Heavy-chain CDR3-engineered B cells facilitate in vivo evaluation of HIV-1 vaccine candidates

Wenhui He; Tianling Ou; Nickolas Skamangas; Charles C. Bailey; Naomi Bronkema; Yan Guo; Yiming Yin; Valerie Kobzarenko; Xia Zhang; Andi Pan; Xin Liu; Jinge Xu; Lizhou Zhang; Ava E. Allwardt; Debasis Mitra; Brian Quinlan; Rogier W. Sanders; Hyeryun Choe; Michael Farzan

doi:https://doi.org/10.1016/j.immuni.2023.07.003

Heavy-chain CDR3-engineered B cells facilitate in vivo evaluation of HIV-1 vaccine candidates

Wenhui He, Tianling Ou, Nickolas Skamangas, Charles C. Bailey, Naomi Bronkema, Yan Guo, Yiming Yin, Valerie Kobzarenko, Xia Zhang, Andi Pan, Xin Liu, Jinge Xu, Lizhou Zhang, Ava E. Allwardt, Debasis Mitra, Brian Quinlan, Rogier W. Sanders, Hyeryun Choe, Michael Farzan

Medical Microbiology and Infection Prevention (AMC)

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

2 Citations (Scopus)

Abstract

V2-glycan/apex broadly neutralizing antibodies (bnAbs) recognize a closed quaternary epitope of the HIV-1 envelope glycoprotein (Env). This closed structure is necessary to elicit apex antibodies and useful to guide the maturation of other bnAb classes. To compare antigens designed to maintain this conformation, we evaluated apex-specific responses in mice engrafted with a diverse repertoire of B cells expressing the HCDR3 of the apex bnAb VRC26.25. Engineered B cells affinity matured, guiding the improvement of VRC26.25 itself. We found that soluble Env (SOSIP) variants differed significantly in their ability to raise anti-apex responses. A transmembrane SOSIP (SOSIP-TM) delivered as an mRNA-lipid nanoparticle elicited more potent neutralizing responses than multimerized SOSIP proteins. Importantly, SOSIP-TM elicited neutralizing sera from B cells engineered with the predicted VRC26.25-HCDR3 progenitor, which also affinity matured. Our data show that HCDR3-edited B cells facilitate efficient in vivo comparisons of Env antigens and highlight the potential of an HCDR3-focused vaccine approach.

Original language	English
Pages (from-to)	2408-2424.e6
Journal	Immunity
Volume	56
Issue number	10
Early online date	2023
DOIs	https://doi.org/10.1016/j.immuni.2023.07.003
Publication status	Published - 10 Oct 2023

Keywords

B cell engineering
HCDR3
HIV-1 vaccine model
SOSIP
SOSIP-TM
affinity maturation
apex bnAb precursor
lipid nanoparticle
mRNA vaccine

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He, W., Ou, T., Skamangas, N., Bailey, C. C., Bronkema, N., Guo, Y., Yin, Y., Kobzarenko, V., Zhang, X., Pan, A., Liu, X., Xu, J., Zhang, L., Allwardt, A. E., Mitra, D., Quinlan, B., Sanders, R. W., Choe, H., & Farzan, M. (2023). Heavy-chain CDR3-engineered B cells facilitate in vivo evaluation of HIV-1 vaccine candidates. Immunity, 56(10), 2408-2424.e6. https://doi.org/10.1016/j.immuni.2023.07.003

@article{bf46492a87404cb6a3c1657ba8f53b70,

title = "Heavy-chain CDR3-engineered B cells facilitate in vivo evaluation of HIV-1 vaccine candidates",

abstract = "V2-glycan/apex broadly neutralizing antibodies (bnAbs) recognize a closed quaternary epitope of the HIV-1 envelope glycoprotein (Env). This closed structure is necessary to elicit apex antibodies and useful to guide the maturation of other bnAb classes. To compare antigens designed to maintain this conformation, we evaluated apex-specific responses in mice engrafted with a diverse repertoire of B cells expressing the HCDR3 of the apex bnAb VRC26.25. Engineered B cells affinity matured, guiding the improvement of VRC26.25 itself. We found that soluble Env (SOSIP) variants differed significantly in their ability to raise anti-apex responses. A transmembrane SOSIP (SOSIP-TM) delivered as an mRNA-lipid nanoparticle elicited more potent neutralizing responses than multimerized SOSIP proteins. Importantly, SOSIP-TM elicited neutralizing sera from B cells engineered with the predicted VRC26.25-HCDR3 progenitor, which also affinity matured. Our data show that HCDR3-edited B cells facilitate efficient in vivo comparisons of Env antigens and highlight the potential of an HCDR3-focused vaccine approach.",

keywords = "B cell engineering, HCDR3, HIV-1 vaccine model, SOSIP, SOSIP-TM, affinity maturation, apex bnAb precursor, lipid nanoparticle, mRNA vaccine",

author = "Wenhui He and Tianling Ou and Nickolas Skamangas and Bailey, {Charles C.} and Naomi Bronkema and Yan Guo and Yiming Yin and Valerie Kobzarenko and Xia Zhang and Andi Pan and Xin Liu and Jinge Xu and Lizhou Zhang and Allwardt, {Ava E.} and Debasis Mitra and Brian Quinlan and Sanders, {Rogier W.} and Hyeryun Choe and Michael Farzan",

note = "Funding Information: This work was supported by National Institutes of Health awards U19 AI149646 (M.F.); R21 AI152836 (M.F.); and R01 DA056771 (M.F.). Publisher Copyright: {\textcopyright} 2023 Elsevier Inc.",

year = "2023",

month = oct,

day = "10",

doi = "https://doi.org/10.1016/j.immuni.2023.07.003",

language = "English",

volume = "56",

pages = "2408--2424.e6",

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He, W, Ou, T, Skamangas, N, Bailey, CC, Bronkema, N, Guo, Y, Yin, Y, Kobzarenko, V, Zhang, X, Pan, A, Liu, X, Xu, J, Zhang, L, Allwardt, AE, Mitra, D, Quinlan, B, Sanders, RW, Choe, H & Farzan, M 2023, 'Heavy-chain CDR3-engineered B cells facilitate in vivo evaluation of HIV-1 vaccine candidates', Immunity, vol. 56, no. 10, pp. 2408-2424.e6. https://doi.org/10.1016/j.immuni.2023.07.003

TY - JOUR

T1 - Heavy-chain CDR3-engineered B cells facilitate in vivo evaluation of HIV-1 vaccine candidates

AU - He, Wenhui

AU - Ou, Tianling

AU - Skamangas, Nickolas

AU - Bailey, Charles C.

AU - Bronkema, Naomi

AU - Guo, Yan

AU - Yin, Yiming

AU - Kobzarenko, Valerie

AU - Zhang, Xia

AU - Pan, Andi

AU - Liu, Xin

AU - Xu, Jinge

AU - Zhang, Lizhou

AU - Allwardt, Ava E.

AU - Mitra, Debasis

AU - Quinlan, Brian

AU - Sanders, Rogier W.

AU - Choe, Hyeryun

AU - Farzan, Michael

PY - 2023/10/10

Y1 - 2023/10/10

N2 - V2-glycan/apex broadly neutralizing antibodies (bnAbs) recognize a closed quaternary epitope of the HIV-1 envelope glycoprotein (Env). This closed structure is necessary to elicit apex antibodies and useful to guide the maturation of other bnAb classes. To compare antigens designed to maintain this conformation, we evaluated apex-specific responses in mice engrafted with a diverse repertoire of B cells expressing the HCDR3 of the apex bnAb VRC26.25. Engineered B cells affinity matured, guiding the improvement of VRC26.25 itself. We found that soluble Env (SOSIP) variants differed significantly in their ability to raise anti-apex responses. A transmembrane SOSIP (SOSIP-TM) delivered as an mRNA-lipid nanoparticle elicited more potent neutralizing responses than multimerized SOSIP proteins. Importantly, SOSIP-TM elicited neutralizing sera from B cells engineered with the predicted VRC26.25-HCDR3 progenitor, which also affinity matured. Our data show that HCDR3-edited B cells facilitate efficient in vivo comparisons of Env antigens and highlight the potential of an HCDR3-focused vaccine approach.

AB - V2-glycan/apex broadly neutralizing antibodies (bnAbs) recognize a closed quaternary epitope of the HIV-1 envelope glycoprotein (Env). This closed structure is necessary to elicit apex antibodies and useful to guide the maturation of other bnAb classes. To compare antigens designed to maintain this conformation, we evaluated apex-specific responses in mice engrafted with a diverse repertoire of B cells expressing the HCDR3 of the apex bnAb VRC26.25. Engineered B cells affinity matured, guiding the improvement of VRC26.25 itself. We found that soluble Env (SOSIP) variants differed significantly in their ability to raise anti-apex responses. A transmembrane SOSIP (SOSIP-TM) delivered as an mRNA-lipid nanoparticle elicited more potent neutralizing responses than multimerized SOSIP proteins. Importantly, SOSIP-TM elicited neutralizing sera from B cells engineered with the predicted VRC26.25-HCDR3 progenitor, which also affinity matured. Our data show that HCDR3-edited B cells facilitate efficient in vivo comparisons of Env antigens and highlight the potential of an HCDR3-focused vaccine approach.

KW - B cell engineering

KW - HCDR3

KW - HIV-1 vaccine model

KW - SOSIP

KW - SOSIP-TM

KW - affinity maturation

KW - apex bnAb precursor

KW - lipid nanoparticle

KW - mRNA vaccine

UR - http://www.scopus.com/inward/record.url?scp=85169010217&partnerID=8YFLogxK

U2 - https://doi.org/10.1016/j.immuni.2023.07.003

DO - https://doi.org/10.1016/j.immuni.2023.07.003

M3 - Article

C2 - 37531955

SN - 1074-7613

VL - 56

SP - 2408-2424.e6

JO - Immunity

JF - Immunity

IS - 10

ER -

Heavy-chain CDR3-engineered B cells facilitate in vivo evaluation of HIV-1 vaccine candidates

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Keywords

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