question: Vaccine breakthrough SARS-CoV-2 infection was monitored in 3694 healthcare workers receiving 2 doses of BNT162b2. SARS-CoV2 infection was detected in 33 subjects, with a 3-months cumulative incidence of 0.90% and 0.42% in SARS-CoV-2-naive and experienced subjects, respectively. Vaccine protection was 87% in naive and 94% in experienced subjects when compared with a pre-vaccination control group. The infection was mildly symptomatic in 16 (48%) and asymptomatic in 17 (52%) subjects. Virus isolation was positive in 7/13 (54%) symptomatic and 4/8 (50%) asymptomatic subjects tested, and B.1.1.7 lineage was detected in all subjects. Antibody and T-cell responses were not reduced in subjects with breakthrough infection. Evidence of virus transmission, determined by contact tracing, was observed in two (6.1%) cases. This real-world data confirm the protective effect of the BNT162b2 vaccine. A triple antigenic exposure, as occurring in experienced subjects, may confer higher protection. Virus transmission from vaccinated subjects is infrequent.