B cell maturation restored ancestral germlines to control Omicron BA.2.86

Ida Paciello; Giulio Pierleoni; Elisa Pantano; Giada Antonelli; Piero Pileri; Giuseppe Maccari; Dario Cardamone; Giulia Realini; Federica Perrone; Martin Mayora Neto; Simone Pozzessere; Massimiliano Fabbiani; Francesca Panza; Ilaria Rancan; Mario Tumbarello; Francesca Montagnani; Duccio Medini; Piet Maes; Nigel James Temperton; Etienne Simon‐Lorière; Olivier Schwartz; Rino Rappuoli; Emanuele Andreano

doi:10.1016/j.celrep.2024.114645

ImmunologyCell ReportsAug 27, 2024

Peer-reviewed journal article

B cell maturation restored ancestral germlines to control Omicron BA.2.86

Ida Paciello iD, Giulio Pierleoni iD, Elisa Pantano iD, Giada Antonelli iD, Piero Pileri iD, Giuseppe Maccari iD, Dario Cardamone iD, Giulia Realini iD, Federica Perrone iD, Martin Mayora Neto iD, Simone Pozzessere, Massimiliano Fabbiani iD, Francesca Panza iD, Ilaria Rancan iD, Mario Tumbarello iD, Francesca Montagnani iD, Duccio Medini iD, Piet Maes iD, Nigel James Temperton iD, Etienne Simon‐Lorière iD, Olivier Schwartz iD, Rino Rappuoli iD, Emanuele Andreano iD

Abstract

The unceasing interplay between SARS-CoV-2 and the human immune system has led to a continuous maturation of the virus and B cell response providing an opportunity to track their evolution in real time. We longitudinally analyzed the functional activity of almost 1,000 neutralizing human monoclonal antibodies (nAbs) isolated from vaccinated people, and from individuals with hybrid and super hybrid immunity (SH), developed after three mRNA vaccine doses and two breakthrough infections. The most potent neutralization and Fc functions against highly mutated variants, including BA.2.86, were found in the SH cohort. Despite different priming, epitope mapping revealed a convergent maturation of the functional antibody response. Neutralization was mainly driven by Class 1/2 nAbs while Fc functions were induced by Class 3/4 antibodies. Remarkably, broad neutralization was mediated by restored IGHV3-53/3-66 B cell germlines which, after heterogenous exposure to SARS-CoV-2 S proteins, increased their level of somatic hypermutations. Our study shows the resilience of the human immune system which restored previously expanded germlines and activated naive B cells to broaden the antibody repertoire of antibodies to control future SARS-CoV-2 variants.

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