Humoral Immune Response to Breakthrough Infection With SARS‐CoV‐2 Delta and Omicron Variants

ABSTRACT Background Coronavirus disease 2019 (COVID‐19), caused by severe acute respiratory syndrome coronavirus 2 (SARS‐CoV‐2), continues to impose a significant global health burden. Limited data exist regarding antibody responses to breakthrough infections caused by the Delta and Omicron variants of SARS‐CoV‐2. This study aimed to compare antibody levels and their relationships with clinical features in patients with breakthrough infections. Methods Sera from patients with breakthrough infections were analyzed for IgG, IgM, IgA, and neutralizing antibodies (NAbs) using a fully automated chemiluminescence immunoassay analyzer. Antibody levels were then compared and correlated with clinical features. Results Booster COVID‐19 vaccination was associated with higher levels of NAb and IgG in breakthrough‐infected individuals ( β = 0.51, 95% confidence interval [CI]: 0.12–0.90, and β = 0.84, 95% CI: 0.35–1.33, respectively). Individuals infected with the Delta variant exhibited higher IgM and IgA levels compared with those infected with the Omicron variant ( β = 0.80, 95% CI: 0.46–1.14, and β = 0.55, 95% CI: 0.13–0.98, respectively). The SARS‐CoV‐2 RNA clearance time was negatively correlated with NAb and IgG levels in Delta infections (correlation coefficient r s = −0.31 and −0.26, respectively) and Omicron infections ( r s = −0.29 and −0.32, respectively). Conclusions Patients with breakthrough infections of the Delta variant exhibited higher IgM and IgA levels than those with breakthrough infections of the Omicron variant. Elevated NAb and IgG levels, associated with booster COVID‐19 vaccination, correlated with shorter SARS‐CoV‐2 RNA clearance times. These findings underscore the enhanced immunogenicity of booster vaccination in mitigating the duration of viral RNA positivity.