Long-term Humoral Immune Dynamics After SARS-CoV-2 Vaccination and Infection in Healthcare Workers: The VaCoMRI Study

ObjectivesThe VaCoMRI study tracked a healthcare worker cohort from 2020 through June 2024 to characterize the long-term sustainability of vaccine- and infection-induced SARS-CoV-2 immunity. MethodsFollowing an initial anti-nucleocapsid (N) IgG screening of 4,554 employees in early 2020, participants were monitored regularly from the BNT162b2 rollout (December 2020). Serum collected at predefined intervals after vaccination and breakthrough infection (BTI) was analyzed for anti-N, quantitative anti-spike (anti-S) IgG, and surrogate viral neutralizing antibody (sVNT) titers. ResultsOver a median follow-up of 1,180 days, 142 healthcare workers contributed longitudinal samples; 66.2% experienced one BTI and 14.1% a second. In previously seronegative individuals, anti-N titers decreased 2.3-fold between 3 and 6 months post-first BTI, with seropositivity dropping from 82% to 40.4% (median time to seronegativity: 179 days). Conversely, prior anti-N seropositivity was associated with 4.5-fold higher anti-N IgG levels during follow-up, and a second BTI led to 3-fold higher titers at 3 months. Before BTI, the third vaccine dose significantly enhanced antibody persistence versus the second dose; at 9 months, titers remained 7.2-fold higher for sVNT and 3.9-fold higher for anti-S IgG. Initial seropositivity also predicted 2.9-fold higher sVNT levels during follow-up. ConclusionsRepeated vaccination and infection synergistically induced robust, durable spike-directed hybrid immunity. Conversely, rapid anti-N IgG waning severely limits its reliability for the retrospective serosurveillance of SARS-CoV-2 exposure in occupational settings.