Novel Stealth Lipid for use in HIV MPER Vaccine

PROJECT SUMMARY A critical roadblock to HIV vaccine development is the inability to induce B cell lineages of broadly neutralizing antibodies (bnAbs) in humans. The HVTN 133 clinical trial (NCT03934541) utilized a peptide-liposome immunogen targeting B cell lineages of the HIV-1 envelope membrane-proximal external region (MPER). The MPER peptide-liposome administered during this clinical trial successfully induced polyclonal HIV-1 B cell lineages of mature bnAbs, the most potent of which neutralized 15% of global tier 2 HIV-1 strains and 35% of clade B strains. While this trial demonstrated proof of concept and outlined a potential path for successful HIV-1 vaccine development, the trial was halted due to a polyethylene glycol (PEG)-associated anaphylaxis reaction that has now been attributed to the use of PEG-lipid. To address this issue, Gateway Bio proposes to replace the PEG-lipid used in previous MPER peptide-liposome formulations with a lipid tethered to poly(oligoethylene glycol) methyl ether methacrylate (POEGMA), a next-generation polymer that resembles PEG but is tailored to address the existing limitations of PEG. POEGMA comprises a brush polymer structure with tri(ethylene glycol) sidechains along a poly(methyl methacrylate) backbone. The high density of tri(ethylene glycol) sidechains fully maintains the stealth properties of PEG, but this unique architecture limits the number of consecutive ethylene glycol units to just 3 repeats, which prior studies have shown eliminates PEG antigenicity—the binding of pre- existing anti-PEG antibodies to POEGMA, and mitigates anti-POEGMA immune reactions—the formation of new antibodies which recognize POEGMA. The goal of this proposal is to support a restart of the promising MPER peptide-liposome vaccine platform for HIV by developing a suitable POEGMA-lipid capable of replacing the problematic PEG-lipid that led to premature termination of the original clinical trial.