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 recently 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, including 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 highly 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 immunogenicity 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, long-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 Relevance: 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 potential 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.
Project Terms: 0-6 weeks old; Aedes; Aedes (genus); Aerosols; Affect; Africa; Alpha Virus; Alphavirus; Americas; Appearance; Arboviruses, Group A; Arthralgia; Asia; Attenuated; Biological; Biotechnology; Breakbone Fever Virus; Cells; Chikungunya virus; Chronic; Clinical Trials; Clinical Trials, Unspecified; Collaborations; Communicable Diseases, Emerging; Complementary DNA; Country; Culicidae; Cultured Cells; DNA, Complementary; Dengue; Dengue Fever; Dengue Virus; Destinations; Development; Disease; Disease Outbreaks; Disorder; Drug Formulations; EEE Virus; Eastern Equine Encephalitis Virus; Egypt 101 virus; Emerging Communicable Diseases; Encephalitis Virus, Eastern Equine; Encephalomyelitis Virus, Eastern Equine; Epidemic; Europe; European; Exanthem; Exanthema; Fever; Formulation; Formulations, Drug; Gamma Globulin, 7S; Genes; Genetic; Genetic Alteration; Genetic Change; Genetic defect; Goals; Human; Human, General; Hyperthermia; IgA; IgG; Immune response; Immunodeficient Mouse; Immunoglobulin A; Immunoglobulin G; Inbred ICR Mice; Indian Ocean; Infant, Newborn; Infectious Diseases, Emerging; Institution; Island; Italy; Joint Pain; Laboratory Infection; Licensing; Macaca mulatta; Mammals, Mice; Man (Taxonomy); Man, Modern; Measures; Mediating; Medical; Mice; Mice, Inbred ICR; Modeling; Mortality; Mortality Vital Statistics; Mosquitoes; Mouse Strains; Mouse, ICR; Movement; Murine; Mus; Mutation; NIAID; National Institute of Allergy and Infectious Disease; Newborn Infant; Newborns; Outbreaks; PROV; Pathogenicity; Persons; Preclinical Testing; Predisposition; Preparation; Preparedness; Principal Investigator; Programs (PT); Programs [Publication Type]; Province; Public Health; Pyrexia; Rash; Readiness; Recombinants; Reporting; Rhesus; Rhesus Macaque; Rhesus Monkey; Rodent Model; Route; SCID; SCID Mice; Safety; Science of Virology; Severe Combined Immunodeficient Mice; Shipping; Ships; Site; Skin Rash; Speed; Speed (motion); Spinal Column; Spine; Structural Protein; Susceptibility; Testing; Texas; Toxicity Testing; Toxicity Tests; Transmission; Universities; Vaccine Design; Vaccine Research; Vaccines; Vero Cells; Vertebral column; Viremia; Virology; Virulence; Virulent; Virus; Viruses, General; WNV; West Nile; West Nile virus; Wisconsin; arboviral disease; arbovirus disease; attenuation; backbone; biodefense; body movement; breakbone fever; cDNA; chikungunya; clinical Diagnosis; clinical investigation; cost; design; designing; disease/disorder; effective therapy; efficacy testing; febrile; febris; genome mutation; host response; human disease; immunogenic; immunogenicity; immunoresponse; improved; mouse model; mutant; neurovirulence; new vaccines; newborn human (0-6 weeks); next generation vaccines; non-human primate; nonhuman primate; novel; novel vaccines; pathogen; prevent; preventing; programs; public health medicine (field); response; severe combined immune deficiency; success; transmission process; vaccine candidate; vaccine development; vector mosquito; viraemia; viral sepsis; virusemia; weapons
