FcγR–ACE2 Cooperative Antibody-Dependent Enhancement in Human and Veterinary Coronaviruses: Mechanisms, Comparative Immunopathology, and Therapeutic Implications

Antibody-dependent enhancement (ADE) is a paradoxical immunological phenomenon in which pre-existing antibodies facilitate viral entry into host cells rather than conferring protection. ADE has been extensively characterised in flaviviral systems, most notably dengue virus (DENV), and presents a significant challenge for vaccine development and antibody-based therapeutic design. In coronavirus infections, ADE operates through both classical Fc gamma receptor (FcγR)-mediated pathways and an intrinsic signalling mechanism involving inhibitory FcγRIIb-mediated suppression of the type I interferon (IFN-I) response. Of critical translational relevance is the proposed cooperative FcγR–angiotensin-converting enzyme 2 (ACE2) entry model for SARS-CoV-2, wherein virus–antibody immune complexes simultaneously engage ACE2 through the viral spike receptor-binding domain (RBD) and FcγRIIa through the antibody Fc region on the same macrophage surface. This cooperative dual-receptor engagement may stabilise virion attachment, augment endosomal uptake, and trigger downstream signalling cascades that suppress antiviral immunity, potentially contributing to severe COVID-19 immunopathology. Feline infectious peritonitis virus (FIPV) represents one of the most rigorously documented biological systems in which antibody-mediated macrophage infection directly determines systemic disease outcome, providing a critical comparative framework for understanding coronavirus ADE across species. This comprehensive review integrates current knowledge of FcγR biology, coronavirus cell entry mechanisms, intracellular signalling cascades, cytokine dysregulation, comparative veterinary immunopathology, and nano-engineered immunomodulatory platforms for ADE-safe vaccine development. We critically evaluate lipid nanoparticle mRNA vaccines, virus-like particles, and polymeric nanoparticle systems as rational strategies to elicit selective neutralising antibody responses while mitigating ADE risk. We also highlight key unresolved mechanistic questions and future research directions essential for the development of safer vaccines and therapeutics against both current and emerging coronaviruses in human and veterinary medicine.