Construction and biological characterization of artificial recombinants between a wild type flavivirus (Kunjin) and a live chimeric flavivirus vaccine (ChimeriVax-JE).
Although the theoretical concern of genetic recombination has been raised related to the use of live attenuated flavivirus vaccines [Seligman, Gould, Lancet 2004;363:2073-5], it has little foundation [e.g., Monath TP, Kanesa-Thasan N, Guirakhoo F, Pugachev K, Almond J, Lang J, et al. Vaccine 2005;23:2956-8]. To investigate biological effects of recombination between a chimeric yellow fever (YF) 17D/Japanese encephalitis (JE) vaccine virus (ChimeriVax-JE) and a wild-type flavivirus Kunjin (KUN-cDNA), the prM-E envelope protein genes were swapped between the two viruses, resulting in new YF 17D/KUN(prM-E) and KUN/JE(prM-E) chimeras. The prM-E genes are easily exchangeable between flavivirues, and thus the exchange was expected to yield the most replication-competent chimeras, while other rationally designed recombinants would be more likely to be crippled or non-viable. The new chimeras proved highly attenuated in comparison with the KUN-cDNA parent, as judged by plaque size and growth kinetics in cell culture, low viremia in hamsters, and reduced neurovirulence/neuroinvasiveness in mice. These data provide strong experimental evidence that the potential of recombinants, should they ever emerge, to cause disease or spread (compete in nature with wild-type flaviviruses) would be indeed extremely low.
Pugachev
Konstantin V
KV
Acambis, Inc., 38 Sidney St., Cambridge, MA 02139, USA. konstantin.pugachev@acambis.com
Schwaiger
Julia
J
Brown
Nathan
N
Zhang
Zhen-xi
ZX
Catalan
John
J
Mitchell
Frederick S
FS
Ocran
Simeon W
SW
Rumyantsev
Alexander A
AA
Khromykh
Alexander A
AA
Monath
Thomas P
TP
Guirakhoo
Farshad
F
D000818:Animals; D001483:Base Sequence; D001835:Body Weight / Q000276:immunology; D002460:Cell Line; D006224:Cricetinae; D005260:Female; D005416:Flavivirus / Q000235:genetics* / Q000276:immunology* / Q000472:pathogenicity; D005818:Genetic Engineering; D016679:Genome, Viral / Q000235:genetics; D006801:Humans; D007700:Kinetics; D051379:Mice; D014613:Vaccines, Attenuated / Q000009:adverse effects / Q000235:genetics* / Q000276:immunology*; D014774:Virulence; D014779:Virus Replication; D053060:West Nile Virus Vaccines / Q000009:adverse effects / Q000235:genetics* / Q000276:immunology*
C445780:ChimeriVax; D014613:Vaccines, Attenuated; D053060:West Nile Virus Vaccines