FcγR–ACE2 Cooperative Antibody-Dependent Enhancement in Human and Veterinary Coronaviruses: Mechanistic Insights, Comparative Immunology, and Implications for Nano-Engineered Immunomodulatory Platforms

Antibody-dependent enhancement (ADE) is a paradoxical immunological phenomenon in which pre-existing antibodies facilitate viral entry into host cells rather than conferring protection [1,2]. 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 [1,3]. In coronavirus infections, ADE may operate 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 [4,5]. Of critical translational relevance is the functionally demonstrated cooperative FcγR–ACE2 entry model for SARS-CoV-2, wherein virus–antibody immune complexes engage Fcγ receptors and require ACE2 interaction for efficient enhancement [6,7]. For SARS-CoV-2 specifically, ADE magnitude appears to be determined by an antibody’s capacity to block spike–ACE2 interaction rather than its neutralisation potency in vitro—a finding distinct from FIPV and other coronavirus ADE systems where classical FcγR-mediated mechanisms predominate without ACE2 co-receptor dependency [6,7]. 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 [8,9]. This comprehensive review integrates current knowledge of FcγR biology, IgG subclass dynamics, antibody glycosylation, coronavirus cell entry mechanisms, intracellular signalling cascades, cytokine dysregulation, comparative veterinary immunopathology, and nano-engineered immunomodulatory platforms for ADE-safe vaccine development. No confirmed clinical ADE has been documented to date in mRNA-vaccinated populations, though theoretical risk windows and population-specific vulnerabilities are critically discussed [26,27].