HIV broadly neutralizing antibody precursor maturation induced by mRNA vaccination in nonhuman primates

The induction of broadly neutralizing antibodies (bnAbs) is a principal goal of prophylactic HIV vaccines. For many bnAbs, priming ultrarare precursors from the naive B cell repertoire is the first major immunological hurdle. Previous studies have shown that the germline-targeting (GT) priming immunogen N332-GT5 delivered as adjuvanted protein to non-human primates (NHPs) activates bnAb precursor B cells for the human bnAb BG18 targeting the V3-glycan supersite on the HIV envelope (Env) glycoprotein. Here, we engineered N332-GT6 to improve binding affinity to diverse BG18-class precursor naive B cells by 9-fold. mRNA-LNP vaccines expressing N332-GT5 or N332-GT6 as membrane-bound (gp151) trimers were evaluated for their ability to prime BG18-class precursor B cells in NHPs across three related studies. Although N332-GT5 gp151 mRNA-LNP priming induced BG18-class precursor B cells in most animals after two vaccinations, the higher-affinity N332-GT6 gp151 induced responses more consistently after only one immunization. Sequential vaccination with two heterologous mRNA-LNP booster immunizations drove affinity maturation and induced BG18-class memory B cells capable of binding wildtype HIV Env. Together, these findings demonstrate that mRNA immunization can achieve GT priming, boosting, and early maturation of ultrarare bnAb-class B cells in NHPs.