Despite progress in clinical care for patients with coronavirus disease 2019 (COVID-19) 1, population-wide interventions are still crucial to manage the pandemic, which has been aggravated by the emergence of new, highly transmissible variants . In this study, we combined the SIDARTHE model2, which predicts the spread of SARS-CoV-2 infections, with a new data-based model that projects new cases onto casualties and healthcare system costs . Based on the Italian case study, we outline several scenarios: mass vaccination campaigns with different paces, different transmission rates due to new variants and different enforced countermeasures, including the alternation of opening and closure phases . Our results demonstrate that non-pharmaceutical interventions (NPIs) have a higher effect on the epidemic evolution than vaccination alone, advocating for the need to keep NPIs in place during the first phase of the vaccination campaign . Our model predicts that, from April 2021 to January 2022, in a scenario with no vaccine rollout and weak NPIs ([ Formula: see text] = 1.27), as many as 298,000 deaths associated with COVID-19 could occur . However, fast vaccination rollouts could reduce mortality to as few as 51,000 deaths . Implementation of restrictive NPIs ([ Formula: see text] = 0.9) could reduce COVID-19 deaths to 30,000 without vaccinating the population and to 18,000 with a fast rollout of vaccines . We also show that, if intermittent open-close strategies are adopted, implementing a closing phase first could reduce deaths (from 47,000 to 27,000 with slow vaccine rollout) and healthcare system costs, without substantive aggravation of socioeconomic losses.