The most lethal hantaviruses, including Andes virus (ANDV) and Sin Nombre virus (SNV), are those that cause hantavirus pulmonary syndrome (HPS). HPS is highly pathogenic in men and women of any age with a case-fatality rate of 30-40% even in modern intensive care units. Progression of the disease from first symptoms to respiratory distress and shock can be rapid. Reported person-to-person transmission during ANDV infection makes this virus especially dangerous. Strikingly, there are no drugs or vaccines licensed for the treatment or prevention of HPS anywhere in the world. Moreover, there are no HPS vaccines in advanced development anywhere in the world. We have developed a candidate HPS vaccine. The vaccine is a DNA vaccine consisting of two plasmids that encode the surface glycoproteins of ANDV and SNV. In proof-of-concept studies, we demonstrated that these DNA vaccines, delivered alone or in combination, elicit high-titer neutralizing antibodies and confer protection in animals. Much of our preliminary data has involved delivering the DNA vaccines using either a gene gun, or muscle electroporation. Recently, we tested delivery of the SNV DNA vaccine using the PharmaJet needle-free jet injection device. High-titer neutralizing antibodies were elicited in rabbits after a single boost. This finding is important because the PharmaJet device is relatively inexpensive and already is 510(k)-cleared by the FDA for injection of vaccines. Here, we propose to 1) test the HPS DNA vaccine delivered using the PharmaJet needle-free device for immunogenicity (neutralizing antibodies) in nonhuman primates, 2) manufacture HPS DNA vaccine plasmids as cGMP DNA, 3) conduct GLP preclinical toxicology testing of the HPS DNA vaccine, and 4) refine our HPS animal model for future use in 'Animal Rule'[21 CFR 601.90] efficacy testing. Our HPS animal model involves adult Syrian hamsters infected with ANDV. HPS in ANDV-infected hamsters closely resembles HPS in humans including: incubation time, rapid onset/progression, target tissue (endothelium), pulmonary edema, pleural effusion, and shock. When completed, this research will have advanced a lead-candidate HPS vaccine, delivered by needle-free technology, to a point where it will be ready for Phase 1 clinical testing. At the same time, an existing animal model of HPS would be refined and standardized for use in licensure strategies involving the 'Animal Rule.'

Public Health Relevance

Since1993 when it was first discovered in the Four Corners region of the United States, hantavirus pulmonary syndrome (HPS) has afflicted more than 2,500 persons in more than 10 countries. HPS, caused by hantaviruses (an NIAID Category A Priority Pathogen), has one of the highest case-fatality rates of any acute viral disease (30-40%). There are no vaccines or specific therapeutic drugs to prevent or treat HPS. The proposed project will advance an HPS vaccine through preclinical development and, at the same time, advance an animal model of lethal HPS for use in pivotal efficacy studies for licensure of the HPS vaccine under the 'Animal Rule.'

National Institute of Health (NIH)
National Institute of Allergy and Infectious Diseases (NIAID)
Research Project (R01)
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Special Emphasis Panel (ZAI1-RGK-M (J2))
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Cassetti, Cristina
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Geneva Foundation
United States
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Vergote, Valentijn; Laenen, Lies; Vanmechelen, Bert et al. (2017) A lethal disease model for New World hantaviruses using immunosuppressed Syrian hamsters. PLoS Negl Trop Dis 11:e0006042
Hammerbeck, Christopher D; Brocato, Rebecca L; Bell, Todd M et al. (2016) Depletion of Alveolar Macrophages Does Not Prevent Hantavirus Disease Pathogenesis in Golden Syrian Hamsters. J Virol 90:6200-6215
Kwilas, Steve; Kishimori, Jennifer M; Josleyn, Matthew et al. (2014) A hantavirus pulmonary syndrome (HPS) DNA vaccine delivered using a spring-powered jet injector elicits a potent neutralizing antibody response in rabbits and nonhuman primates. Curr Gene Ther 14:200-10
Brocato, Rebecca L; Hammerbeck, Christopher D; Bell, Todd M et al. (2014) A lethal disease model for hantavirus pulmonary syndrome in immunosuppressed Syrian hamsters infected with Sin Nombre virus. J Virol 88:811-9
Hooper, Jay W; Josleyn, Matthew; Ballantyne, John et al. (2013) A novel Sin Nombre virus DNA vaccine and its inclusion in a candidate pan-hantavirus vaccine against hantavirus pulmonary syndrome (HPS) and hemorrhagic fever with renal syndrome (HFRS). Vaccine 31:4314-21