Simultaneous priming of HIV broadly neutralizing antibody precursors to multiple epitopes by germline-targeting mRNA-LNP immunogens in mouse models
Zhenfei Xie, Xuesong Wang, Yu Yan, Jon M. Steichen, M. Krystal, Christopher A. Cottrell, Eleonora Melzi, Maria Bottermann, Paula Maldonado Villavicencio, Kimmo Rantalainen, Torben Schiffner, John E. Warner, Stephanie R. Weldon, Thavaleak Prum, Jordan Renae Ellis-Pugh, Jonathan L. Torres, Abigail M. Jackson, Claudia T. Flynn, Gabriel Ozorowski, Sunny Himansu, Andrea Carfı́, Andrew B. Ward, Usha Nair, William R. Schief, Facundo D. Batista
Abstract
Germline-targeting is a promising approach to HIV vaccine development that begins with the elicitation of precursors to broadly neutralizing antibodies (bnAbs), but it remains unclear whether simultaneous elicitation of precursors to multiple epitopes on the HIV envelope (Env) would be inhibited by competition. This study used preclinical mouse models with physiologically relevant frequencies of bnAb precursor-bearing B cells to compare precursor elicitation by coadministration of multiple protein or mRNA lipid nanoparticle (mRNA-LNP) germline-targeting immunogens. These immunogens activate multiple bnAb precursor classes targeting distinct epitopes on Env but with evidence of potential competition. Simultaneous delivery of immunogens encoded by mRNA-LNPs, however, drove maturation across different precursor frequencies and immunogen doses. Furthermore, administration of a cocktail of mRNA-LNP immunogens (N332-GT5 gp151, ApexGT5 gp151, eOD-GT8 60mer, and 10E8-GT12 24mer) led to balanced activation of four distinct bnAb precursor classes, indicating that multiepitope HIV bnAb precursor priming might be successfully implemented in humans but might be immunogen dependent.