Effective preexposure and postexposure prophylaxis of rabies with a highly attenuated recombinant rabies virus

Abstract

Rabies remains an important public health problem with more than 95% of all human rabies cases caused by exposure to rabid dogs in areas where effective, inexpensive vaccines are unavailable. Because of their ability to induce strong innate and adaptive immune responses capable of clearing the infection from the CNS after a single immunization, live-attenuated rabies virus (RV) vaccines could be particularly useful not only for the global eradication of canine rabies but also for late-stage rabies postexposure prophylaxis of humans. To overcome concerns regarding the safety of live-attenuated RV vaccines, we developed the highly attenuated triple RV G variant, SPBAANGAS-GAS-GAS. In contrast to most attenuated recombinant RVs generated thus far, SPBAANGAS-GAS-GAS is completely nonpathogenic after intracranial infection of mice that are either developmentally immunocompromised (e.g., 5-day-old mice) or have inherited deficits in immune function (e.g., antibody production or type I IFN signaling), as well as normal adult animals. In addition, SPBAANGAS-GAS-GAS induces immune mechanisms capable of containing a CNS infection with pathogenic RV, thereby preventing lethal rabies encephalopathy. The lack of pathogenicity together with excellent immunogenicity and the capacity to deliver immune effectors to CNS tissues makes SP-BAANGAS-GAS-GAS a promising vaccine candidate for both the preexposure and postexposure prophylaxis of rabies.blood-brain barrier permeability ͉ live-attenuated rabies virus vaccine ͉ postexposure treatment R abies causes an estimated 55,000 human deaths globally each year, 23,750 of which occur in Africa (1). Moreover, 11 million people undergo rabies postexposure prophylaxis (PEP) worldwide each year. Rabies is a zoonotic disease with dogs remaining the principal host in Asia, parts of America, and large parts of Africa, and rabid dogs are the cause of most human rabies cases (2). Between 30% to 60% of the victims of dog bites are children under the age of 15 (3). Inappropriate dog vaccination programs, limited access to vaccination, and postexposure treatment of individuals that have been exposed to rabid dogs are major problems in developing countries.Rabies virus (RV), a negative-stranded RNA virus of the rhabdoviridae family, has a relatively simple, modular genome that encodes 5 structural proteins: a RNA-dependent RNA polymerase (L), a nucleoprotein (N), a phosphorylated protein (P), a matrix protein (M), and an external surface glycoprotein (G). The N, P, and L together with the genomic RNA form the ribonucleoprotein complex (RNP). The main feature of rabies virus is neuroinvasiveness, which refers to its unique ability to invade the CNS from peripheral sites. Virus uptake, axonal transport, transsynaptic spread, and the rate of viral replication are key factors that determine the neuroinvasiveness of a RV (4-7). The regulation of viral replication also appears to be one of the important mechanisms contributing to RV pathogenesis. Pathogenic RV strains replicate at a lower rate than atten...

Enhancement of Blood-Brain Barrier Permeability and Reduction of Tight Junction Protein Expression Are Modulated by Chemokines/Cytokines Induced by Rabies Virus Infection

“…However, transiently increased BBB permeability has been associated with the clearance of RABV from the CNS and the prevention of rabies (13). Laboratory-attenuated and recombinant RABVs (17,18) can transiently enhance BBB permeability in a mouse model as early as day 6 after infection. On the other hand, wt RABV does not induce the enhancement of BBB permeability (6,10,13).…”

“…Enhancement of BBB permeability is important in RABV attenuation by allowing immune effectors to enter the CNS and clear RABV (6,10,14). Therefore, enhancement of BBB permeability by using a disease model (experimental autoimmune encephalomyelitis [EAE]) (15,16), as well as by administering laboratoryattenuated RABV, recombinant RABVs expressing three copies of the glycoprotein (G) (17), or immune-stimulating agents (18), resulted in clearing of wt RABV from the CNS and prevention of the development of rabies in mice.…”

Protective role of interferon against cytotoxcicity induced by rabies virus in mice

“…Rabies is a zoonotic disease caused by RNA virus from family Rhabdoviridae, genus Lyssavirus (Manning et al, 2008;Faber et al, 2009;Ogawa et al, 2009). Most human deaths from rabies occur in tropical resource *Corresponding author.…”

A New Rabies Vaccine Based on a Recombinant Orf Virus (Parapoxvirus) Expressing the Rabies Virus Glycoprotein

“…Since the recent introduction of "reverse genetics" technology (12,13), new live attenuated RABV can be designed, for instance, by gene mutations (see reference 14), duplication or triplication of the RabG gene (15,16), or simultaneous expression of inserted cytokine genes to stimulate the innate immune response (17,18). Some of them are promising candidates of rabies vaccines due to their apathogenicity and improved immunogenicity in animal models.…”