Rational design of a live attenuated dengue vaccine: 2'-o-methyltransferase mutants are highly attenuated and immunogenic in mice and macaques.
Dengue virus is transmitted by Aedes mosquitoes and infects at least 100 million people every year. Progressive urbanization in Asia and South-Central America and the geographic expansion of Aedes mosquito habitats have accelerated the global spread of dengue, resulting in a continuously increasing number of cases. A cost-effective, safe vaccine conferring protection with ideally a single injection could stop dengue transmission. Current vaccine candidates require several booster injections or do not provide protection against all four serotypes. Here we demonstrate that dengue virus mutants lacking 2'-O-methyltransferase activity are highly sensitive to type I IFN inhibition. The mutant viruses are attenuated in mice and rhesus monkeys and elicit a strong adaptive immune response. Monkeys immunized with a single dose of 2'-O-methyltransferase mutant virus showed 100% sero-conversion even when a dose as low as 1,000 plaque forming units was administrated. Animals were fully protected against a homologous challenge. Furthermore, mosquitoes feeding on blood containing the mutant virus were not infected, whereas those feeding on blood containing wild-type virus were infected and thus able to transmit it. These results show the potential of 2'-O-methyltransferase mutant virus as a safe, rationally designed dengue vaccine that restrains itself due to the increased susceptibility to the host's innate immune response.
Singapore Immunology Network, Agency for Science, Technology and Research, Singapore.
Roland
R
Züst
Hongping
H
Dong
Xiao-Feng
XF
Li
David C
DC
Chang
Bo
B
Zhang
Thavamalar
T
Balakrishnan
Ying-Xiu
YX
Toh
Tao
T
Jiang
Shi-Hua
SH
Li
Yong-Qiang
YQ
Deng
Brett R
BR
Ellis
Esther M
EM
Ellis
Michael
M
Poidinger
Francesca
F
Zolezzi
Cheng-Feng
CF
Qin
Pei-Yong
PY
Shi
Katja
K
Fink
D000818:Animals; D006224:Cricetinae; D003715:Dengue / Q000201:enzymology / Q000235:genetics / Q000276:immunology* / Q000517:prevention & control; D053059:Dengue Vaccines / Q000235:genetics / Q000276:immunology* / Q000494:pharmacology; D003716:Dengue Virus / Q000235:genetics / Q000276:immunology*; D057809:HEK293 Cells; D006801:Humans; D007370:Interferon Type I / Q000235:genetics / Q000276:immunology; D008253:Macaca mulatta; D008780:Methyltransferases / Q000235:genetics / Q000276:immunology*; D051379:Mice; D008817:Mice, Mutant Strains; D009154:Mutation; D014613:Vaccines, Attenuated / Q000235:genetics / Q000276:immunology / Q000494:pharmacology
D053059:Dengue Vaccines; D007370:Interferon Type I; D014613:Vaccines, Attenuated; D008780:Methyltransferases; C052744:RNA 2'-O-methyltransferase