Vaccine Induction of Heterologous HIV-1 Neutralizing Antibody B Cell Lineages in Humans

Summary 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 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.