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

• Published in: Nature communications Vol. 15; no. 1; pp. 6338 - 13
• Main Authors: Mandolesi, Marco, Das, Hrishikesh, de Vries, Liset, Yang, Yiqiu, Kim, Changil, Dhinakaran, Manojj, Castro Dopico, Xaquin, Fischbach, Julian, Kim, Sungyong, Guryleva, Mariia V, Àdori, Monika, Chernyshev, Mark, Stålmarck, Aron, Hanke, Leo, McInerney, Gerald M, Sheward, Daniel J, Corcoran, Martin, Hällberg, B Martin, Murrell, Ben, Karlsson Hedestam, Gunilla B
• Format: Journal Article
• Language: English
• Published: England Nature Publishing Group 27.07.2024; Nature Publishing Group UK; Nature Portfolio
• Subjects: Animals; Antibodies, Monoclonal - immunology; Antibodies, Neutralizing - immunology; Antibodies, Viral - immunology; B-cell receptor; B-Lymphocytes - immunology; Bone marrow; Compartments; COVID-19 - immunology; COVID-19 - virology; COVID-19 Vaccines - immunology; Epitopes; Epitopes - immunology; Evolution; Glycoproteins; Humans; Immune response; Immune response (humoral); Immune system; Immunization; Lymph nodes; Lymphocytes B; Macaca mulatta; Medicin och hälsovetenskap; Monoclonal antibodies; Neutralization; Neutralizing; Phylogeny; Receptors, Antigen, B-Cell - genetics; Receptors, Antigen, B-Cell - immunology; SARS-CoV-2 - genetics; SARS-CoV-2 - immunology; Severe acute respiratory syndrome coronavirus 2; Somatic hypermutation; Somatic Hypermutation, Immunoglobulin; Spike glycoprotein; Spike Glycoprotein, Coronavirus - genetics; Spike Glycoprotein, Coronavirus - immunology; Structural analysis; Vaccines
• ISSN: 2041-1723; 2041-1723
• DOI: 10.1038/s41467-024-50286-0

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.