Please use this identifier to cite or link to this item: https://doi.org/10.1371/journal.ppat.1003521
Title: Rational Design of a Live Attenuated Dengue Vaccine: 2?-O-Methyltransferase Mutants Are Highly Attenuated and Immunogenic in Mice and Macaques
Authors: Züst R.
Dong H.
Li X.-F.
Chang D.C.
Zhang B.
Balakrishnan T.
Toh Y.-X.
Jiang T.
Li S.-H.
Deng Y.-Q.
Ellis B.R.
Ellis E.M.
Poidinger M. 
Zolezzi F.
Qin C.-F.
Shi P.-Y. 
Fink K.
Keywords: 2 O methyltransferase
dengue vaccine
immunoglobulin G
interferon
neutralizing antibody
unclassified drug
virus envelope protein
virus enzyme
virus RNA
dengue vaccine
interferon
live vaccine
methyltransferase
RNA 2'-O-methyltransferase
adaptive immunity
animal experiment
animal model
animal tissue
antibody dependent enhancement
article
CD8+ T lymphocyte
cell strain BHK
cell strain HEK293
controlled study
dengue
Dengue virus 1
Dengue virus 2
enzyme linked immunosorbent assay
female
flow cytometry
human
human cell
immunofluorescence
innate immunity
male
methylation
mosquito
mouse
nonhuman
reverse transcription polymerase chain reaction
rhesus monkey
seroconversion
viremia
virus isolation
virus mutant
virus neutralization
virus transmission
animal
dengue
Dengue virus
enzymology
genetics
hamster
HEK293 cell line
immunology
mutant mouse strain
mutation
Animals
Cricetinae
Dengue
Dengue Vaccines
Dengue Virus
HEK293 Cells
Humans
Interferon Type I
Macaca mulatta
Methyltransferases
Mice
Mice, Mutant Strains
Mutation
Vaccines, Attenuated
Issue Date: 2013
Citation: Züst R., Dong H., Li X.-F., Chang D.C., Zhang B., Balakrishnan T., Toh Y.-X., Jiang T., Li S.-H., Deng Y.-Q., Ellis B.R., Ellis E.M., Poidinger M., Zolezzi F., Qin C.-F., Shi P.-Y., Fink K. (2013). Rational Design of a Live Attenuated Dengue Vaccine: 2?-O-Methyltransferase Mutants Are Highly Attenuated and Immunogenic in Mice and Macaques. PLoS Pathogens 9 (8) : e1003521. ScholarBank@NUS Repository. https://doi.org/10.1371/journal.ppat.1003521
Abstract: 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. © 2013 Züst et al.
Source Title: PLoS Pathogens
URI: https://scholarbank.nus.edu.sg/handle/10635/161619
ISSN: 15537366
DOI: 10.1371/journal.ppat.1003521
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