Recent Advances in Rabies Virus Genomics with Special Emphasis on Immunogenic Glycoprotein Ectodomain: Structure, Evolution, and Intervention Implications

Rabies remains an invariably fatal encephalitis claiming approximately 59,000 human lives annually, with the burden concentrated in low- and middle-income countries of Asia and Africa. Prevention depends almost exclusively upon vaccination and post-exposure prophylaxis (PEP) regimens that elicit virus-neutralizing antibodies directed against the viral glycoprotein (G). This review synthesizes recent advances in rabies virus (RABV) genomics and structural virology with particular emphasis upon the G ectodomain, the sole surface-exposed viral component and the primary immunological target of protective immunity. This review examines the RABV evolution across phylogenetically distinct lyssavirus lineages, the molecular determinants of virulence and neuroinvasiveness encoded within the G gene, and structural characterization of the ectodomain by contemporary cryo-electron microscopy and crystallography. High-resolution structural studies have resolved the quaternary organization of the prefusion trimer engaged by neutralizing antibodies, indicating that the conformational stability of these epitopes is an important determinant of vaccine-induced immunity, and cryo-electron microscopy of nine antibody complexes reported in 2026 has extended the antigenic map to six sites, two of them newly defined, unusually well conserved across lyssaviruses and recognized by the most broadly cross-reactive antibodies yet described. The applied literature is then organized around the three translational uses of the protein: its diagnostic application in ectodomain-based serology and antigen detection, its therapeutic application in monoclonal antibody cocktails replacing serum-derived immunoglobulin, and its vaccinal application across inactivated, subunit, virus-like particle, vectored, and nucleic acid platforms. Ectodomain architecture therefore underpins next-generation vaccines, improved post-exposure therapeutics and diagnostics, and with them the global target of zero human deaths from dog-mediated rabies by 2030.