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Leveraging membrane Env liposome vaccine design to elicit multi-target cross-neutralization of HIV

Award Number: R01AI183472
ORGANIZATION: NATIONAL INSTITUTE OF ALLERGY & INFECTIOUS DISEASES
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)

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Leveraging membrane Env liposome vaccine design to elicit multi-target cross-neutralization of HIV - PROJECT SUMMARY Developing a vaccine that elicits HIV broadly neutralizing antibodies (bnAbs) remains a top priority in HIV vaccine design. However, typically HIV bnAbs originate from rare B-cell germline precursors (‘UCAs’) and require improbable somatic hypermutations (SHM) in HIV+ human repertoires. To reproducibly activate such B-cells, ‘Germline Targeting’ (GT) vaccine priming strategies appear to be useful for activating specific bnAb UCAs particularly in polyclonal systems including rhesus macaques, a key preclinical animal model. We recently developed a novel membrane (m)Env liposome (MEL) platform using mEnvs that contain GT mutations. One novel GT-MEL regimen targets a ‘CDRH3 dominated’ nAb response to the CD4-binding site (CD4bs) and reproducibly elicited tier 2 serum neutralization in CH103 UCA knockin (KI) mice after only two boosts. This GT-MEL regimen offers an alternative to the more commonly studied VH restricted CD4BS cluster often targeted by soluble (s)Env immunogens. Meanwhile, we have generated GT-MELs based on described GT-sEnvs that have been reported previously to elicit VH-restricted CD4BS HIV nAbs, i.e., activation of CH235 bnAb UCA in KI mice and possible CH235 homologs in macaques. The overall objective of this proposal is use novel GT-MELs to elicit HCDR3-dominated and VH restricted CD4BS responses in rhesus macaques, in addition to responses targeting HIV’s Fusion Peptide (FP). We will test a hypothesis that a CD4BS CDRH3- dominated plus VH-restricted CD4BS GT-MEL prime-boost regimen tested in macaques will elicit serum neutralization against tier 2 HIV (SA1). In SA2, we will use a fusion peptide nanoparticle (FP-NP) ‘pre-prime’ strategy followed by BG505 variant MEL boosting regimen designed to elicit tier 2 serum neutralization based in part on a prior report by others using a sEnv immunization protocol that elicited tier 2 serum neutralization and FP bnAbs. In Phase 2 of this ‘Innovation’ grant proposal, we will use the results of the above studies to integrate the CD4BS (CH505) MEL and FP (BG505) vaccine approaches into one regimen meant to elicit HIV nAbs to both the CD4BS and the FP supersites. These studies, will reveal the serum HIV nAb breadth that can be elicited by the MEL vaccine platform in rhesus macaques against multiple overlapping targets on the CD4BS and FP, and may inform the development of an HIV vaccine for humans. 1


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 = $839,102 )
2025	2025	SCRIPPS RESEARCH INSTITUTE	10550 N TORREY PINES RD	LA JOLLA	CA	92037	SAN DIEGO	USA	Allergy and Infectious Diseases Research	000	2	2/13/2025	NON-COMPETING CONTINUATION	$839,102
														Subtotal = $839,102

Issue Date FY: 2024 ( Subtotal = $816,634 )
2024	2024	SCRIPPS RESEARCH INSTITUTE	10550 N TORREY PINES RD	LA JOLLA	CA	92037	SAN DIEGO	USA	Allergy and Infectious Diseases Research	000	1	3/18/2024	NEW	$816,634
2024	2024	SCRIPPS RESEARCH INSTITUTE	10550 N TORREY PINES RD	LA JOLLA	CA	92037	SAN DIEGO	USA	Allergy and Infectious Diseases Research	001	1	9/4/2024	NEW	$0
														Subtotal = $816,634

Grand Total All Awards = $1,655,736

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Leveraging membrane Env liposome vaccine design to elicit multi-target cross-neutralization of HIV

Award Number: R01AI183472

ORGANIZATION: NATIONAL INSTITUTE OF ALLERGY & INFECTIOUS DISEASES

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

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