SBIR-STTR Award

Yellow fever virus (YFV) was at one time endemic in the United States and represents an emerging/re-emerging human pathogen that causes up to 20% mortality. Although YFV is typically spread by the bite of Aedes aegypti mosquitoes, it also represents a viral encephalitide with potential for use as a bioterrorism agent because; 1) clinical isolates of YFV are available and/or easily obtained during natural outbreaks, 2) YFV grows to high titers in vitro with relatively simple equipment, and 3) YFV can cause lethal encephalitis when administered by an aerosol route. 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. This vaccine causes 4 cases of encephalitis per million doses administered. The overall mortality rate following YFV vaccination is estimated at 1 to 2 deaths per million doses, indicating that this vaccine is as dangerous as the live smallpox vaccine, Dryvax. YFV vaccination of infants <9 months of age has been contraindicated since the 1960's due to the discovery of high rates of vaccine-associated encephalitis in this age group. More recently, YFV vaccination has been found to cause severe viscerotropic disease in a substantial number of patients >60 years of age (incidence rate is 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 may soon be contraindicated in the elderly as well 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. To date, there is no alternative to live YFV vaccination. In this proposal, we will use a proprietary new technology to develop an inactivated vaccine formulation that can be used to immunize vulnerable populations such as infants and elderly, in addition to other healthy populations. Our preliminary studies demonstrate that this vaccine approach is feasible and highly immunogenic. In this project, we will evaluate candidate vaccine formulations, perform scale-up development, and test in vivo efficacy against lethal YFV infection.

Public Health Relevance:
In this feasibility Phase I proposal, we provide strong preliminary data demonstrating the antigenicity, immunogenicity, and protective efficacy of a proprietary new vaccine platform that can be used to develop a safer and more effective YFV vaccine.

Thesaurus Terms:
21+ Years Old; Adjuvant; Adult; Aedes; Aedes (Genus); Aerosols; Age Group Unspecified; Age-Months; Age-Years; Aged 65 And Over; Antibodies, Viral; Antibody Formation; Antibody Production; Antibody Response; Arbovirus, Group B; Attenuated; Attenuated Live Virus Vaccine; Attenuated Vaccines; Biological Terrorism; Bioterrorism; Bite; Cessation Of Life; Clinical; Communicable Diseases; Communities; Culicidae; Data; Death; Development; Disease; Disease Outbreaks; Disorder; Dose; Drug Formulations; Elderly; Elderly, Over 65; Encephalitis; Epidemic Acute Poliomyelitis; Equipment; Filtration; Flavivirus; Formulation; Formulations, Drug; Fractionation, Filtration; Generations; H2o2; Heterogeneity, Population; Human; Human, Adult; Human, General; Hydrogen Peroxide; Hydrogen Peroxide (H2o2); Hydroperoxide; Immune; In Vitro; Inactivated Vaccines; Inactivated Virus Vaccine; Incidence; Individual; Infant; Infection; Infectious Disease Pathway; Infectious Diseases; Infectious Diseases And Manifestations; Infectious Disorder; Inflammation, Brain; Japanese B Encephalitis Virus; Japanese Encephalitis Virus; Killings; Life; Live-Attenuated Vaccine; Mammals, Mice; Man (Taxonomy); Man, Modern; Medicine; Methods; Mice; Monitor; Morbidity; Morbidity - Disease Rate; Mortality; Mortality Vital Statistics; Mosquitoes; Murine; Mus; Nigeria; Numbers; Oral; Oral Poliovirus Vaccine; Outbreaks; Palsy; Paralysed; Patients; Phase; Plant Embryos; Play; Plegia; Polio; Poliomyelitis; Poliomyelitis, Acute; Poliovirus Vaccine, Oral; Population; Population Heterogeneity; Price; Public Health; Purpose; Rate; Research Resources; Resources; Risk; Role; Route; Sabin Vaccine; Science Of Medicine; Scourge; Seeds; Smallpox; Smallpox Vaccine; Soldier; System; System, Loinc Axis 4; Technology; Testing; Tick-Borne Encephalitis Virus; Tick-Borne Encephalitis Viruses; Time; Ultracentrifugation; Uncertainty; United States; Vaccination; Vaccines; Vaccines, Attenuated; Vaccines, Inactivated; Vaccines, Killed; Variola; Viral; Viral Antibodies; Viral Inactivation; Virus; Virus Inactivation; Viruses, General; Vulnerable Populations; Who; World Health Organization; Yellow Fever; Yellow Fever Vaccine; Yellow Fever Virus Infection; Yellow Fever Virus; Zygotes, Plant; Adult Human (21+); Advanced Age; Age Group; Antibody Biosynthesis; Antiviral Antibody; Base; Biodefense; Clinical Relevance; Clinically Relevant; Design; Designing; Disease/Disorder; Diverse Populations; Doubt; Elderly Patient; Elders; Geriatric; Heterogeneous Population; Immunogenic; Immunogenicity; Immunoglobulin Biosynthesis; Improved; In Vivo; Innovate; Innovation; Innovative; Late Life; Later Life; Live Vaccine; Neurotropic; New Technology; New Vaccines; Next Generation Vaccines; Novel Vaccines; Older Adult; Older Patient; Older Person; Paralysis; Paralytic; Pathogen; Pricing; Public Health Medicine (Field); Scale Up; Seed; Senior Citizen; Small Pox; Small Pox Vaccine; Social Role; Tissue Culture; Variola Major

Yellow fever virus (YFV) was at one time endemic in the United States and represents an emerging/re-emerging human pathogen that causes up to 20% mortality. Although YFV is typically spread by the bite of Aedes aegypti mosquitoes, it also represents a viral encephalitide with potential for use as a bioterrorism agent because; 1) clinical isolates of YFV are available and/or easily obtained during natural outbreaks, 2) YFV grows to high titers in vitro with relatively simple equipment, and 3) YFV can cause lethal encephalitis when administered by an aerosol route. 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. This vaccine causes 4 cases of encephalitis per million doses administered. The overall mortality rate following YFV vaccination is estimated at 1 to 2 deaths per million doses, indicating that this vaccine is as dangerous as the live smallpox vaccine, Dryvax. YFV vaccination of infants <9 months of age has been contraindicated since the 1960's due to the discovery of high rates of vaccine-associated encephalitis in this age group. More recently, YFV vaccination has been found to cause severe viscerotropic disease in a substantial number of patients >60 years of age (incidence rate is 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 may soon be contraindicated in the elderly as well 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. To date, there is no alternative to live YFV vaccination. In this proposal, we will use a proprietary new technology to develop an inactivated vaccine formulation that can be used to immunize vulnerable populations such as infants and elderly, in addition to other healthy populations. Our preliminary studies demonstrate that this vaccine approach is feasible and highly immunogenic. In this project, we will evaluate candidate vaccine formulations, perform scale-up development, and test in vivo efficacy against lethal YFV infection.

Public Health Relevance:
In this feasibility Phase I proposal, we provide strong preliminary data demonstrating the antigenicity, immunogenicity, and protective efficacy of a proprietary new vaccine platform that can be used to develop a safer and more effective YFV vaccine.

Thesaurus Terms:
21+ Years Old; Adjuvant; Adult; Aedes; Aedes (Genus); Aerosols; Age Group Unspecified; Age-Months; Age-Years; Aged 65 And Over; Antibodies, Viral; Antibody Formation; Antibody Production; Antibody Response; Arbovirus, Group B; Attenuated; Attenuated Live Virus Vaccine; Attenuated Vaccines; Biological Terrorism; Bioterrorism; Bite; Cessation Of Life; Clinical; Communicable Diseases; Communities; Culicidae; Data; Death; Development; Disease; Disease Outbreaks; Disorder; Dose; Drug Formulations; Elderly; Elderly, Over 65; Encephalitis; Encephalitis Viruses, Japanese; Epidemic Acute Poliomyelitis; Equipment; Filtration; Flavivirus; Formulation; Formulations, Drug; Fractionation, Filtration; Generations; H2o2; Heterogeneity, Population; Human; Human, Adult; Human, General; Hydrogen Peroxide; Hydrogen Peroxide (H2o2); Hydroperoxide; Immune; In Vitro; Inactivated Vaccines; Inactivated Virus Vaccine; Incidence; Individual; Infant; Infection; Infectious Disease Pathway; Infectious Diseases; Infectious Diseases And Manifestations; Infectious Disorder; Inflammation, Brain; Japanese B Encephalitis Virus; Japanese Encephalitis Viruses; Japanese Encephalitis Virus; Japanese Encephalitis Virus Group; Killings; Life; Live-Attenuated Vaccine; Mammals, Mice; Man (Taxonomy); Man, Modern; Medicine; Methods; Mice; Monitor; Morbidity; Morbidity - Disease Rate; Mortality; Mortality Vital Statistics; Mosquitoes; Murine; Mus; Nigeria; Oral; Oral Poliovirus Vaccine; Outbreaks; Palsy; Paralysed; Patients; Phase; Plant Embryos; Play; Plegia; Polio; Poliomyelitis; Poliomyelitis, Acute; Poliovirus Vaccine, Oral; Population; Population Heterogeneity; Price; Research Resources; Resources; Risk; Role; Route; Sabin Vaccine; Science Of Medicine; Scourge; Seeds; Smallpox; Smallpox Vaccine; Soldier; System; System, Loinc Axis 4; Technology; Testing; Tick-Borne Encephalitis Virus; Tick-Borne Encephalitis Viruses; Time; Ultracentrifugation; Uncertainty; United States; Vaccination; Vaccines; Vaccines, Attenuated; Vaccines, Inactivated; Vaccines, Killed; Variola; Viral; Viral Antibodies; Viral Inactivation; Virus; Virus Inactivation; Viruses, General; Vulnerable Populations; Who; World Health Organization; Yellow Fever; Yellow Fever Vaccine; Yellow Fever Virus Infection; Yellow Fever Virus; Zygotes, Plant; Adult Human (21+); Advanced Age; Age Group; Antibody Biosynthesis; Antiviral Antibody; Base; Biodefense; Clinical Relevance; Clinically Relevant; Design; Designing; Disease/Disorder; Diverse Populations; Doubt; Elderly Patient; Elders; Geriatric; Heterogeneous Population; Immunogenic; Immunogenicity; Immunoglobulin Biosynthesis; Improved; In Vivo; Innovate; Innovation; Innovative; Late Life; Later Life; Live Vaccine; Neurotropic; New Technology; New Vaccines; Next Generation Vaccines; Novel Vaccines; Older Adult; Older Patient; Older Person; Paralysis; Paralytic; Pathogen; Pricing; Protective Efficacy; Public Health Relevance; Scale Up; Seed; Senior Citizen; Small Pox; Small Pox Vaccine; Social Role; Tissue Culture; Vaccine Candidate; Variola Major