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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. [ABSTRACT FROM AUTHOR]

Highlights: [•] Using chimeric 4G2 antibody, viral production was enhanced in PBMC, KU812 and THP-1 cells. [•] A robust, FACS based method was developed for screening compounds for dengue in PBMC. [•] Using the FACS, we established the infected CD14+ cells correlated well with dengue viremia in PBMC. [•] The FACS based method was validated with a reference compound NITD008. [ABSTRACT FROM AUTHOR]