Background: We analyzed coronavirus disease 2019 (COVID-19) vaccine efficacy in older persons who received the second booster compared to unvaccinated people and those receiving only a single COVID-19 vaccine booster. Methods: We collected information on vaccine efficacy from the ongoing Italian nationwide COVID-19 vaccination campaign in subjects aged 80 years or older from official data published by the Italian National Institute of Health. Results: The second vaccine booster maintained high effectiveness against adverse COVID-19 outcomes such as hospitalization, intensive care unit admission and death (i.e., between 77 and 86%), and also showed around 10% higher efficacy than the single booster. Nonetheless, the efficacy of the second vaccine booster declined over time, decreasing by 33–46% when assessed at >120 days from administration. Conclusions: The results of our ad interim analysis of the ongoing Italian nationwide COVID-19 vaccination campaign suggest that regular boosting with COVID-19 vaccines may be advisable in older persons.