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Despite its importance to counter the COVID-19 pandemic, vaccination has raised hesitation in large segments of the population. This hesitation makes it important to understand the mechanisms underlying vaccine acceptance. To this end, the study adopts the Semiotic Cultural Psychology Theory, holding that social behaviors – and therefore, vaccination acceptance – depend on the cultural meanings in terms of which people interpret the social world. The study aims at estimating the impact a) of the way people interpret the socio-institutional context of the pandemic and b) of the underlying cultural worldviews on vaccine acceptance. More particularly, the study tested the three following hypotheses. a) The meanings grounding the interpretation of the socio-institutional framework – that is, trust in institutions and political values – are an antecedent of vaccination acceptance. b) The impact of these meanings is moderated by the cultural worldviews (operationalized as symbolic universes). And c), the magnitude of the symbolic universes' moderator effect depends on the uncertainty to which the respondent is exposed. The exposure to uncertainty was estimated in terms of socioeconomic status – the lower the status, the high the exposure to uncertainty. An Italian representative sample (N = 3020) completed a questionnaire, measuring vaccination acceptance, the meanings attributed to the socio-institutional context – that is, political values and trust in institutions – and symbolic universes. The findings were consistent with the hypotheses. a) Structural equation modelling proved that vaccine acceptance was predicted by trust in institutions. b) Multigroup analysis revealed that symbolic universes moderated the correlation between trust in institutions and vaccine acceptance. And c), the moderation effect of symbolic universes proved to occur only in the segment of lower socio-economic status (i.e., the group exposed to higher uncertainty). Vaccination acceptance is not only a medical issue; it is also dependent upon the rationalization of the socio-institutional context. Implications for the promotion of vaccination acceptance are discussed. • Views of the socio-institutional context affect COVID-19 vaccine demand. • Worldviews moderate the impact of interpretations of context on COVID vaccine demand. • The moderation effect of worldviews is higher for people exposed to uncertainty. [ABSTRACT FROM AUTHOR]