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Fort Collins, CO, United States

Agency: Department of Health and Human Services | Branch: | Program: SBIR | Phase: Phase I | Award Amount: 410.92K | Year: 2008

DESCRIPTION (provided by applicant): Chikungunya virus (CHIKV), an emerging, mosquito-borne alphavirus and potential biological weapon that has caused debilitating and often chronic arthralgia in at least 2 million persons during the past 2 years, was rece ntly placed on the NIAID list of priority pathogens as a recognition of its emergence potential. Due to difficulties with clinical diagnosis, CHIKV is grossly underreported and probably causes far more disease than is recognized in Africa and Asia, includi ng occasional fatalities. Like dengue virus, CHIKV uses humans as amplifying hosts and therefore can disseminate readily in travelers, suggesting that it will eventually become established the Americas. There are no licensed vaccines or effective therapies , and the only vaccine strain tested in humans is reactogenic. We will capitalize on our recent successes with chimeric alphaviruses to develop novel CHIKV vaccine candidates that are superior to traditionally derived, cell culture-passaged mutants. Using genetic backbones derived from 3 relatively avirulent alphavirus strains, and structural protein genes from CHIKV, we will generate and optimize chimeric cDNA clones to produce candidate vaccine strains that replicate efficiently in Vero cells, and are hig hly attenuated yet rapidly immunogenic and efficacious in preventing CHIK disease. Several vaccine candidates will be evaluated for attenuation and efficacy in a murine model, and the most promising strains will then be tested extensively in mice for immun ogenicity and efficacy in preventing disease, viremia and mortality. Vaccine constructs with the best efficacy will be evaluated for safety using neurovirulence and SCID mice testing. Vaccine formulations will be identified to optimize thermal stability, l ong-term storage and ease of distribution. The resulting product will dramatically improve U.S. preparedness for this important emerging virus, as well as provide the first effective vaccine for an important emerging infectious disease. PUBLIC HEALTH RELEV ANCE: Chikungunya virus (CHIKV) is a mosquito-borne alphavirus that has emerged on islands off the east cost of Africa, spread to the Indian subcontinent and recently to Italy, affecting over 2 million persons during the past 2 years. CHIKV is also a poten tial biological weapon and was recently added to the NIAID priority pathogen biodefense list. A safe, effective chimeric Chikungunya vaccine would improve public health worldwide and would be an important asset to our biodefense portfolio.

Agency: Department of Health and Human Services | Branch: | Program: SBIR | Phase: Phase I | Award Amount: 599.97K | Year: 2009

DESCRIPTION (provided by applicant): Dengue (DEN) is the most important arthropod-borne viral infection of humans with about 100 million cases and 25,000 deaths annually, threatening over 3.5 billion people worldwide. The dengue viruses cause dengue fever (DF), dengue hemorrhagic fever (DHF), and dengue shock syndrome (DSS), and are endemic throughout the world's subtropical and tropical regions. To date, there is no effective vaccine to prevent against DF and no drug treatment for the disease. Dengue infection is caused by one of four different RNA viruses: dengue type 1 (DEN-1), DEN-2, DEN-3 and DEN-4. For a dengue vaccine to be safe and effective, it must be capable of neutralizing all four of the dengue viruses. Inviragen's tetravalent DEN vaccine (DENVax) consists of the live attenuated DEN-2 PDK-53 virus and three chimeras expressing the structural genes (prM and E) from DEN-1, DEN-3 and DEN-4, and retaining the genetic alterations responsible for the safety of the original DEN-2 vaccine. We have demonstrated the safety and efficacy of DENVax in AG129 mice and monkeys. In these studies we have identified tetravalent formulations that induce neutralizing antibodies to all four DENV serotypes. However, the responses to DENVax-4 were limited by interference from the other, more robust chimeras. In this proposal, we will test the hypothesis that the immune responses to the DENVax-4 vaccine construct can be further optimized through genetic manipulation of the DENVax-4 infectious clone. We propose to design and characterize a new chimeric DEN2/4 vaccine, and test the safety and efficacy of this vaccine in mice and monkeys. This proposal uniquely utilizes resources, facilities and reagents available at Inviragen Inc, CDC, and the University of Wisconsin-Madison. The development of an effective dengue vaccine represents an important approach to the prevention and control of this global emerging disease. Inviragen's long term goal is to develop a safe and effective dengue vaccine. PUBLIC HEALTH RELEVANCE: Dengue virus (DEN), a mosquito-borne RNA virus, is the most important arthropod-borne viral infection of humans with about 100 million cases and 25,000 deaths annually. We are developing a safe and effective tetravalent dengue vaccine that will protect against all four dengue serotypes. Such a vaccine would protect U.S. travelers from dengue infection, and significantly improve global public health as dengue threatens over 3.5 billion people worldwide.

Agency: Department of Health and Human Services | Branch: | Program: SBIR | Phase: Phase II | Award Amount: 2.86M | Year: 2009

DESCRIPTION (provided by applicant): The threat of terrorist attacks using biological weapons continues to be a major national security issue. A new congressional report (www.preventwmd.gov, Dec 3, 2008) indicates that a terrorist attack with bioweapons or other weapons of mass destruction might occur before 2013. Plague and smallpox could be devastating bioweapons if intentionally released. A release of 50 kg of Y. pestis over a city of 5 million people could result in as many as 150,000 clinical cases and 36,000 deaths. At this time, no human vaccines are available for plague and the current smallpox vaccine has significant side effects. Our long-term goal is to develop a highly safe and efficacious poxvirus-based vaccine that provides protection against aerosol exposure to Y. pestis and also against smallpox. As part of a phase 1-funded SBIR, we have optimized expression of Y. pestis antigens in the poxvirus vector, modified vaccinia virus Ankara (MVA) and evaluated the efficacy and safety profile of several recombinant MVA-based plague vaccines. As a result of these studies, we have selected for further development a recombinant MVA virus expressing a novel form of the Y. pestis V antigen (MVA/V). We propose here to manufacture GMP-quality vaccine seeds and conduct preclinical studies required for FDA approval under the Animal Rule (21 CFR, 314.600) and required to initiate human clinical trials. Our specific aims are: 1) develop master seed virus stocks for the MVA/V vaccine virus, 2) optimize the efficacy of MVA/V vaccine in mice, 3) determine the efficacy of a MVA/Vin two non-human primate species, 4) test for any toxicity of the MVA/V vaccine, and 5) develop quality control and release tests for GMP manufacturing of MVA/V. This project involves productive collaborations between a small business (Inviragen), research institutions (University of Wisconsin, Colorado State University), and government agencies (United States Army Medical Research Institute of Infectious Diseases, USGS National Wildlife Health Center). Inviragen's extensive experience with the manufacture, preclinical testing and regulatory submissions for recombinant viral vaccines will speed the progress of this needed product from the bench to the clinic. PUBLIC HEALTH RELEVANCE: Plague has caused severe epidemics in many parts of the world, resulting in human deaths and significant economic losses and could be a devastating bioweapon. The release of smallpox is a deadly bioterrorist threat given that much of the population is now unvaccinated. A safe, easily stored and easily administered combination vaccine that simultaneously protects against both plague and smallpox would improve the security and safety of military, first responder personnel and civilian populations worldwide.

Embodiments herein relate to compositions of and methods for live attenuated alphaviruses. In certain embodiments, a live, attenuated virus composition includes, but is not limited to, one or more live, attenuated alphaviruses and compositions to reduce inactivation and/or degradation of the live, attenuated alphavirus. In other embodiments, the live, attenuated virus composition may be a vaccine composition. In yet other compositions, a live, attenuated alphavirus composition may include HEPES buffer. In other embodiments, the HEPES buffer may further include a carbohydrate and gelatin and/or a salt.

The Government Of The United States Of America As Represented By The Secretary Of Health & Human S and Inviragen | Date: 2013-11-08

Embodiments herein report compositions, methods and uses for dengue-4 (DENV-4) virus constructs. Some embodiments concern a composition that includes, but is not limited to, DENV-4 virus constructs alone or in combination with other constructs, can be used in a vaccine composition to induce an immune response in a subject. In certain embodiments, compositions can include constructs of more than one serotypes of dengue virus, such as dengue-1 virus, dengue-2 virus, or dengue-3 virus in combination with DENV-4 virus constructs disclosed herein. In other embodiments, DENV-4 constructs disclosed herein can be combined in a composition with other flavivirus constructs to generate a vaccine against more than one flavivirus. Other embodiments provide methods and uses for DENV-4 virus constructs in vaccine compositions that when administered to a subject induce an immune response in the subject against DENV-4 that is improved by modified constructs compared to other vaccine compositions.

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