Time-Varying Effect of Hybrid Immunity on the Risk of Breakthrough Infection after Booster Dose of mRNA COVID-19 Vaccine: The MOSAICO Study

This longitudinal observational study investigated the risk of breakthrough SARS-CoV-2 infection up to 6 months after a booster dose of an mRNA COVID-19 vaccine in infection-naïve vs. previously infected healthcare workers (HCWs), and whether this difference varied over time. A Cox proportional hazard regression model with Aalen’s additive analysis was fitted to examine the association between the risk of infections and predictor variables. Overall, we observed an incidence rate of 2.5 cases per 1000 person-days (95% confidence interval [CI] 2.0–3.0), which dropped at 0.8 per 1000 person-days (95% CI 0.3–2.0) in recipients with prior SARS-CoV-2 infection. The fitted analysis indicated an adjusted hazard ratio of 0.32 (95% CI 0.13–0.80; p-value = 0.01) for those with hybrid immunity with a slope that became steeply negative roughly starting from day 90. No difference was seen according to participants’ smoking habits. Characteristics of infected HCWs were also described. Our study quantifies the time-varying effects of vaccine-induced and hybrid immunity after the booster dose (during the Omicron variant predominance in Italy) and observed that the protection waned more rapidly in infection-naïve recipients starting from the third month. The results add important evidence that can be used to inform COVID-19 vaccination strategies.