REVIEW Rabies vaccine development by expression of recombinant viral glycoprotein Renato Mancini Astray 1 • Soraia Attie Calil Jorge 1 • Carlos Augusto Pereira 1 Received: 8 June 2016 / Accepted: 24 October 2016 / Published online: 31 October 2016 Ó Springer-Verlag Wien 2016 Abstract The rabies virus envelope glycoprotein (RVGP) is the main antigen of rabies virus and is the only viral component present in all new rabies vaccines being pro- posed. Many approaches have been taken since DNA recombinant technology became available to express an immunogenic recombinant rabies virus glycoprotein (rRVGP). These attempts are reviewed here, and the rele- vant results are discussed with respect to the general characteristics of the rRVGP, the expression system used, the expression levels achieved, the similarity of the rRVGP to the native glycoprotein, and the immunogenicity of the vaccine preparation. The most recent studies of rabies vaccine development have concentrated on in vivo expression of rRVGP by viral vector transduction, serving as the biotechnological basis for a new generation of rabies vaccines. The rabies vaccine and the rabies virus glycoprotein (RVGP) Rabies is one of the most fatal diseases caused by viral infection in humans. With few exceptions, humans that develop symptoms of rabies virus infection inevitably die. Like other members of the genus Lyssavirus, family Rhabdoviridae, rabies virus is a negative sense, single- strand RNA virus carrying five proteins: a nucleoprotein, a phosphoprotein, a matrix protein, an envelope glycoprotein (RVGP) and a viral polymerase [1] (Fig. 1). The structure of the glycoprotein of vesicular stomatitis virus, a well- studied member of the family Rhabdoviridae, has recently been determined [2, 3]. Since then, considerable insight has been gained into rhabdovirus structure [4] and virus entry mechanisms [5]. Nevertheless, due to essential differences in the immune mechanisms involved in infections by dif- ferent rhabdoviruses, studies related to rabies vaccine development need to involve the RVGP directly. Classical rabies vaccines consist of whole inactivated viruses, that have the same antigenic characteristics as wild type viruses. Immunization with whole inactivated virus has been shown to induce virus-neutralizing antibodies directed against RVGP, activation of helper and cytotoxic T cells and protection against lethal intracerebral challenge with rabies virus [6, 7]. The main reason that further research toward a new rabies vaccine candidate is needed is the high cost of producing rabies vaccine in rabies-virus- infected cell culture [8, 9]. In some developing countries with high incidence of rabies, it is necessary to have a less expensive vaccine, allowing preventive immunization, preferentially after a single dose [10, 11]. Other important reasons include the risks of production and administration of the current whole inactivated virus vaccine and the logistic concerns of a multi-vaccination schedule for pre- and, particularly, post-exposure vaccination [12, 13]. The RVGP is the only antigen able to confer full pro- tection against rabies [14] and is the only component pre- sent in all new rabies vaccines that have been proposed [10]. When properly folded and glycosylated [15, 16], the RVGP molecule (Fig. 1B and C) is fully immunogenic, bearing epitopes for humoral and cell-mediated immune responses [6, 7, 17–19]. It has been shown that RVGP is an important determinant for the induction of innate immune responses and different pathogenic mechanisms induced by different rabies virus strains [20]. & Carlos Augusto Pereira carlos.pereira@butantan.gov.br 1 Laborato ´rio de Imunologia Viral, Instituto Butantan, Sa ˜o Paulo, Brazil 123 Arch Virol (2017) 162:323–332 DOI 10.1007/s00705-016-3128-9