Long-term persistence of humoral immunity after SARS-CoV-2 mRNA booster vaccination in SARS-CoV-2-naïve individuals

Background Humoral immunity wanes following SARS-CoV-2 mRNA vaccination. However, frequent breakthrough infections following the emergence of the Omicron variant make it difficult to evaluate long-term antibody decline attributable solely to vaccination. This study addresses this gap by characterizing long-term antibody waning after booster vaccination in SARS-CoV-2-naïve individuals. Methods SARS-CoV-2 spike protein-specific IgG (S-IgG) titers in the Keio University Healthcare Worker Vaccination Cohort have been monitored since February 2021. Using serial measurements of stored serum samples, we identified SARS-CoV-2-naïve participants who had received at least three doses of mRNA vaccine and had not received any additional vaccination for ≥2 years. Absence of previous SARS-CoV-2 infection was confirmed by serial questionnaires and persistently negative nucleocapsid protein-specific IgG (N-IgG). Temporal waning of S-IgG after the final vaccination was modeled using one-compartment, two-compartment, and bi-exponential decay models. Predictive performance of the models was compared using the leave-one-out information criterion. Results 19 individuals (11 with three doses, 7 with four doses, and 1 with five doses) met the selection criteria. S-IgG waning after the final vaccination was best described by the two-compartment model, with an initial phase of relatively rapid decline followed by a second phase with a substantially smaller decay slope. Conclusions Long-term waning of S-IgG following mRNA booster vaccination is best characterized by a two-compartment model. These findings provide a framework for evaluating long-term binding antibody kinetics after booster vaccination and may facilitate the evaluation of current and future mRNA vaccines.