Combining membrane ENV vaccine regimens to elicit multiple bnab lineages and consistent cross-neutralization of HIV

Active Project Grant Awarded Last action

Award ID
R01AI181784
Recipient
Awarding agency
Obligated
$6,389,326

Award facts

Assistance listing
93.855 Allergy and Infectious Diseases Research
Completion date 60% complete
Place of performance
La Jolla, CA 92037, USA

Award details come from USAspending.gov.

Description

As the agency reported it.

Abstract
Developing a preventative HIV vaccine remains a global health priority and to be effective will most likely need to elicit broadly neutralizing antibodies (BNABS). HIV BNABS are derived from rare, unmutated common ancestor (UCA) B-cell precursors in elite HIV+ human repertoires. To reproducibly activate such UCA+ B-cells to affinity mature and acquire bnab function, `germline targeting' (GT) vaccine protocols are being developed typically for a single bnab lineage, and only induce sporadic and/or weak serum bnab responses using protracted boosting schemes that are clinically impractical. Clearly, more efficient GT regimens are needed that can elicit multiple bnab specificities, and appropriate animal models to track and follow up on promising lead neutralization signals in the serum. We recently equipped a new membrane (M)ENV liposome (MEL) platform with a GT mutation in menv that reproducibly induces tier 2 serum neutralization using semi- polyclonal CH103 UCA knockin (KI) mice after only two boosts. This represents the first GT regimen to elicit a `CDRH3 dominated' NAB response to the CD4-binding site (CD4BS) in which UCA B-cells are also under anergy control. The overall objective of this proposal is to build on this novel GT platform, to both improve HCDR3-dominated specific responses, and to adapt IT to target the relatively better-studied VH restricted- targeted CD4BS cluster and HIV's fusion peptide (FP) domain. We hypothesize that GT MEL sequential priming modalities (and mrna-lnps) tested in strategically selected CD4BS bnab UCA knock in models (while manipulating frequencies and tracking development of multiple UCA lineages), will help US identify a vaccine regimen that will elicit HIV serum neutralization in "higher bar", fully polyclonal humanpre-clinical animal models. Specifically, in aim 1, we will optimize the existing MEL-based GT regimen, as above, in the lead CH103 UCA KI model. Then, in aim 2, we will test the ability of menv modalities first to drive physiological numbers of `VRC01-class' CH31 UCA precursors towards breadth in WTACH31 KI chimeric mice, and then evaluate CH31/CH103 UCA multi-GT menv regimens promoting elicitation of both CD4BS bnab lineages (in CH31ACH103 chimeras). Finally, in aim 3, we will test the ability of FP nanoparticle (FP-NP) prime-menv boosting regimens to elicit serum NAB responses in WT and ucaawt chimeric mice, and ultimately test the best FP and CD4BS regimens combined in omni mice and omni rats, which express fully polyclonal, unrearranged human V (D)J repertoires. These studies, even if partially successful, will reveal the serum HIV NAB breadth that can be elicited by next-generation menv vaccine platforms against multiple overlapping targets on the CD4BS and FP, and may be advantageous in overcomingrepertoire holes across individuals, preventing viral escape, and requiring less overall boosting. 1

Transactions

Action Obligated Date
Amendment $940,820
Amendment $912,596
Amendment $912,596
Amendment $0
Amendment $0
Amendment $95,351
Amendment $95,351
Amendment $0
Amendment $0
Amendment $0
Amendment $858,153
Amendment $858,153
Amendment $858,153
Original award $858,153
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Subawards

Subrecipient Amount Awarded
Applied Biomedical Science Institute Award revised ro reflect Year 03 funding. $476,877
Applied Biomedical Science Institute Yr 2 funding $462,571
Applied Biomedical Science Institute This Amendment serves to increase year 1 funding by $48,724. $48,724
Applied Biomedical Science Institute Expediting elicitation of HIV-1 bnAbs with membrane Env vaccines $428,153

Quick answers

Who received award R01AI181784?

R01AI181784 was awarded to Scripps Research Institute by National Institute of Allergy and Infectious Diseases (National Institutes of Health) on December 1, 2023.

How much is award R01AI181784 worth?

$6,389,326 has been obligated on R01AI181784.

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