Breakthrough varicella infection: a retrospective cohort study based on large-scale real-world data in Guangxi,...

Although varicella is a vaccine-preventable disease, the number of breakthrough infection cases has been increasing in recent years. However, data remain limited regarding the dynamics of breakthrough infections, especially in relation to vaccine dosage and dosing schedules.

This retrospective study analyzed surveillance data from Guangxi, China, from 2014 to 2025. Varicella cases were derived from the China Information System for Disease Control and Prevention (CISDCP), while varicella vaccination records were extracted from the Guangxi Immunization Information System (IIS). Cumulative incidence of breakthrough varicella was estimated using the Kaplan-Meier method, and cox proportional hazards models with time-varying variables were used to evaluate factors associated with breakthrough varicella.

Of 5,755,799 varicella vaccine recipients, 70,013 (1.22%) had breakthrough infections: 63,619 (1.71%) among one-dose, 6382 (0.31%) among two-dose, and 12 (0.15%) among three-dose recipients. The cumulative breakthrough varicella rate was 0.09% at 12 months, exceeding 1.00% at 72 months, and 2.15% at 132 months. Compared with an interval of 42 days to <1 year since the last dose, the adjusted hazard ratios (aHRs) for breakthrough varicella increased progressively with longer intervals: 1.31 (95% CI: 1.22-1.40) for 12-<24 months, 1.94 (95% CI: 1.82-2.07) for 24-<36 months, and 5.01 (95% CI: 4.71-5.32) for ≥36 months (all P < 0.001). Receipt of a second dose was associated with a lower hazard than one dose (aHR = 0.29; 95% CI: 0.27-0.30; P < 0.001), after adjustment for age, sex, and calendar year.

Our study confirms waning immunity after varicella vaccination. Increasing two-dose coverage, optimizing the vaccination interval, and including the vaccine in national programs are key to reducing breakthrough infections. Prospective studies with immune monitoring are needed to assess long-term protection and the optimal dosing interval.