Abstract / Summary
Introduction Viral RNA clearance following mild SARS-CoV-2 infection varies considerably among individuals, but the early humoral immune features underlying this heterogeneity remain incompletely understood. Methods We investigated whether the kinetics and functional maturation of the antibody response were associated with viral RNA clearance in a longitudinal study of 78 healthcare professionals infected with the ancestral Wuhan SARS-CoV-2 strain and followed for up to three years. Participants were stratified according to viral RNA clearance kinetics as nonpersistent (≤21 days) or persistent (>21 days). Humoral responses were longitudinally characterized by seroconversion kinetics, antibody isotypes and IgG subclasses, affinity, cross-variant recognition, and neutralizing activity. Results Nonpersistent individuals exhibited accelerated seroconversion to Spike and receptor-binding domain antigens within the first 11 days after symptom onset, accompanied by significantly greater neutralizing activity against the ancestral strain. In contrast, persistent individuals displayed delayed seroconversion, prolonged IgM responses, and reduced coordination among IgG subclasses during acute infection, consistent with delayed early humoral maturation. Total immunoglobulin levels did not distinguish the groups, whereas cross-variant antibody recognition during acute infection remained limited and predominantly strain-focused in both groups. During convalescence, durable anti-Spike IgG responses were maintained independently of persistence status, without significant differences in cross-variant breadth. Vaccination robustly enhanced antibody titers, variant recognition, and ACE2-blocking responses in both groups. Discussion Accelerated functional maturation of the early anti-Spike antibody response, rather than overall antibody magnitude, was associated with efficient SARS-CoV-2 RNA clearance. These findings identify early functional maturation of the humoral response as an immunological correlate of efficient viral clearance and provide mechanistic insight into the immune processes underlying heterogeneous SARS-CoV-2 RNA clearance during mild infection.