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Germline-Targeted Vaccines Using Membrane Env Liposomes to Elicit HIV-1 MPER bnAbs

Award Number: R56AI203658
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: 08/17/2026
PERIOD OF PERFORMANCE END DATE: 07/31/2027

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Germline-Targeted Vaccines Using Membrane Env Liposomes to Elicit HIV-1 MPER bnAbs - Summary An HIV/AIDS vaccine will likely need to elicit broadly neutralizing antibodies (bnAbs) that target conserved sites on the HIV envelope glycoprotein spike (Env). The membrane-proximal external region (MPER) of gp41 is a conserved target for multiple HIV bnAbs, but it is often omitted from vaccine candidates, or those that include it have failed to generate significant bnAb titers in humans or animal models. A recent clinical trial showed that a MPER peptide liposome vaccine elicited mAbs targeting the N-terminal MPER (N-MPER) that cross-neutralized HIV, renewing interest in the MPER. We recently described a vaccine platform, membrane Env liposomes (MEL), which display the MPER multivalently, in the relevant context of membrane (m)Env trimers. Preliminary studies show that MELs administered to bnAb iGL 2F5 Ig knock-in (KI) mice elicited tier 2 serum neutralization targeting the N-MPER. Meanwhile, the 4E10 class bnAb PGZL1 achieves near-pan HIV neutralization and has structural and genetic features common in people with HIV (PWH) that allow it to recognize the more conserved, C-terminal C-MPER on mEnv. Unlike other C-MPER bnAbs, PGZL1 iGL neutralizes sensitive HIV isolates and directly binds the MPER on mEnv. Furthermore, we show that PGZL1 iGL HC is minimally polyreactive in vitro and expressed well on B cells at vaccine-targeted immune sites of PGZL1 gH+ KI mice in vivo. Finally, have described 10E8 class germline-targeting (GT) scaffold can bind to PGZL1-class iGLs and primes a MPER-specific Ab response in iGL PGZL1 gH+ KI mice. We thus hypothesize that by developing MELs and GT scaffold prime-boost regimens in iGL PGZL1 KI mice, HIV bnAbs can be elicited in sera (Aim 1). In Aim 2, we will identify new C-MPER bnAb and associated human germline Abs (“HuGLs”), determine structures of PGZL1 class Abs bound to the MPER and mEnv, and define structure-activity relationships (SAR) that will inform vaccine development in Aims 1 and 3. Finally, we will use in-house created, rearranging VH1-69.D3-10.JH4 Ig KI mice and fully humanized Ig mini- gene KI mice as progressively ‘higher bar’ models to identify and evaluate lead PGZL1 GT MEL vaccine candidate(s) alone or in combination with MEL GTs to other targets such as the CD4bs (Aim 3).


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: 2026 ( Subtotal = $1,097,774 )
2026	2026	SCRIPPS RESEARCH INSTITUTE	10550 N TORREY PINES RD	LA JOLLA	CA	92037	SAN DIEGO	USA	Allergy and Infectious Diseases Research	000	1	8/17/2026	NEW	$1,097,774
														Subtotal = $1,097,774

Grand Total All Awards = $1,097,774

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Germline-Targeted Vaccines Using Membrane Env Liposomes to Elicit HIV-1 MPER bnAbs

Award Number: R56AI203658

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: 08/17/2026

PERIOD OF PERFORMANCE END DATE: 07/31/2027

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