Emerging Challenges and Advances in Porcine Circovirus: A Decade in Review.

Over the past decade, porcine circoviruses (PCVs) have continued to pose a significant threat to global swine health, and pivotal discoveries have significantly reshaped our understanding of their biology and control. Extensive genomic surveillance has expanded porcine circovirus 2 (PCV2) genotyping from four to at least eight lineages, with PCV2d now globally dominant under vaccine-driven selection pressure. Since 2016, three novel species, PCV3, PCV4, and PCV5, have been identified, linked to reproductive failure, myocarditis, multisystemic inflammation, and potential neuroinvasion; however, their pathogenic potential remains under active investigation. Recent studies have revealed that PCVs evade host defenses by targeting the cyclic GMP-AMP synthase (cGAS)-stimulator of interferon genes (STING)-type I interferon (IFN-I) pathway and modulating regulated cell death pathways, thereby fostering viral persistence and immune dysregulation. PCV-induced immunosuppression not only exacerbates bacterial and viral coinfections but also impairs vaccine efficacy, leading to complex clinical outcomes. Advances in structural virology have clarified the roles of the Cap protein, identifying key antigenic loops and posttranslational modifications that influence immunogenicity and vaccine escape. This knowledge has accelerated the development of novel diagnostic assays and next-generation vaccines. Furthermore, vaccine innovation has progressed beyond traditional inactivated formulations to recombinant subunit, virus-like particle, and DNA platforms, some of which incorporate modular or multivalent designs to address genotype diversity and coinfection scenarios. Despite these advances, challenges persist, including the continuous emergence of immune-escape variants, inconsistent vaccine performance under field conditions, and an incomplete understanding of the pathogenicity of PCV3 to PCV5. Therefore, multidisciplinary strategies integrating molecular epidemiology, structural vaccinology, and advanced biotechnologies will be critical to closing current knowledge gaps and ensuring sustainable PCV control.