Proteome-Wide Analysis of Antibody Responses in Asymptomatic Omicron BA.2-Infected Individuals at the Amino Acid Resolution

Humoral immunity plays a critical role in clearing SARS-CoV-2 during viral invasion. However, the proteome-wide characteristics of antibody responses in individuals infected with Omicron variant, both asymptomatic and symptomatic, remain poorly understood. We profiled the serum antibodies from 108 individuals, including healthy controls and those infected with Omicron BA.2, using a SARS-CoV-2 proteome microarray at the amino acid resolution. We constructed a landscape of B-cell epitopes across the SARS-CoV-2 proteome in symptomatic and asymptomatic individuals. Immunodominant epitopes were mainly derived from S, N, Nsp3, M, and ORF3a proteins, with some epitopes overlapping with T-cell epitopes. Using machine learning, we identified a proteomic signature capable of distinguishing asymptomatic individuals from healthy controls in both training and validation cohorts, achieving AUCs of 0.988 and 0.857, respectively. These findings provide crucial immunological insights into BA.2 infections of the Omicron and have implications for future COVID-19 diagnostics and therapeutics.