Immune Serum Produced by DNA Vaccination Protects Hamsters against Lethal Respiratory Challenge with Andes Virus

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...

Human pathogenic hantaviruses and prevention of infection

“…[50][51][52][53] Finally, passive immunization of Syrian hamsters with neutralizing antibodies against ANDV-encoded Gn and Gc that were produced in other species (macaques, rabbits) confers protective immunity against lethal challenge with ANDV. 11,45,51,54 Collectively, these data support the concept that strong induction of neutralizing antibodies against envelope glycoproteins represents a prime goal in hantavirus vaccine development.…”

“…found a protective effect of anti-ANDV sera even as late as 5 days after virus infection. 11 On the basis of these findings, one can speculate about the future establishment ©2 0 1 1 L a n d e s B i o s c i e n c e .…”

“…In addition, direct transmission through bites seems to be important for the circulation of the virus in rodent populations in nature. Moreover, the capability to induce lethal ANDV infection of Syrian hamsters by intragastric administration 11 allows to speculate that transmission…”

Puumala Hantavirus Excretion Kinetics in Bank Voles (Myodes glareolus)

“…Ingestion could occur when several bank voles share a common food source. Hooper et al have recently shown that Andes hantavirus is infectious to hamsters when administered by intragastric injection and speculate that ingestion of contaminated material might be a mode of transmission to humans (18). We have shown that intranasal inoculation of saliva, urine, or feces enables subsequent detection of viral RNA in all types of excretions, which indicates that virions excreted by different routes do not show restricted tropism for particular tissues.…”

Vesicular Stomatitis Virus-Based Vaccine Protects Hamsters against Lethal Challenge with Andes Virus

“…The hantavirus glycoproteins are typically thought to be the principal targets of neutralizing antibodies (1,8,39,51), and although a few potential vaccine candidates have been evaluated with various degrees of success, largely in infection rather than disease models (2,7,10,21,24,25,35,56,60,72,73), the mechanism of protection against hantavirus infections remain unidentified. Here we constructed an attenuated, replication-competent recombinant VSV expressing the ANDV GPC in order to investigate its efficacy as a hantavirus vaccine in the Syrian hamster HPS disease model and to gain further insight into the mechanism of protection against lethal ANDV infection.…”