Multi-compartmental diversification of neutralizing antibody lineages dissected in SARS-CoV-2 spike-immunized macaques

Marco Mandolesi (), Hrishikesh Das, Liset Vries, Yiqiu Yang, Changil Kim, Manojj Dhinakaran, Xaquin Castro Dopico, Julian Fischbach, Sungyong Kim, Mariia V. Guryleva, Monika Àdori, Mark Chernyshev, Aron Stålmarck, Leo Hanke, Gerald M. McInerney, Daniel J. Sheward, Martin Corcoran, B. Martin Hällberg, Ben Murrell and Gunilla B. Karlsson Hedestam ()
Additional contact information
Marco Mandolesi: Karolinska Institutet
Hrishikesh Das: Karolinska Institutet
Liset Vries: Karolinska Institutet
Yiqiu Yang: Karolinska Institutet
Changil Kim: Karolinska Institutet
Manojj Dhinakaran: Karolinska Institutet
Xaquin Castro Dopico: Karolinska Institutet
Julian Fischbach: Karolinska Institutet
Sungyong Kim: Karolinska Institutet
Mariia V. Guryleva: Karolinska Institutet
Monika Àdori: Karolinska Institutet
Mark Chernyshev: Karolinska Institutet
Aron Stålmarck: Karolinska Institutet
Leo Hanke: Karolinska Institutet
Gerald M. McInerney: Karolinska Institutet
Daniel J. Sheward: Karolinska Institutet
Martin Corcoran: Karolinska Institutet
B. Martin Hällberg: Karolinska Institutet
Ben Murrell: Karolinska Institutet
Gunilla B. Karlsson Hedestam: Karolinska Institutet

Nature Communications, 2024, vol. 15, issue 1, 1-13

Abstract: Abstract The continued evolution of SARS-CoV-2 underscores the need to understand qualitative aspects of the humoral immune response elicited by spike immunization. Here, we combine monoclonal antibody (mAb) isolation with deep B cell receptor (BCR) repertoire sequencing of rhesus macaques immunized with prefusion-stabilized spike glycoprotein. Longitudinal tracing of spike-sorted B cell lineages in multiple immune compartments demonstrates increasing somatic hypermutation and broad dissemination of vaccine-elicited B cells in draining and non-draining lymphoid compartments, including the bone marrow, spleen and, most notably, periaortic lymph nodes. Phylogenetic analysis of spike-specific monoclonal antibody lineages identified through deep repertoire sequencing delineates extensive intra-clonal diversification that shaped neutralizing activity. Structural analysis of the spike in complex with a broadly neutralizing mAb provides a molecular basis for the observed differences in neutralization breadth between clonally related antibodies. Our findings highlight that immunization leads to extensive intra-clonal B cell evolution where members of the same lineage can both retain the original epitope specificity and evolve to recognize additional spike variants not previously encountered.

Date: 2024
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DOI: 10.1038/s41467-024-50286-0

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