Vaccination is a cornerstone of global public health. Although licensed vaccines are generally extremely safe, both experimental and licensed vaccines are sometimes associated with rare serious adverse events. Vaccine-enhanced disease (VED) is a type of adverse event in which disease severity is increased when a person who has received the vaccine is later infected with the relevant pathogen. VED can occur during research with experimental vaccines and/or after vaccine licensure, sometimes months or years after a person receives a vaccine. Both research ethics and public health policy should therefore address the potential for disease enhancement. Significant VED has occurred in humans with vaccines for four pathogens: measles virus, respiratory syncytial virus, Staphylococcus aureus, and dengue virus; it has also occurred in veterinary research and in animal studies of human coronavirus vaccines. Some of the immunological mechanisms involved are now well-described, but VED overall remains difficult to predict with certainty, including during public health implementation of novel vaccines. This paper summarises the four known cases in humans and explores key ethical implications. Although rare, VED has important ethical implications because it can cause serious harm, including death, and such harms can undermine vaccine confidence more generally - leading to larger public health problems. The possibility of VED remains an important challenge for current and future vaccine development and deployment. We conclude this paper by summarising approaches to the reduction of risks and uncertainties related to VED, and the promotion of public trust in vaccines.