A similar concept has been developed for other vaccines given simultaneously with the challenge virus, resulting in a subclinical infection that allows the development of a protective humoral immune response (48), and this was detected in our studies (Fig. to the ANDV nucleocapsidprotein in nearly all animals, suggested largely sterile immunity. The vaccine was able to generate high levels of neutralizing anti-ANDV GN/GC antibodies, which seem to play a role as a mechanism of vaccine protection. Administration of the vaccine at 7 or 3 days before challenge also resulted in full protection but with no specific neutralizing humoral immune response, suggesting a possible role of innate responses in protection against challenge virus replication. Administration of MKI67 the vaccine 24 h postchallenge was successful in protecting 90% of hamsters and again AOH1160 suggested the induction of a potent antiviral state by the recombinant vector as a potential mechanism. Overall, our data suggest the potential for the use of the VSV platform as a fast-acting and effective prophylaxis/postexposure treatment against lethal hantavirus infections. INTRODUCTION Hantaviruses are enveloped viruses containing a trisegmented, negative-sense, single-stranded RNA genome that are members of the family (46, 63). Hantaviruses are a closely related group of mostly rodent borne viruses that are roughly AOH1160 divided by their geographical locations and rodent hosts. Old World hantaviruses are found throughout Asia and Europe and cause a disease characterized by vascular leakage and renal involvement known as hemorrhagic fever with renal syndrome (HFRS). More than 200,000 cases of HFRS requiring hospitalization are documented annually, with lethality rates ranging from 0.1% to 15% (41, 66). New World hantaviruses were discovered in the Americas in 1993 (31, 47, 52). These hantaviruses were found to cause a vascular leakage syndrome characterized by massive pulmonary edema, followed by a shock syndrome known as hantavirus pulmonary syndrome (HPS) or hantavirus cardiopulmonary syndrome (HCPS). HPS occurs throughout North and South America at a much lower incidence than HFRS, although lethality rates can range as high as 30 to 50% (29, 30, 41). Transmission of the AOH1160 virus to humans usually occurs through the inhalation of infectious materials found in the urine, feces, and saliva of infected animals (6, 30, 46). In addition, for at least one South American hantavirus, Andes virus (ANDV), there is evidence of human-to-human transmission (11, 34, 43, 50, 70). ANDV is carried primarily by (long-tailed pygmy rice rat) and was first identified in a series of HPS outbreaks in Argentina and Chile in 1995 (36, 38). A lethal-disease model for HPS involving ANDV-infected Syrian hamsters was described in 2001 (26). To date, this ANDV hamster model remains the only small-animal model for the study of hantavirus disease, where the disease course closely mimics what is seen in human cases with regard to disease progression and pathology (5, 26). A limited number of different postexposure treatment modalities and potential vaccine candidates have been evaluated for efficacy in the treatment or prevention of HPS disease (41, 62). Ribavirin appears to be an effective treatment for HFRS; however, its use in the treatment of HPS is not well documented (45, 59, 71). Vaccination approaches have been focused primarily on HFRS-causing hantaviruses and have used exclusively nonlethal infection models that do not exhibit disease manifestations similar to those in humans (23, 29, 30, 41). In the Syrian hamster ANDV HPS model, two strategies have been successful. First, passive immune transfer with serum derived from DNA-vaccinated nonhuman primates or rabbits using a vector expressing the ANDV glycoprotein precursor (GPC) protected hamsters against lethal ANDV challenge (10, 24); however, direct immunization of the hamsters with the DNA vaccine did not afford protection. Second, recombinant human adenovirus 5 (Ad5)-based vaccines expressing either an ANDV glycoprotein (GN or GC) or the nucleocapsid (N) protein protected hamsters from lethal ANDV infection following a single immunization (60). In this study, BALB/c mice immunized with the Ad vectors developed a fairly robust CD8+ cytotoxic lymphocyte response, although CD8+ responses in hamsters were not monitored, due to a lack of available reagents. Neutralizing antibody titers in the hamsters were low. The results of these two different immune strategies suggest that the exact role that humoral and cellular immunity plays in protection remains unclear. The aim of this study was.
