The coronavirus disease 2019 (COVID-19) vaccine story is continuously unfolding. Since our previous COVID-19 commentaries, much new information has transpired on the subject, and here we revisit this topic, which has practical implications for all stakeholders in dentistry, as well as the public. This article, on current vaccine epidemiology, provides an account of why vaccines fail in general, and the particular concerns in relation to the new Delta variant of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) and related ‘variants of concern’. Issues related to vaccine failure are fundamentally dichotomous in nature, appertaining either to the vaccine strain (type) per se, and/or the numerous endogenous factors of the vaccine recipient/vaccinee. Societal factors such as vaccine hesitancy and its impact on herd immunity appear to overarch the long-term goal of total or partial global suppression of SARS-CoV-2, and its eventual endemicity. CPD/Clinical Relevance: To describe the reasons for the failure of currently administered COVID-19 vaccines, particularly in relation to the advent of the SARS-CoV-2 ‘variants of concern’, and discuss implications for clinical dental practice.