Cross-protection against African swine fever virus upon intranasal vaccination is associated with an adaptive-innate immune crosstalk

African swine fever virus (ASFV) is causing a worldwide pandemic affecting the porcine industry and leading to important global economic consequences. The virus causes a highly lethal hemorrhagic disease in wild boars and domestic pigs. Lack of effective vaccines hampers the control of virus spread, thus increasing the pressure on the scientific community for urgent solutions. However, knowledge on the immune components associated with protection is very limited. Here we characterized the in vitro recall response induced by immune cells from pigs intranasally vaccinated with the BA71ΔCD2 deletion mutant virus. Vaccination conferred dose-dependent cross-protection associated with both ASFV-specific antibodies and IFNγ-secreting cells. Importantly, bulk and single-cell transcriptomics of blood and lymph node cells from vaccinated pigs revealed a positive feedback from adaptive to innate immunity. Indeed, activation of Th1 and cytotoxic T cells was concomitant with a rapid IFNγ-dependent triggering of an inflammatory response characterized by TNF-producing macrophages, as well as CXCL10-expressing lymphocytes and cross-presenting dendritic cells. Altogether, this study provides a detailed phenotypic characterization of the immune cell subsets involved in cross-protection against ASFV, and highlights key functional immune mechanisms to be considered for the development of an effective ASF vaccine. African swine fever (ASF) pandemic is currently the number one threat for the porcine industry worldwide. Lack of treatments hampers its control, and the insufficient knowledge regarding the immune effector mechanisms required for protection hinders rational vaccine design. Here we present the first comprehensive study characterizing the complex cellular immune response involved in cross-protection against ASF. We show that, upon in vitro reactivation, cells from immune pigs induce a Th1-biased recall response that in turn enhances the antiviral innate response. Our results suggest that this positive feedback regulation of innate immunity plays a key role in the early control of ASF virus infection. Altogether, this work represents a step forward in the understanding of ASF immunology and provide critical immune components that should be considered to more rationally design future ASF vaccines.