use novel slow release technologies to probe the biology of germinal centers relevant to affinity maturation against a difficult HIV trimer immunogen in non-human primates (NHP, rhesus macaques).


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 = $874,385 )
2025	2025	LA JOLLA INSTITUTE FOR IMMUNOLOGY	9420 ATHENA CIR	LA JOLLA	CA	92037	SAN DIEGO	USA	Allergy and Infectious Diseases Research	000	10	1/17/2025	NON-COMPETING CONTINUATION	$874,385
														Subtotal = $874,385

Issue Date FY: 2024 ( Subtotal = $882,023 )
2024	2024	LA JOLLA INSTITUTE FOR IMMUNOLOGY	9420 ATHENA CIR	LA JOLLA	CA	92037	SAN DIEGO	USA	Allergy and Infectious Diseases Research	001	9	5/23/2024	NON-COMPETING CONTINUATION	$88,202
2024	2024	LA JOLLA INSTITUTE FOR IMMUNOLOGY	9420 ATHENA CIR	LA JOLLA	CA	92037	SAN DIEGO	USA	Allergy and Infectious Diseases Research	000	9	1/9/2024	NON-COMPETING CONTINUATION	$793,821
														Subtotal = $882,023

Issue Date FY: 2023 ( Subtotal = $869,654 )
2023	2023	LA JOLLA INSTITUTE FOR IMMUNOLOGY	9420 ATHENA CIR	LA JOLLA	CA	92037	SAN DIEGO	USA	Allergy and Infectious Diseases Research	000	8	1/4/2023	NON-COMPETING CONTINUATION	$869,654
														Subtotal = $869,654

Issue Date FY: 2022 ( Subtotal = $883,119 )
2022	2022	LA JOLLA INSTITUTE FOR IMMUNOLOGY	9420 ATHENA CIR	LA JOLLA	CA	92037	SAN DIEGO	USA	Allergy and Infectious Diseases Research	000	7	2/2/2022	NON-COMPETING CONTINUATION	$883,119
														Subtotal = $883,119

Issue Date FY: 2021 ( Subtotal = $922,142 )
2021	2021	LA JOLLA INSTITUTE FOR IMMUNOLOGY	9420 ATHENA CIR	LA JOLLA	CA	92037	SAN DIEGO	USA	Allergy and Infectious Diseases Research	000	6	2/11/2021	COMPETING CONTINUATION	$922,142
														Subtotal = $922,142

Grand Total All Awards = $4,431,323

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Maximizing germinal centers and somatic hypermutation to HIV Env immunogens

Award Number: R37AI125068

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: 02/01/2016

PERIOD OF PERFORMANCE END DATE: 01/31/2026

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