Characterization of a candidate tetravalent vaccine based on 2'-O-methyltransferase mutants

Dengue virus (DENV) is one of the most widespread arboviruses. The four DENV serotypes infect about 400 million people every year, causing 96 million clinical dengue cases, of which approximately 500'000 are severe and potentially life-threatening. The only licensed vaccine has a limited effica...

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Bibliographic Details
Published in:PloS one 2018-01, Vol.13 (1), p.e0189262
Main Authors: Züst, Roland, Li, Shi-Hua, Xie, Xuping, Velumani, Sumathy, Chng, Melissa, Toh, Ying-Xiu, Zou, Jing, Dong, Hongping, Shan, Chao, Pang, Jassia, Qin, Cheng-Feng, Newell, Evan W, Shi, Pei-Yong, Fink, Katja
Format: Article
Language:English
Subjects:
Animals
Antibodies, Neutralizing - analysis
Antibodies, Neutralizing - immunology
Attenuation
Biochemistry
Biology and Life Sciences
Blood & organ donations
Cell Line
Dengue
Dengue fever
Dengue Vaccines - immunology
Dengue virus
Dengue Virus - immunology
Disease
Enzyme-Linked Immunosorbent Assay
Epidemiology
Female
Gene mutation
Humans
Immunogenicity
Immunology
Infections
Interferon
Laboratory animals
Licenses
Macaca fascicularis
Male
Medicine and Health Sciences
Methyltransferase
Methyltransferases
Methyltransferases - genetics
Mice
Molecular biology
Mutagenesis
Mutants
Mutation
Pathogens
Proteins
Research and Analysis Methods
RNA polymerase
Serotypes
Tropical diseases
Vaccines
Vector-borne diseases
Viral vaccines
Viruses
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Summary:Dengue virus (DENV) is one of the most widespread arboviruses. The four DENV serotypes infect about 400 million people every year, causing 96 million clinical dengue cases, of which approximately 500'000 are severe and potentially life-threatening. The only licensed vaccine has a limited efficacy and is only recommended in regions with high endemicity. We previously reported that 2'-O-methyltransferase mutations in DENV-1 and DENV-2 block their capacity to inhibit type I IFNs and render the viruses attenuated in vivo, making them amenable as vaccine strains; here we apply this strategy to all four DENV serotypes to generate a tetravalent, non-chimeric live-attenuated dengue vaccine. 2'-O-methyltransferase mutants of all four serotypes are highly sensitive to type I IFN inhibition in human cells. The tetravalent formulation is attenuated and immunogenic in mice and cynomolgus macaques and elicits a response that protects from virus challenge. These results show the potential of 2'-O-methyltransferase mutant viruses as a safe, tetravalent, non-chimeric dengue vaccine.
ISSN:1932-6203
1932-6203
DOI:10.1371/journal.pone.0189262