Vaccine effectiveness (VE) against emerging SARS-CoV-2 variants is a growing issue. The aim of this work is to evaluate the impact of the COVID-19 additional/booster dose against COVID-19-related symptoms, hospitalization, and death using surveillance data (December 2021-May 2022) from the Italian National Institute of Health (ISS). As of 18 May 2022, for people fully vaccinated with three doses, VE was 87.8% (95% confidence interval (CI): 87.6-88.0), whereas VE decreased from 71.5% (95% CI: 71.0–72.0) in those vaccinated > 120 days to 69.6% (95% CI: 68.3-70.8) within 91-120 days. Results support the importance of receiving a third dose of mRNA COVID-19 vaccine.