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

Authors:

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

Details:

Immunity, Volume 58, Issue 4, 2025-04-08

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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.