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 Flynn; Amelia Zhou; Mariane B. Melo; Ashley Lemnios; Nicole Phelps; Erik Georgeson; Nushin Alavi; Michael Kubitz; Danny Lu; Saman Eskandarzadeh; Amanda Metz; Oscar L. Rodriguez; Kaitlyn Shields; Steven Schultze; Melissa L. Smith; Brandon S. Healy; Deuk Lim; Vanessa R. Lewis; Elana Ben-Akiva; William Pinney; Justin 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

doi:10.1016/j.immuni.2025.03.003

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 Flynn, Amelia Zhou, Mariane B. Melo, Ashley Lemnios, Nicole PhelpsErik Georgeson, Nushin Alavi, Michael Kubitz, Danny Lu, Saman Eskandarzadeh, Amanda Metz, Oscar L. Rodriguez, Kaitlyn Shields, Steven Schultze, Melissa L. Smith, Brandon S. Healy, Deuk Lim, Vanessa R. Lewis, Elana Ben-Akiva, William Pinney, Justin 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

Research output: Contribution to journal › Article › peer-review

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.

Original language	English
Pages (from-to)	997-1014.e11
Journal	Immunity
Volume	58
Issue number	4
DOIs	https://doi.org/10.1016/j.immuni.2025.03.003
State	Published - 8 Apr 2025
Externally published	Yes

Keywords

BG18
HIV bnAbs
HIV vaccines
adjuvants
bnAb precursors
escalating dose
germline-targeting
naive B cells

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10.1016/j.immuni.2025.03.003

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Madden, P. J., Marina-Zárate, E., Rodrigues, K. A., Steichen, J. M., Shil, M., Ni, K., Michaels, K. K., Maiorino, L., Upadhyay, A. A., Saha, S., Pradhan, A., Kalyuzhiny, O., Liguori, A., Lopez, P. G., Phung, I., Flynn, C., Zhou, A., Melo, M. B., Lemnios, A., ... Crotty, S. (2025). Diverse priming outcomes under conditions of very rare precursor B cells. Immunity, 58(4), 997-1014.e11. https://doi.org/10.1016/j.immuni.2025.03.003

@article{3a949be3911449139e2fa20672bc6bac,

title = "Diverse priming outcomes under conditions of very rare precursor B cells",

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.",

keywords = "BG18, HIV bnAbs, HIV vaccines, adjuvants, bnAb precursors, escalating dose, germline-targeting, naive B cells",

author = "Madden, {Patrick J.} and Ester Marina-Z{\'a}rate and Rodrigues, {Kristen A.} and Steichen, {Jon M.} and Monolina Shil and Kaiyuan Ni and Michaels, {Katarzyna Kaczmarek} and Laura Maiorino and Upadhyay, {Amit A.} and Swati Saha and Arpan Pradhan and Oleksandr Kalyuzhiny and Alessia Liguori and Lopez, {Paul G.} and Ivy Phung and Claudia Flynn and Amelia Zhou and Melo, {Mariane B.} and Ashley Lemnios and Nicole Phelps and Erik Georgeson and Nushin Alavi and Michael Kubitz and Danny Lu and Saman Eskandarzadeh and Amanda Metz and Rodriguez, {Oscar L.} and Kaitlyn Shields and Steven Schultze and Smith, {Melissa L.} and Healy, {Brandon S.} and Deuk Lim and Lewis, {Vanessa R.} and Elana Ben-Akiva and William Pinney and Justin Gregory and Shuhao Xiao and Carnathan, {Diane G.} and {Pai Kasturi}, Sudhir and Watson, {Corey T.} and Bosinger, {Steven E.} and Guido Silvestri and Schief, {William R.} and Irvine, {Darrell J.} and Shane Crotty",

note = "Publisher Copyright: {\textcopyright} 2025 The Author(s)",

year = "2025",

month = apr,

day = "8",

doi = "10.1016/j.immuni.2025.03.003",

language = "English",

volume = "58",

pages = "997--1014.e11",

journal = "Immunity",

issn = "1074-7613",

publisher = "Cell Press",

number = "4",

}

Madden, PJ, Marina-Zárate, E, Rodrigues, KA, Steichen, JM, Shil, M, Ni, K, Michaels, KK, Maiorino, L, Upadhyay, AA, Saha, S, Pradhan, A, Kalyuzhiny, O, Liguori, A, Lopez, PG, Phung, I, Flynn, C, Zhou, A, Melo, MB, Lemnios, A, Phelps, N, Georgeson, E, Alavi, N, Kubitz, M, Lu, D, Eskandarzadeh, S, Metz, A, Rodriguez, OL, Shields, K, Schultze, S, Smith, ML, Healy, BS, Lim, D, Lewis, VR, Ben-Akiva, E, Pinney, W, Gregory, J, Xiao, S, Carnathan, DG, Pai Kasturi, S, Watson, CT, Bosinger, SE, Silvestri, G, Schief, WR, Irvine, DJ & Crotty, S 2025, 'Diverse priming outcomes under conditions of very rare precursor B cells', Immunity, vol. 58, no. 4, pp. 997-1014.e11. https://doi.org/10.1016/j.immuni.2025.03.003

TY - JOUR

T1 - Diverse priming outcomes under conditions of very rare precursor B cells

AU - Madden, Patrick J.

AU - Marina-Zárate, Ester

AU - Rodrigues, Kristen A.

AU - Steichen, Jon M.

AU - Shil, Monolina

AU - Ni, Kaiyuan

AU - Michaels, Katarzyna Kaczmarek

AU - Maiorino, Laura

AU - Upadhyay, Amit A.

AU - Saha, Swati

AU - Pradhan, Arpan

AU - Kalyuzhiny, Oleksandr

AU - Liguori, Alessia

AU - Lopez, Paul G.

AU - Phung, Ivy

AU - Flynn, Claudia

AU - Zhou, Amelia

AU - Melo, Mariane B.

AU - Lemnios, Ashley

AU - Phelps, Nicole

AU - Georgeson, Erik

AU - Alavi, Nushin

AU - Kubitz, Michael

AU - Lu, Danny

AU - Eskandarzadeh, Saman

AU - Metz, Amanda

AU - Rodriguez, Oscar L.

AU - Shields, Kaitlyn

AU - Schultze, Steven

AU - Smith, Melissa L.

AU - Healy, Brandon S.

AU - Lim, Deuk

AU - Lewis, Vanessa R.

AU - Ben-Akiva, Elana

AU - Pinney, William

AU - Gregory, Justin

AU - Xiao, Shuhao

AU - Carnathan, Diane G.

AU - Pai Kasturi, Sudhir

AU - Watson, Corey T.

AU - Bosinger, Steven E.

AU - Silvestri, Guido

AU - Schief, William R.

AU - Irvine, Darrell J.

AU - Crotty, Shane

PY - 2025/4/8

Y1 - 2025/4/8

N2 - 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.

AB - 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.

KW - BG18

KW - HIV bnAbs

KW - HIV vaccines

KW - adjuvants

KW - bnAb precursors

KW - escalating dose

KW - germline-targeting

KW - naive B cells

UR - http://www.scopus.com/inward/record.url?scp=105001596044&partnerID=8YFLogxK

U2 - 10.1016/j.immuni.2025.03.003

DO - 10.1016/j.immuni.2025.03.003

M3 - Article

AN - SCOPUS:105001596044

SN - 1074-7613

VL - 58

SP - 997-1014.e11

JO - Immunity

JF - Immunity

IS - 4

ER -

Diverse priming outcomes under conditions of very rare precursor B cells

Abstract

Keywords

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