Recombinant sindbis/Venezuelan equine encephalitis virus is highly attenuated and immunogenic.
Venezuelan equine encephalitis virus (VEEV) is an important, naturally emerging zoonotic virus. VEEV was a significant human and equine pathogen for much of the past century, and recent outbreaks in Venezuela and Colombia (1995), with about 100,000 human cases, indicate that this virus still poses a serious public health threat. The live attenuated TC-83 vaccine strain of VEEV was developed in the 1960s using a traditional approach of serial passaging in tissue culture of the virulent Trinidad donkey (TrD) strain. This vaccine presents several problems, including adverse, sometimes severe reactions in many human vaccinees. The TC-83 strain also retains residual murine virulence and is lethal for suckling mice after intracerebral (i.c.) or subcutaneous (s.c.) inoculation. To overcome these negative effects, we developed a recombinant, chimeric Sindbis/VEE virus (SIN-83) that is more highly attenuated. The genome of this virus encoded the replicative enzymes and the cis-acting RNA elements derived from Sindbis virus (SINV), one of the least human-pathogenic alphaviruses. The structural proteins were derived from VEEV TC-83. The SIN-83 virus, which contained an additional adaptive mutation in the nsP2 gene, replicated efficiently in common cell lines and did not cause detectable disease in adult or suckling mice after either i.c. or s.c. inoculation. However, SIN-83-vaccinated mice were efficiently protected against challenge with pathogenic strains of VEEV. Our findings suggest that the use of the SINV genome as a vector for expression of structural proteins derived from more pathogenic, encephalitic alphaviruses is a promising strategy for alphavirus vaccine development.
Paessler
Slobodan
S
Center for Biodefense and Emerging Infectious Diseases, Department of Pathology, University of Texas Medical Branch, Galveston, Texas 77555-0609, USA.
Fayzulin
Rafik Z
RZ
Anishchenko
Michael
M
Greene
Ivorlyne P
IP
Weaver
Scott C
SC
Frolov
Ilya
I
D000818:Animals; D001483:Base Sequence; D002460:Cell Line; D002522:Chlorocebus aethiops; D006224:Cricetinae; D004666:Encephalitis Virus, Venezuelan Equine / Q000235:genetics* / Q000276:immunology* / Q000472:pathogenicity / Q000502:physiology; D004685:Encephalomyelitis, Venezuelan Equine / Q000276:immunology / Q000517:prevention & control; D005260:Female; D008297:Male; D051379:Mice; D008969:Molecular Sequence Data; D012313:RNA / Q000235:genetics; D012367:RNA, Viral / Q000235:genetics; D011995:Recombination, Genetic; D012845:Sindbis Virus / Q000235:genetics* / Q000276:immunology* / Q000472:pathogenicity / Q000502:physiology; D014613:Vaccines, Attenuated / Q000235:genetics; D014614:Vaccines, Synthetic / Q000235:genetics; D014709:Vero Cells; D014765:Viral Vaccines / Q000235:genetics; D014774:Virulence; D014779:Virus Replication
D012367:RNA, Viral; C039919:RNA, recombinant; D014613:Vaccines, Attenuated; D014614:Vaccines, Synthetic; D014765:Viral Vaccines; D012313:RNA