No abstract

Hantavirus pulmonary syndrome (HPS) is a highly pathogenic disease (40% case fatality rate) carried by rodents chronically infected with certain viruses within the genus Hantavirus of the family Bunyaviridae. The primary mode of transmission to humans is thought to be inhalation of excreta from infected rodents; however, ingestion of contaminated material and rodent bites are also possible modes of transmission. Person-to-person transmission of HPS caused by one species of hantavirus, Andes virus (ANDV), has been reported. Previously, we reported that ANDV injected intramuscularly causes a disease in Syrian hamsters that closely resembles HPS in humans. Here we tested whether ANDV was lethal in hamsters when it was administered by routes that more accurately model the most common routes of human infection, i.e., the subcutaneous, intranasal, and intragastric routes. We discovered that ANDV was lethal by all three routes. Remarkably, even at very low doses, ANDV was highly pathogenic when it was introduced by the mucosal routes (50% lethal dose [LD 50 ], ϳ100 PFU). We performed passive transfer experiments to test the capacity of neutralizing antibodies to protect against lethal intranasal challenge. The neutralizing antibodies used in these experiments were produced in rabbits vaccinated by electroporation with a previously described ANDV M gene-based DNA vaccine, pWRG/AND-M. Hamsters that were administered immune serum on days ؊1 and ؉5 relative to challenge were protected against intranasal challenge (21 LD 50 ). These findings demonstrate the utility of using the ANDV hamster model to study transmission across mucosal barriers and provide evidence that neutralizing antibodies produced by DNA vaccine technology can be used to protect against challenge by the respiratory route.Hantaviruses are rodent-borne enveloped viruses that have a trisegmented, negative-sense, single-stranded RNA genome and are members of the family Bunyaviridae (20,24, 28). Pathogenic hantaviruses found in Europe and Asia cause a vascular leak disease known as hemorrhagic fever with renal syndrome. In 1993, pathogenic hantaviruses were discovered in the Americas (reviewed in references 14 and 21). The "New World" hantaviruses cause a vascular leak syndrome characterized by massive pulmonary edema followed by shock. Hantavirus pulmonary syndrome (HPS), also known as hantavirus cardiopulmonary syndrome, is highly lethal (30 to 50% case fatality rate), and at least one of the HPS-associated hantaviruses, Andes virus (ANDV), can spread from person to person (7,19,25,27).ANDV is the only pathogenic hantavirus for which there is an animal model that closely resembles human disease. When ANDV is injected into Syrian hamsters, the animals develop a disease that closely mimics human HPS (12). Similarities include the incubation time, rapid disease onset, infected endothelial cells, pulmonary edema, pleural effusion, thrombocytopenia, neutrophilia, and shock (4,12). This model has been used to test candidate medical countermeasures to prevent and t...

Naturally occurring smallpox was eradicated as a result of successful vaccination campaigns during the 1960s and 70s. Because of its highly contagious nature and high mortality rate, smallpox has significant potential as a biological weapon. Unfortunately, the current vaccine for orthopoxviruses is contraindicated for large portions of the population. Thus, there is a need for new, safe, and effective orthopoxvirus vaccines. Alphavirus replicon vectors, derived from strains of Venezuelan equine encephalitis virus, are being used to develop alternatives to the current smallpox vaccine. Here, we demonstrated that virus-like replicon particles (VRP) expressing the vaccinia virus A33R, B5R, A27L, and L1R genes elicited protective immunity in mice comparable to vaccination with livevaccinia virus. Furthermore, cynomolgus macaques vaccinated with a combination of the four poxvirus VRPs (4pox-VRP) developed antibody responses to each antigen. These antibody responses were able to neutralize and inhibit the spread of both vaccinia virus and monkeypox virus. Macaques vaccinated with 4pox-VRP, flu HA VRP (negative control), or live-vaccinia virus (positive control) were challenged intravenously with 5 × 10 6 PFU of monkeypox virus 1 month after the second VRP vaccination. Four of the six negative control animals succumbed to monkeypox and the remaining two animals demonstrated either severe or grave disease. Importantly, all 10 macaques vaccinated with the 4pox-VRP vaccine survived without developing severe disease. These findings revealed that a single-boost VRP smallpox vaccine shows promise as a safe alternative to the currently licensed live-vaccinia virus smallpox vaccine.