Comprehensive profiling of humoral immune responses to pan-respiratory pathogens: Insights from diverse cohorts.

The COVID-19 pandemic profoundly disrupted respiratory pathogen circulation and reshaped population-level humoral immunity. Using a high-throughput pan-respiratory pathogen protein microarray containing 56 antigens, we profiled serum immunoglobulin G (IgG) responses in 287 individuals across pre-pandemic, COVID-19, and post-pandemic periods, as well as validated the findings in an independent cohort of 175 participants. SARS-CoV-2 exposure induced strong cross-reactivity with SARS-CoV but minimal reactivity to MERS-CoV, while variant-specific immunity progressively shifted from pre-Omicron strains toward Omicron lineages. Spike-specific IgG declined over time, whereas nucleocapsid-specific IgG remained relatively stable. Immune responses to common respiratory pathogens were also broadly reorganized, with decreases in human coronaviruses, influenza B, respiratory syncytial viruses, and human parainfluenza viruses, stable influenza A responses, and increased human metapneumovirus-specific IgG. These findings define a post-pandemic humoral immune landscape and support sustained serological surveillance to identify immunity gaps, anticipate changing infection susceptibility, and strengthen preparedness for future respiratory epidemics.