Diverse priming outcomes under conditions of very rare precursor B cells
Patrick Madden, Ester Marina-Zárate, Kristen A. Rodrigues, Jon M. Steichen, Monolina Shil, Kaiyuan Ni, Katarzyna Kaczmarek Michaels, Laura Maiorino, Amit A. Upadhyay, Swati Saha, Arpan Pradhan, Oleksandr Kalyuzhiny, Alessia Liguori, Paul Lopez, Ivy Phung, Claudia T. Flynn, Amelia Zhou, Mariane B. Melo, Ashley A. Lemnios, Nicole Phelps, Erik Georgeson, Nushin Alavi, Michael Kubitz, Danny Lu, Saman Eskandarzadeh, Amanda Metz, Oscar L. Rodriguez, Kaitlyn Shields, Steven Schultze, Melissa Smith, Brandon S. Healy, Deuk Lim, Vanessa Lewis, Elana Ben‐Akiva, William Pinney, Justin M. Gregory, Shuhao Xiao, Diane G. Carnathan, Sudhir Pai Kasturi, Corey T. Watson, Steven E. Bosinger, Guido Silvestri, William R. Schief, Darrell J. Irvine, Shane Crotty
Abstract
Rare naive B cells have special pathogen-recognition features that enable outsized contributions to protective immunity but infrequently participate in immune responses. We investigatee how germline-targeting vaccine delivery and adjuvant selection affect priming of exceptionally rare BG18-like HIV broadly neutralizing antibody-precursor B cells (<1-in-50 million) in non-human primates. Only escalating dose (ED) priming immunization using the saponin adjuvant SMNP elicited detectable BG18-like cells in germinal centers (GCs) compared with other conditions. All groups had strong GC responses, but only ED+SMNP and bolus+SMNP induced BG18-like memory B cells in >50% of animals. One group had vaccine-specific GC responses equivalent to ED+SMNP but scarce BG18-like B cells. Following homologous boosting, BG18-like memory B cells were present in a bolus priming group but with lower somatic hypermutation and affinities than ED+SMNP. This outcome inversely associated with post-prime antibody titers, suggesting antibody feedback significantly influences rare precursor B cell responses. Thus, antigen and inflammatory stimuli extensively impact priming and affinity maturation of rare B cells.