Vaccine induction of heterologous HIV-1-neutralizing antibody B cell lineages in humans

A critical roadblock to HIV vaccine development is the inability to induce B cell lineages of broadly neutralizing antibodies (bnAbs) in humans. In people living with HIV-1, bnAbs take years to develop. The HVTN 133 clinical trial studied a peptide/liposome immunogen targeting B cell lineages of HIV-1 envelope (Env) membrane-proximal external region (MPER) bnAbs (NCT03934541). Here, we report MPER peptide-liposome induction of polyclonal HIV-1 B cell lineages of mature bnAbs and their precursors, the most potent of which neutralized 15% of global tier 2 HIV-1 strains and 35% of clade B strains with lineage initiation after the second immunization. Neutralization was enhanced by vaccine selection of improbable mutations that increased antibody binding to gp41 and lipids. This study demonstrates proof of concept for rapid vaccine induction of human B cell lineages with heterologous neutralizing activity and selection of antibody improbable mutations and outlines a path for successful HIV-1 vaccine development. [Display omitted] •HIV gp41 MPER peptide-liposome vaccine elicited polyclonal NAbs in humans•Vaccine-induced MPER-reactive antibodies matured from precursors to bnAb status•Vaccine-selected improbable mutations conferred lipid binding and HIV neutralization•MPER bnAb lineage was initiated after two immunizations The HVTN 133 human clinical trial demonstrated the first success of vaccine induction of polyclonal heterologous HIV-1-neutralizing antibodies that target gp41 MPER. Williams and colleagues show that proximal-MPER bnAbs can be induced by gp41 MPER peptide-liposomes in humans to neutralize HIV-1.