Yellow fever virus (YFV) was at one time endemic in the United States and represents a mosquito-borne emerging/re-emerging human pathogen that causes up to 20% mortality. The current live attenuated YFV vaccine was developed in 1936 and following the development of a virus seed lot system, it has not been modified or otherwise improved in over 50 years. According to the CDC, this vaccine causes 47 severe adverse events (defined as resulting in hospitalization, long-term disability, or death) per million vaccinations. More recent reports indicate that vaccine-associated neurological disease occurs at an approximate rate of 1 case per 10,000 vaccinations. YFV vaccination of infants <9 months of age has been contraindicated since the 1960's due to high rates of vaccine-associated encephalitis in this age group. The overall (all ages) mortality rate following YFV vaccination is estimated at 1 to 2 deaths per million doses. More recently, YFV vaccination has been found to cause severe viscerotropic disease in a substantial number of patients >60 years of age (an incidence rate of approximately 1:50,000 doses administered) and these cases result in approximately 50% mortality. This indicates that YFV vaccination is not only contraindicated in infants, but is also not recommended in the elderly due to the increased risk of severe and life-threatening disease. Increased monitoring efforts have also documented several cases of vaccine-related fatalities in young, otherwise healthy adults with no known pre-existing immune deficiencies. There is currently no alternative to live YFV vaccination. In this proposal, we will prepare an inactivated YFV vaccine under GMP conditions and perform the necessary safety, potency, and stability studies required for a future IND submission to the FDA. This vaccine is based on proprietary new technology used to develop inactivated vaccine formulations that can be used to immunize vulnerable populations such as infants and the elderly, in addition to other healthy populations. Preliminary data is provided demonstrating that an H2O2-YFV vaccine is feasible to manufacture, highly immunogenic, and provides full protective immunity against lethal viscerotropic yellow fever. In this project, we will prepare clinical grade vaccine under cGMP conditions, perform in vitro and in vivo safety/toxicity tests, and determine vaccine potency and long-term stability. The successful completion of these objectives will result in cGMP-grade vaccine material suitable for future initiation of a Phase I clinical trial.

Public Health Relevance

In this Phase II proposal, we provide strong preliminary data from our Phase I application demonstrating the antigenicity, immunogenicity, and protective efficacy of a proprietary new vaccine platform that can be used to develop a safer and highly effective YFV vaccine.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Small Business Innovation Research Grants (SBIR) - Phase II (R44)
Project #
5R44AI079898-05
Application #
8402575
Study Section
Special Emphasis Panel (ZRG1-IMM-G (12))
Program Officer
Repik, Patricia M
Project Start
2008-07-01
Project End
2014-12-31
Budget Start
2013-01-01
Budget End
2014-12-31
Support Year
5
Fiscal Year
2013
Total Cost
$994,154
Indirect Cost
Name
Najit Technologies, Inc.
Department
Type
DUNS #
147965243
City
Beaverton
State
OR
Country
United States
Zip Code
97006
Slifka, Mark K; Amanna, Ian (2014) How advances in immunology provide insight into improving vaccine efficacy. Vaccine 32:2948-57
Engelmann, Flora; Josset, Laurence; Girke, Thomas et al. (2014) Pathophysiologic and transcriptomic analyses of viscerotropic yellow fever in a rhesus macaque model. PLoS Negl Trop Dis 8:e3295
Amanna, Ian J; Slifka, Mark K (2014) Current trends in West Nile virus vaccine development. Expert Rev Vaccines 13:589-608
Slifka, Mark K; Hammarlund, Erika; Lewis, Matthew W et al. (2013) Antiviral immune response after live yellow fever vaccination of a kidney transplant recipient treated with IVIG. Transplantation 95:e59-61
Stein, David A; Perry, Stuart T; Buck, Michael D et al. (2011) Inhibition of dengue virus infections in cell cultures and in AG129 mice by a small interfering RNA targeting a highly conserved sequence. J Virol 85:10154-66
Judkowski, Valeria; Bunying, Alcinette; Ge, Feng et al. (2011) GM-CSF production allows the identification of immunoprevalent antigens recognized by human CD4+ T cells following smallpox vaccination. PLoS One 6:e24091
Amanna, Ian J; Slifka, Mark K (2011) Contributions of humoral and cellular immunity to vaccine-induced protection in humans. Virology 411:206-15