Objectives: To describe the dynamics and factors related to natural and hybrid humoral response against the SARS-CoV-2 and risk of reinfection among first-wave patients. Methods: A prospective longitudinal study with periodic serological follow-up after acute onset of all recovered patients with SARS-CoV-2 infection cared in Udine Hospital (March–May 2020). Nucleocapsid (N) protein and spike receptor-binding domain (S-RBD) antibody tests were used to distinguish natural and vaccine-induced response. Results: Overall, 153 patients (66 men, mean age 56 years) were followed for a median of 27.3 (interquartile range 26.9–27.8) months. Seroreversion was 98.5% (95% CI: 96.8–99.4) for SARS-CoV-2-N IgM at 1 year and 57.4% (95% CI: 51.5–63.5) for SARS-CoV-2-N IgG at 2 years. Initial serological response (hazard ratio [HR]: 0.99, 95% CI: 0.99–0.99, p 0.002 for IgM and HR: 0.97, 95% CI: 0.97–0.98, p < 0.001 for IgG) and severity of acute infection (HR: 0.62, 95% CI: 0.39–0.96, p 0.033 for IgM and HR: 0.60, 95% CI: 0.37–0.99, p < 0.001 for IgG) were independently associated with persistent SARS-CoV-2-N IgM/IgG response. Older age and smoker status were associated with long-term SARS-CoV-2-N IgM and SARS-CoV-2-N IgG, respectively (HR: 0.75, 95% CI: 0.57–0.98, p 0.038; HR: 1.77, 95% CI: 1.19–2.61, p 0.004 respectively). All patients maintained SARS-CoV-2-S-RBD IgG response at 24-month follow-up. Reinfections occurred in 25 of 153 (16.3%) patients, mostly during the omicron circulation. Reinfection rates did not differ significantly between SARS-CoV-2-N IgG seronegative and seropositive patients (14/89, 15.7% vs. 10/62, 16.1%, p 0.947). Unvaccinated patients had higher risk of reinfection (4/7, 57.1% vs. vaccinated 21/146, 14.4%, p 0.014). Discussion: First-wave patients had durable natural humoral immunity in 40% and anti-S-RBD response in 100% up to 2 years after infection. Natural humoral response alone was not protective against reinfections with omicron SARS-CoV-2 variants, whereas vaccination was effective to reduce the risk of a new infection.
