mRNA-LNP prime boost evolves precursors toward VRC01-like broadly neutralizing antibodies in preclinical humanized mouse models
Xuesong Wang, Christopher A. Cottrell, Xiaozhen Hu, Rashmi Ray, Maria Bottermann, Paula Maldonado Villavicencio, Yu Yan, Zhenfei Xie, John E. Warner, Jordan Renae Ellis-Pugh, Oleksandr Kalyuzhniy, Alessia Liguori, Jordan R. Willis, Sergey Menis, Sebastian Rämisch, Saman Eskandarzadeh, Michael Kubitz, Ryan Tingle, Nicole Phelps, Bettina Gröschel, Sunny Himansu, Andrea Carfı́, Kathrin H. Kirsch, Stephanie R. Weldon, Usha Nair, William R. Schief, Facundo D. Batista
Abstract
Germline-targeting (GT) protein immunogens to induce VRC01-class broadly neutralizing antibodies (bnAbs) to the CD4-binding site of the HIV envelope (Env) have shown promise in clinical trials. Here, we preclinically validated a lipid nanoparticle-encapsulated nucleoside mRNA (mRNA-LNP) encoding eOD-GT8 60mer as a soluble self-assembling nanoparticle in mouse models. In a model with three humanized B cell lineages bearing distinct VRC01-precursor B cell receptors (BCRs) with similar affinities for eOD-GT8, all lineages could be simultaneously primed and undergo diversification and affinity maturation without exclusionary competition. Boosts drove precursor B cell participation in germinal centers; the accumulation of somatic hypermutations, including in key VRC01-class positions; and affinity maturation to boost and native-like antigens in two of the three precursor lineages. We have preclinically validated a prime-boost regimen of soluble self-assembling nanoparticles encoded by mRNA-LNP, demonstrating that multiple lineages can be primed, boosted, and diversified along the bnAb pathway.