Adaptive immune responses against African swine fever

African swine fever virus (ASFV) is a large, enveloped DNA virus from the Asfarviridae family that causes a hemorrhagic disease in wild boars and domestic pigs, with mortality rates reaching up to 100%. Since the introduction of genotype II ASFV into Georgia in 2007, the virus has spread extensively across Eurasia, resulting in significant economic losses in affected regions. Currently, live attenuated vaccines (LAVs) represent the most effective tool for controlling ASFV spread. However, their widespread use is limited due to safety concerns and an incomplete understanding of the mechanisms underlying protection and pathogenicity. Therefore, a rigorous framework for evaluating the efficacy of vaccine candidates is urgently needed. In the present work, we aimed to identify innate and adaptive correlates of protection (CoPs) using a previously established model comparing specific pathogen-free (SPF) pigs to conventional (farm-raised) pigs, which differ in baseline immune status and hygienic conditions. For this purpose, two groups of animals were immunized with the attenuated Estonia 2014 strain and, after viral clearance, were challenged with the highly virulent Armenia 2008 strain. SPF pigs were more resilient to challenge, with 80% surviving without clinical signs, whereas only 40% of farm pigs survived and showed signs of disease. To define CoPs, we employed a systems immunology approach by integrating multiple immunological datasets (serum cytokines, virus-specific cellular responses, antibody levels, and transcriptional signatures) and correlating them with individual clinical outcomes following challenge. As a result, we developed a temporally resolved model that highlights the critical role of host factors in vaccine efficacy, providing a valuable framework for rational ASFV vaccine design and enabling the distinction between protective and detrimental immune responses. In parallel to that, pursuing the aim of developing a safer subunit vaccine against ASFV, we characterized B-cell antigen diversity using a whole-proteome microarray and identified novel targets for informed vaccine formulation. Several of these antigens were selected to generate virus-like particle (VLP)-based vaccine candidates, which induced robust antigen-specific antibody responses in both mice and pigs. Although they did not confer protection in pigs against a lethal genotype II ASFV strain, the data generated will be valuable for future subunit vaccine development.