Diverse priming outcomes under conditions of very rare precursor B cells

Patrick J. 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 G. Lopez; Ivy Phung; Claudia T. Flynn; Amelia Zhou; Mariane B. Melo; Ashley A. Lemnios; Nicole Phelps; Erik Georgeson; Nushin B. Alavi; Michael Kubitz; Danny Lu; Saman Eskandarzadeh; Amanda Metz; Oscar L. Rodriguez; Kaitlyn M. Shields; Steven Schultze; Melissa Laird Smith

doi:10.1016/j.immuni.2025.03.003

ImmunologyImmunityApr 1, 2025

Peer-reviewed journal article

Diverse priming outcomes under conditions of very rare precursor B cells

Patrick J. Madden iD, Ester Marina-Zárate iD, Kristen A. Rodrigues iD, Jon M. Steichen iD, Monolina Shil, Kaiyuan Ni iD, Katarzyna Kaczmarek Michaels iD, Laura Maiorino iD, Amit A. Upadhyay iD, Swati Saha iD, Arpan Pradhan iD, Oleksandr Kalyuzhiny, Alessia Liguori iD, Paul G. Lopez iD, Ivy Phung iD, Claudia T. Flynn iD, Amelia Zhou, Mariane B. Melo iD, Ashley A. Lemnios iD, Nicole Phelps iD, Erik Georgeson iD, Nushin B. Alavi iD, Michael Kubitz iD, Danny Lu iD, Saman Eskandarzadeh iD, , Shane Crotty iD

Abstract

Rare B cells can have special pathogen-recognition features giving them the potential to make outsized contributions to protective immunity. However, rare naive B cells infrequently participate in immune responses. We investigated how germline-targeting vaccine antigen 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). 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 BG18-like memory B cells were rarely detected. Following homologous boosting, BG18-like memory B cells were more frequent in a bolus priming group, but had lower somatic hypermutation and affinities. This outcome was inversely associated with post-prime antibody titers, suggesting antibody feedback can significantly influence rare precursor B cell responses.

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