BackgroundDespite being a major advancement in modern medicine, vaccines face widespread hesitancy and refusal, posing challenges to immunization campaigns. The COVID-19 pandemic accentuated vaccine hesitancy, emphasizing the pivotal role of beliefs in efficacy and safety on vaccine acceptance rates. This study explores the influence of efficacy and safety perceptions on vaccine uptake in Italy during the pandemic.MethodsWe administered a 70-item questionnaire to a representative sample of 600 Italian speakers. Participants were tasked with assessing the perceived effectiveness and safety of each vaccine dose, along with providing reasons influencing their vaccination choices. Additionally, we conducted an experimental manipulation, exploring the effects of four framing messages that emphasized safety and/or efficacy on participants’ willingness to receive a hypothetical fourth vaccine dose. Furthermore, participants were asked about their level of trust in the scientific community and public authorities, as well as their use of different information channels for obtaining COVID-19-related information.ResultsOur study reveals a dynamic shift in vaccine efficacy and safety perceptions throughout the COVID-19 pandemic, potentially influencing vaccination compliance. Initially perceived as more effective than safe, this assessment reversed by the time of the third dose. Beliefs regarding safety, rather than efficacy, played a significant role in anticipating future vaccinations (e.g., the booster dose). Safety-focused messages positively affected vaccination intent, while efficacy-focused messages showed limited impact. We also observed a changing trend in reasons for vaccination, with a decline in infection-related reasons and an increase in social related ones. Furthermore, trust dynamics evolved differently for public authorities and the scientific community.ConclusionsVaccine perception is a dynamic process shaped by evolving factors like efficacy and safety perceptions, trust levels, and individual motivations. Our study sheds light on the complex dynamics that underlie the perception of vaccine safety and efficacy, and their impact on willingness to vaccinate. We discuss these results in light of bounded rationality, loss aversion and classic utility theory.