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.
Highlights
Dengue virus (DENV) is a member of the Flaviviridae family
The MTase mutant virus is immediately recognized by the host’s immune response and hardly has a chance to spread in the organism while an immune response is efficiently triggered by the initially infected cells
Mice and monkeys infected with the mutant virus developed an immune response that fully protected them from a challenge with wild-type virus
Summary
DENV infection causes dengue fever (DF) and the more severe forms of the disease, dengue hemorrhagic fever (DHF) and dengue shock syndrome (DSS). The frequency, severity, and geographical spread of cases have increased over the past decades [1,2]. Despite intensive global research efforts, no vaccine or antiviral treatment for dengue infection is available. Vaccine development is complex due to multiple factors. (ii) A sub-protective vaccine potentially increases the risk of vaccinees to develop the more severe forms of dengue during repeated infection because of a known association of pre-existing immunity with severity [3,4]. (iii) Since most infections occur in developing countries, an ideal vaccine should be affordable and fully protective [5]. A vaccine inducing a robust level of immunity ideally with only one inoculation is required
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