Germline-targeted vaccines using membrane ENV liposomes to elicit HIV-1 mper bnabs

The National Institute of Allergy and Infectious Diseases awarded the Scripps Research Institute $1.097 million on August 17, 2026, under the Allergy and Infectious Diseases Research program (CFDA 93.855) to develop germline-targeted HIV vaccines using membrane ENV liposomes designed to elicit broadly neutralizing antibodies against the membrane-proximal external region (MPER) of the HIV envelope glycoprotein.

The research program uses a vaccine platform (membrane ENV liposomes) that displays the MPER multivalently in the context of trimeric structures and combines it with germline-targeting scaffold prime-boost regimens in transgenic mice. The work aims to generate tier 2 serum neutralization targeting conserved MPER domains and to identify new MPER-specific broadly neutralizing antibody targets and human germline antibodies. The project also defines structural relationships between MPER-targeting antibody classes and the vaccine antigens to establish structure-activity relationships informing future vaccine design.

The award obligates $1,097,774 with performance through July 31, 2027, at the recipient's location in La Jolla, California. The Scripps Research Institute, a nonprofit biomedical research organization, serves as the recipient and performs the work directly.

Abstract

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 2F5KNOCK-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.JH4KI mice and fully humanizedmini- 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).