Multivalent antigen display on nanoparticle immunogens increases B cell clonotype diversity and neutralization breadth to pneumoviruses

Sebastian Ols; Klara Lenart; Rodrigo Arcoverde Cerveira; Marcos C. Miranda; Natalie Brunette; Jana Kochmann; Martin Corcoran; Rebecca Skotheim; Annika Philomin; Alberto Cagigi; Brooke Fiala; Samuel Wrenn; Jessica Marcandalli; Fredrika Hellgren; Elizabeth A. Thompson; Ang Lin; Florian Gegenfurtner; Azad Kumar; Man Chen; Ganesh E. Phad; Barney S. Graham; Laurent Perez; Andrew J. Borst; Gunilla B. Karlsson Hedestam; Tracy J. Ruckwardt; Neil P. King; Karin Loré

doi:10.1016/j.immuni.2023.08.011

Multivalent antigen display on nanoparticle immunogens increases B cell clonotype diversity and neutralization breadth to pneumoviruses

Sebastian Ols, Klara Lenart, Rodrigo Arcoverde Cerveira, Marcos C. Miranda, Natalie Brunette, Jana Kochmann, Martin Corcoran, Rebecca Skotheim, Annika Philomin, Alberto Cagigi, Brooke Fiala, Samuel Wrenn, Jessica Marcandalli, Fredrika Hellgren, Elizabeth A. Thompson, Ang Lin, Florian Gegenfurtner, Azad Kumar, Man Chen, Ganesh E. PhadBarney S. Graham, Laurent Perez, Andrew J. Borst, Gunilla B. Karlsson Hedestam, Tracy J. Ruckwardt, Neil P. King, Karin Loré

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

Abstract

Nanoparticles for multivalent display and delivery of vaccine antigens have emerged as a promising avenue for enhancing B cell responses to protein subunit vaccines. Here, we evaluated B cell responses in rhesus macaques immunized with prefusion-stabilized respiratory syncytial virus (RSV) F glycoprotein trimer compared with nanoparticles displaying 10 or 20 copies of the same antigen. We show that multivalent display skews antibody specificities and drives epitope-focusing of responding B cells. Antibody cloning and repertoire sequencing revealed that focusing was driven by the expansion of clonally distinct B cells through recruitment of diverse precursors. We identified two antibody lineages that developed either ultrapotent neutralization or pneumovirus cross-neutralization from precursor B cells with low initial affinity for the RSV-F immunogen. This suggests that increased avidity by multivalent display facilitates the activation and recruitment of these cells. Diversification of the B cell response by multivalent nanoparticle immunogens has broad implications for vaccine design.

Original language	English (US)
Pages (from-to)	2425-2441.e14
Journal	Immunity
Volume	56
Issue number	10
DOIs	https://doi.org/10.1016/j.immuni.2023.08.011
State	Published - Oct 10 2023
Externally published	Yes

Keywords

B cells
MPV
RSV
affinity threshold
antibody
avidity
clonality
immunogen size
nanoparticle vaccine
valency

ASJC Scopus subject areas

Infectious Diseases
Immunology and Allergy
Immunology

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10.1016/j.immuni.2023.08.011

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Ols, S., Lenart, K., Arcoverde Cerveira, R., Miranda, M. C., Brunette, N., Kochmann, J., Corcoran, M., Skotheim, R., Philomin, A., Cagigi, A., Fiala, B., Wrenn, S., Marcandalli, J., Hellgren, F., Thompson, E. A., Lin, A., Gegenfurtner, F., Kumar, A., Chen, M., ... Loré, K. (2023). Multivalent antigen display on nanoparticle immunogens increases B cell clonotype diversity and neutralization breadth to pneumoviruses. Immunity, 56(10), 2425-2441.e14. https://doi.org/10.1016/j.immuni.2023.08.011

Ols, S, Lenart, K, Arcoverde Cerveira, R, Miranda, MC, Brunette, N, Kochmann, J, Corcoran, M, Skotheim, R, Philomin, A, Cagigi, A, Fiala, B, Wrenn, S, Marcandalli, J, Hellgren, F, Thompson, EA, Lin, A, Gegenfurtner, F, Kumar, A, Chen, M, Phad, GE, Graham, BS, Perez, L, Borst, AJ, Karlsson Hedestam, GB, Ruckwardt, TJ, King, NP & Loré, K 2023, 'Multivalent antigen display on nanoparticle immunogens increases B cell clonotype diversity and neutralization breadth to pneumoviruses', Immunity, vol. 56, no. 10, pp. 2425-2441.e14. https://doi.org/10.1016/j.immuni.2023.08.011

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abstract = "Nanoparticles for multivalent display and delivery of vaccine antigens have emerged as a promising avenue for enhancing B cell responses to protein subunit vaccines. Here, we evaluated B cell responses in rhesus macaques immunized with prefusion-stabilized respiratory syncytial virus (RSV) F glycoprotein trimer compared with nanoparticles displaying 10 or 20 copies of the same antigen. We show that multivalent display skews antibody specificities and drives epitope-focusing of responding B cells. Antibody cloning and repertoire sequencing revealed that focusing was driven by the expansion of clonally distinct B cells through recruitment of diverse precursors. We identified two antibody lineages that developed either ultrapotent neutralization or pneumovirus cross-neutralization from precursor B cells with low initial affinity for the RSV-F immunogen. This suggests that increased avidity by multivalent display facilitates the activation and recruitment of these cells. Diversification of the B cell response by multivalent nanoparticle immunogens has broad implications for vaccine design.",

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doi = "10.1016/j.immuni.2023.08.011",

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AU - Ols, Sebastian

AU - Lenart, Klara

AU - Arcoverde Cerveira, Rodrigo

AU - Miranda, Marcos C.

AU - Brunette, Natalie

AU - Kochmann, Jana

AU - Corcoran, Martin

AU - Skotheim, Rebecca

AU - Philomin, Annika

AU - Cagigi, Alberto

AU - Fiala, Brooke

AU - Wrenn, Samuel

AU - Marcandalli, Jessica

AU - Hellgren, Fredrika

AU - Thompson, Elizabeth A.

AU - Lin, Ang

AU - Gegenfurtner, Florian

AU - Kumar, Azad

AU - Chen, Man

AU - Phad, Ganesh E.

AU - Graham, Barney S.

AU - Perez, Laurent

AU - Borst, Andrew J.

AU - Karlsson Hedestam, Gunilla B.

AU - Ruckwardt, Tracy J.

AU - King, Neil P.

AU - Loré, Karin

PY - 2023/10/10

Y1 - 2023/10/10

N2 - Nanoparticles for multivalent display and delivery of vaccine antigens have emerged as a promising avenue for enhancing B cell responses to protein subunit vaccines. Here, we evaluated B cell responses in rhesus macaques immunized with prefusion-stabilized respiratory syncytial virus (RSV) F glycoprotein trimer compared with nanoparticles displaying 10 or 20 copies of the same antigen. We show that multivalent display skews antibody specificities and drives epitope-focusing of responding B cells. Antibody cloning and repertoire sequencing revealed that focusing was driven by the expansion of clonally distinct B cells through recruitment of diverse precursors. We identified two antibody lineages that developed either ultrapotent neutralization or pneumovirus cross-neutralization from precursor B cells with low initial affinity for the RSV-F immunogen. This suggests that increased avidity by multivalent display facilitates the activation and recruitment of these cells. Diversification of the B cell response by multivalent nanoparticle immunogens has broad implications for vaccine design.

AB - Nanoparticles for multivalent display and delivery of vaccine antigens have emerged as a promising avenue for enhancing B cell responses to protein subunit vaccines. Here, we evaluated B cell responses in rhesus macaques immunized with prefusion-stabilized respiratory syncytial virus (RSV) F glycoprotein trimer compared with nanoparticles displaying 10 or 20 copies of the same antigen. We show that multivalent display skews antibody specificities and drives epitope-focusing of responding B cells. Antibody cloning and repertoire sequencing revealed that focusing was driven by the expansion of clonally distinct B cells through recruitment of diverse precursors. We identified two antibody lineages that developed either ultrapotent neutralization or pneumovirus cross-neutralization from precursor B cells with low initial affinity for the RSV-F immunogen. This suggests that increased avidity by multivalent display facilitates the activation and recruitment of these cells. Diversification of the B cell response by multivalent nanoparticle immunogens has broad implications for vaccine design.

KW - B cells

KW - MPV

KW - RSV

KW - affinity threshold

KW - antibody

KW - avidity

KW - clonality

KW - immunogen size

KW - nanoparticle vaccine

KW - valency

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ER -

Multivalent antigen display on nanoparticle immunogens increases B cell clonotype diversity and neutralization breadth to pneumoviruses

Abstract

Keywords

ASJC Scopus subject areas

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