Development of protective immunity against African swine fever depends on host-environment interactions

African swine fever virus (ASFV) is a major threat for pig health and meat production in many countries. The development and commercialization of vaccine candidates are complicated by efficacy and safety concerns. Improved vaccine design requires further studies to identify factors that regulate immune responses to vaccines leading to protective immunity against a virulent challenge. Our findings suggest that reduced prior immune exposure to other pathogens and/or of the microbiome composition of specific pathogen free (SPF) pigs promotes resilience to infection with a moderately virulent strain such as Estonia 2014, and importantly promotes the development of a strong protective immune response against a second challenge with a virulent ASFV strain.