Immune pressure and paratope plasticity in antibody viral spike glycoprotein interactions

Abstract

SARS-CoV-2, an RNA virus within the sarbecovirus subgenus, is now the fifth endemic human coronavirus, having transitioned from zoonotic spillover and pandemic emergence to sustained global circulation. Unlike viruses that cause self-limited outbreaks, SARS-CoV-2 now produces waves of reinfection driven by waning population-level immunity in the face of ongoing antigenic drift. As SARS-CoV-2 continues to evolve, it has evaded vaccine-elicited humoral responses and the protection of clinically deployed monoclonal antibodies, highlighting the need to define mechanisms of resilient antibody-mediated neutralization in emerging viruses. Viral entry in sarbecoviruses such as SARS-CoV-2 is mediated by the trimeric spike glycoprotein, and specifically by the receptor-binding domain (RBD), which engages the cellular receptor, angiotensin-converting enzyme 2 (ACE2) through a highly variable receptor-binding motif (RBM). Our work combines structural and molecular approaches to characterize the function of a broadly neutralizing monoclonal antibody, ABBV-1403, and applies B-cell sequencing and serum proteomics to study time-resolved polyclonal humoral responses following breakthrough infection. ABBV-1403 potently neutralizes variants spanning six years of SARS-CoV-2 evolution and cross-neutralizes antigenically distinct ACE2–utilizing sarbecoviruses. Structural analysis of antibody–RBD complexes with multiple SARS-CoV-2 variants shows that ABBV-1403 engages the receptor-binding motif through a uniquely flexible hydrophobic paratope, enabling resilience to viral evolution and sarbecovirus diversity despite targeting a highly polymorphic epitope. To understand how the human antibody response is remodeled in individuals with repeated exposures to variants of SARS-CoV-2, we performed longitudinal profiling of individuals with SARS-CoV-2 breakthrough infection by Omicron sublineages EG.5 and XBB.1, which circulated in 2023–2024. We identified multiple antibody lineages contributing to the circulating antibody pool in serum and mucosa, characterizing dynamics in clonal abundance over the course of infection. Our work defines structural features associated with antibody resilience to antigenic drift and proposes new approaches for the selection and engineering of monoclonal antibody therapeutics with sustained activity against evolving viruses.