Long-lasting B cell convergence to distinct broadly reactive epitopes following vaccination with chimeric influenza virus hemagglutinins

Jenna J. Guthmiller; Linda Yu-Ling Lan; Lei Li; Yanbin Fu; Sean A. Nelson; Carole Henry; Christopher T. Stamper; Henry A. Utset; Alec W. Freyn; Julianna Han; Olivia Stovicek; Jiaolong Wang; Nai Ying Zheng; Min Huang; Haley L. Dugan; Micah E. Tepora; Xueyong Zhu; Yao Qing Chen; Anna Karin E. Palm; Dustin G. Shaw; Madhumathi Loganathan; Benjamin F. Francis; Jiayi Sun; Jordan Chervin; Chloe Troxell; Philip Meade; Nancy H.L. Leung; Sophie A. Valkenburg; Sarah Cobey; Benjamin J. Cowling; Ian A. Wilson; Adolfo García-Sastre; Raffael Nachbagauer; Andrew B. Ward; Lynda Coughlan; Florian Krammer; Patrick C. Wilson

doi:10.1016/j.immuni.2025.02.025

Long-lasting B cell convergence to distinct broadly reactive epitopes following vaccination with chimeric influenza virus hemagglutinins

Jenna J. Guthmiller, Linda Yu-Ling Lan, Lei Li, Yanbin Fu, Sean A. Nelson, Carole Henry, Christopher T. Stamper, Henry A. Utset, Alec W. Freyn, Julianna Han, Olivia Stovicek, Jiaolong Wang, Nai Ying Zheng, Min Huang, Haley L. Dugan, Micah E. Tepora, Xueyong Zhu, Yao Qing Chen, Anna Karin E. Palm, Dustin G. ShawMadhumathi Loganathan, Benjamin F. Francis, Jiayi Sun, Jordan Chervin, Chloe Troxell, Philip Meade, Nancy H.L. Leung, Sophie A. Valkenburg, Sarah Cobey, Benjamin J. Cowling, Ian A. Wilson, Adolfo García-Sastre, Raffael Nachbagauer, Andrew B. Ward, Lynda Coughlan, Florian Krammer, Patrick C. Wilson

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

Abstract

In a phase 1 clinical trial, a chimeric hemagglutinin (cHA) immunogen induced antibody responses against the conserved hemagglutinin (HA) stalk domain as designed. Here, we determined the specificity, function, and subsets of B cells induced by cHA vaccination by pairing single-cell RNA sequencing and B cell receptor repertoire sequencing. We have shown that the cHA-inactivated vaccine with a squalene-based adjuvant induced a robust activated B cell and memory B cell (MBC) phenotype against two broadly neutralizing epitopes in the stalk domain. The overall specificities of the acute plasmablast (PB) and MBC responses clonally overlapped, suggesting B cell convergence to these broadly protective epitopes. At 1 year post immunization, we identified that cHA vaccination reshaped the HA-specific MBC pool to enrich for stalk-binding B cells. Altogether, these data indicate the cHA vaccine induced robust and durable B cell responses against broadly protective epitopes of the HA stalk domain, in line with serological data.

Original language	English
Pages (from-to)	980-996.e7
Journal	Immunity
Volume	58
Issue number	4
DOIs	https://doi.org/10.1016/j.immuni.2025.02.025
State	Published - 8 Apr 2025

Keywords

broadly neutralizing epitopes
chimeric hemagglutinin
durable B cell responses
HA anchor epitope
HA stalk epitope
influenza
next-generation influenza vaccine
universal influenza vaccine

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10.1016/j.immuni.2025.02.025

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Guthmiller, J. J., Yu-Ling Lan, L., Li, L., Fu, Y., Nelson, S. A., Henry, C., Stamper, C. T., Utset, H. A., Freyn, A. W., Han, J., Stovicek, O., Wang, J., Zheng, N. Y., Huang, M., Dugan, H. L., Tepora, M. E., Zhu, X., Chen, Y. Q., Palm, A. K. E., ... Wilson, P. C. (2025). Long-lasting B cell convergence to distinct broadly reactive epitopes following vaccination with chimeric influenza virus hemagglutinins. Immunity, 58(4), 980-996.e7. https://doi.org/10.1016/j.immuni.2025.02.025

@article{6a35916cb69d43babb2c89d9d3657fcc,

title = "Long-lasting B cell convergence to distinct broadly reactive epitopes following vaccination with chimeric influenza virus hemagglutinins",

abstract = "In a phase 1 clinical trial, a chimeric hemagglutinin (cHA) immunogen induced antibody responses against the conserved hemagglutinin (HA) stalk domain as designed. Here, we determined the specificity, function, and subsets of B cells induced by cHA vaccination by pairing single-cell RNA sequencing and B cell receptor repertoire sequencing. We have shown that the cHA-inactivated vaccine with a squalene-based adjuvant induced a robust activated B cell and memory B cell (MBC) phenotype against two broadly neutralizing epitopes in the stalk domain. The overall specificities of the acute plasmablast (PB) and MBC responses clonally overlapped, suggesting B cell convergence to these broadly protective epitopes. At 1 year post immunization, we identified that cHA vaccination reshaped the HA-specific MBC pool to enrich for stalk-binding B cells. Altogether, these data indicate the cHA vaccine induced robust and durable B cell responses against broadly protective epitopes of the HA stalk domain, in line with serological data.",

keywords = "broadly neutralizing epitopes, chimeric hemagglutinin, durable B cell responses, HA anchor epitope, HA stalk epitope, influenza, next-generation influenza vaccine, universal influenza vaccine",

author = "Guthmiller, {Jenna J.} and {Yu-Ling Lan}, Linda and Lei Li and Yanbin Fu and Nelson, {Sean A.} and Carole Henry and Stamper, {Christopher T.} and Utset, {Henry A.} and Freyn, {Alec W.} and Julianna Han and Olivia Stovicek and Jiaolong Wang and Zheng, {Nai Ying} and Min Huang and Dugan, {Haley L.} and Tepora, {Micah E.} and Xueyong Zhu and Chen, {Yao Qing} and Palm, {Anna Karin E.} and Shaw, {Dustin G.} and Madhumathi Loganathan and Francis, {Benjamin F.} and Jiayi Sun and Jordan Chervin and Chloe Troxell and Philip Meade and Leung, {Nancy H.L.} and Valkenburg, {Sophie A.} and Sarah Cobey and Cowling, {Benjamin J.} and Wilson, {Ian A.} and Adolfo Garc{\'i}a-Sastre and Raffael Nachbagauer and Ward, {Andrew B.} and Lynda Coughlan and Florian Krammer and Wilson, {Patrick C.}",

note = "Publisher Copyright: {\textcopyright} 2025 Elsevier Inc.",

year = "2025",

month = apr,

day = "8",

doi = "10.1016/j.immuni.2025.02.025",

language = "English",

volume = "58",

pages = "980--996.e7",

journal = "Immunity",

issn = "1074-7613",

publisher = "Cell Press",

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Guthmiller, JJ, Yu-Ling Lan, L, Li, L, Fu, Y, Nelson, SA, Henry, C, Stamper, CT, Utset, HA, Freyn, AW, Han, J, Stovicek, O, Wang, J, Zheng, NY, Huang, M, Dugan, HL, Tepora, ME, Zhu, X, Chen, YQ, Palm, AKE, Shaw, DG, Loganathan, M, Francis, BF, Sun, J, Chervin, J, Troxell, C, Meade, P, Leung, NHL, Valkenburg, SA, Cobey, S, Cowling, BJ, Wilson, IA, García-Sastre, A, Nachbagauer, R, Ward, AB, Coughlan, L, Krammer, F & Wilson, PC 2025, 'Long-lasting B cell convergence to distinct broadly reactive epitopes following vaccination with chimeric influenza virus hemagglutinins', Immunity, vol. 58, no. 4, pp. 980-996.e7. https://doi.org/10.1016/j.immuni.2025.02.025

TY - JOUR

T1 - Long-lasting B cell convergence to distinct broadly reactive epitopes following vaccination with chimeric influenza virus hemagglutinins

AU - Guthmiller, Jenna J.

AU - Yu-Ling Lan, Linda

AU - Li, Lei

AU - Fu, Yanbin

AU - Nelson, Sean A.

AU - Henry, Carole

AU - Stamper, Christopher T.

AU - Utset, Henry A.

AU - Freyn, Alec W.

AU - Han, Julianna

AU - Stovicek, Olivia

AU - Wang, Jiaolong

AU - Zheng, Nai Ying

AU - Huang, Min

AU - Dugan, Haley L.

AU - Tepora, Micah E.

AU - Zhu, Xueyong

AU - Chen, Yao Qing

AU - Palm, Anna Karin E.

AU - Shaw, Dustin G.

AU - Loganathan, Madhumathi

AU - Francis, Benjamin F.

AU - Sun, Jiayi

AU - Chervin, Jordan

AU - Troxell, Chloe

AU - Meade, Philip

AU - Leung, Nancy H.L.

AU - Valkenburg, Sophie A.

AU - Cobey, Sarah

AU - Cowling, Benjamin J.

AU - Wilson, Ian A.

AU - García-Sastre, Adolfo

AU - Nachbagauer, Raffael

AU - Ward, Andrew B.

AU - Coughlan, Lynda

AU - Krammer, Florian

AU - Wilson, Patrick C.

PY - 2025/4/8

Y1 - 2025/4/8

N2 - In a phase 1 clinical trial, a chimeric hemagglutinin (cHA) immunogen induced antibody responses against the conserved hemagglutinin (HA) stalk domain as designed. Here, we determined the specificity, function, and subsets of B cells induced by cHA vaccination by pairing single-cell RNA sequencing and B cell receptor repertoire sequencing. We have shown that the cHA-inactivated vaccine with a squalene-based adjuvant induced a robust activated B cell and memory B cell (MBC) phenotype against two broadly neutralizing epitopes in the stalk domain. The overall specificities of the acute plasmablast (PB) and MBC responses clonally overlapped, suggesting B cell convergence to these broadly protective epitopes. At 1 year post immunization, we identified that cHA vaccination reshaped the HA-specific MBC pool to enrich for stalk-binding B cells. Altogether, these data indicate the cHA vaccine induced robust and durable B cell responses against broadly protective epitopes of the HA stalk domain, in line with serological data.

AB - In a phase 1 clinical trial, a chimeric hemagglutinin (cHA) immunogen induced antibody responses against the conserved hemagglutinin (HA) stalk domain as designed. Here, we determined the specificity, function, and subsets of B cells induced by cHA vaccination by pairing single-cell RNA sequencing and B cell receptor repertoire sequencing. We have shown that the cHA-inactivated vaccine with a squalene-based adjuvant induced a robust activated B cell and memory B cell (MBC) phenotype against two broadly neutralizing epitopes in the stalk domain. The overall specificities of the acute plasmablast (PB) and MBC responses clonally overlapped, suggesting B cell convergence to these broadly protective epitopes. At 1 year post immunization, we identified that cHA vaccination reshaped the HA-specific MBC pool to enrich for stalk-binding B cells. Altogether, these data indicate the cHA vaccine induced robust and durable B cell responses against broadly protective epitopes of the HA stalk domain, in line with serological data.

KW - broadly neutralizing epitopes

KW - chimeric hemagglutinin

KW - durable B cell responses

KW - HA anchor epitope

KW - HA stalk epitope

KW - influenza

KW - next-generation influenza vaccine

KW - universal influenza vaccine

UR - http://www.scopus.com/inward/record.url?scp=105001636523&partnerID=8YFLogxK

U2 - 10.1016/j.immuni.2025.02.025

DO - 10.1016/j.immuni.2025.02.025

M3 - Article

AN - SCOPUS:105001636523

SN - 1074-7613

VL - 58

SP - 980-996.e7

JO - Immunity

JF - Immunity

IS - 4

ER -

Long-lasting B cell convergence to distinct broadly reactive epitopes following vaccination with chimeric influenza virus hemagglutinins

Abstract

Keywords

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