The licensing of three vaccines in the UK and preliminary data from further vaccine candidates give reason to hope for substantial reductions of COVID-19 incidence in 2021. Uptake will depend on securing sufficient vaccine supplies, creating a robust and equitable distribution scheme, and fostering public trust in the safety of the vaccines with adequate legal safeguards to prevent and compensate for inadvertent harm. Surveys and sociological research indicate a worrying increase in vaccine hesitancy in some countries over the past decade. It is, therefore, vital to invest sufficient resources in creating conditions that maximise uptake and minimise opportunities for hesitancy. The time to do so is now. The novel technologies on which leading COVID-19 vaccine candidates are based and misinformation campaigns are already contributing to public uncertainty. Now that roll-outs have started, existing concerns will probably be exacerbated by reports of adverse effects—regardless of whether confirmed to be connected to vaccines or not—such as the (contributory) role of the Pfizer-BioNTech vaccine for allergic reactions or the (non-contributory) role in deaths among Norwegian care home residents. In 1976, fears of an imminent pandemic triggered the rapid US roll-out of a new vaccine against swine flu (H1N1). Low H1N1 mortality and adverse effect reports led to an abrupt halt of the vaccination programme and reputational damage for public health authorities. Rumours and conspiracy theories will also occur, as in 2019, when rumours about the new Ebola vaccine being unsafe led to hesitancy. The Serum Institute of India (Pune, India) is already facing the prospect of litigation based on a volunteer alleging neurological illness after receiving the Oxford-AstraZeneca vaccine.