In this paper, I argue that evidence of biological and socio-behavioural mechanisms can contribute to the management of Covid-19. I discuss two examples that show how scientists are using different forms of evidence, among which mechanistic evidence, to answer questions about the efficacy of vaccines against Covid-19 and the effectiveness of vaccination interventions in different contexts. In the first example I claim that, due to the fast pace of the pandemic, mechanistic reasoning and evidence of biological mechanisms play an important role in the study of vaccines’ efficacy and the development of new adaptations based on possible future virus mutations. In the second example, I explore the use of evidence of the socio-behavioural mechanisms influencing vaccination behaviours and I show that the World Health Organisation is promoting the collection of this type of evidence to understand whether particular vaccination interventions can fit in local contexts. Overall, this discussion supports the claim that the dominant evidence-based medicine (EBM) approach, which relies heavily on difference-making studies to assess the effectiveness of clinical and public health intervention, is inadequate and should be replaced by a new approach, EBM+, that systematically considers mechanistic studies alongside association studies.