@article{PAR00013078,
  title = {{A}ttenuation of tick-borne encephalitis virus using large-scale random codon reencoding},
  author = {{F}abritus, {L}. de and {N}ougairede, {A}. and {A}ubry, {F}. and {G}ould, {E}. {A}. and {D}e {L}amballerie, {X}avier},
  editor = {},
  language = {{ENG}},
  abstract = {{L}arge-scale codon re-encoding (i.e. introduction of a large number of synonymous mutations) is a novel method of generating attenuated viruses. {H}ere, it was applied to the pathogenic flavivirus, tick-borne encephalitis virus ({TBEV}) which causes febrile illness and encephalitis in humans in forested regions of {E}urope and {A}sia. {U}sing an infectious clone of the {O}shima 5-10 strain ("wild-type virus"), a cassette of 1.4kb located in the {NS}5 coding region, was modified by randomly introducing 273 synonymous mutations ("re-encoded virus"). {W}hilst the in cellulo replicative fitness of the re-encoded virus was only slightly reduced, the re-encoded virus displayed an attenuated phenotype in a laboratory mouse model of non-lethal encephalitis. {F}ollowing intra-peritoneal inoculation of either 2.10(5) or 2.10(6) {TCID}50 of virus, the frequency of viraemia, neurovirulence (measured using weight loss and appearance of symptoms) and neuroinvasiveness (detection of virus in the brain) were significantly decreased when compared with the wild-type virus. {M}ice infected by wildtype or re-encoded viruses produced comparable amounts of neutralising antibodies and results of challenge experiments demonstrated that mice previously infected with the re-encoded virus were protected against subsequent infection by the wild-type virus. {T}his constitutes evidence that a mammalian species can be protected against infection by a virulent wild-type positive-stranded {RNA} virus following immunisation with a derived randomly reencoded strain. {O}ur results demonstrate that random codon re-encoding is potentially a simple and effective method of generating live-attenuated vaccine candidates against pathogenic flaviviruses.},
  keywords = {},
  booktitle = {},
  journal = {{P}los {P}athogens},
  volume = {11},
  numero = {3},
  pages = {e1004738 [18 p.]},
  ISSN = {1553-7366},
  year = {2015},
  DOI = {10.1371/journal.ppat.1004738},
  URL = {https://www.documentation.ird.fr/hor/{PAR}00013078},
}