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      Rational Design of a Live Attenuated Dengue Vaccine: 2′- O-Methyltransferase Mutants Are Highly Attenuated and Immunogenic in Mice and Macaques


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          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.

          Author Summary

          The four serotypes of dengue virus cause severe outbreaks globally in tropical countries with thousands of patients requiring hospitalization. The health care and indirect economic cost of dengue in endemic countries is huge. Despite this, no clinically approved vaccine or antiviral treatment is currently available. Dengue transmission could be stopped with a vaccine that provides full protection to all serotypes. Dengue afflicts many developing countries and a vaccine should therefore be cost-effective and should provide protection with ideally a single injection. Here we present a novel dengue vaccine approach that harbours mutation(s) in the 2′- O-methyltransferase (MTase), a viral enzyme that methylates viral RNA as a strategy to escape the host immune response. Non-methylated RNA is recognized as “foreign” and triggers an interferon response in the cell. 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. Furthermore, we show that MTase mutant dengue virus cannot infect Aedes mosquitoes. Collectively, the results suggest 2′- O-MTase mutant dengue virus as a safe, highly immunogenic vaccine approach.

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          Most cited references64

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          The Sequence Alignment/Map format and SAMtools

          Summary: The Sequence Alignment/Map (SAM) format is a generic alignment format for storing read alignments against reference sequences, supporting short and long reads (up to 128 Mbp) produced by different sequencing platforms. It is flexible in style, compact in size, efficient in random access and is the format in which alignments from the 1000 Genomes Project are released. SAMtools implements various utilities for post-processing alignments in the SAM format, such as indexing, variant caller and alignment viewer, and thus provides universal tools for processing read alignments. Availability: http://samtools.sourceforge.net Contact: rd@sanger.ac.uk
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            Fast gapped-read alignment with Bowtie 2.

            As the rate of sequencing increases, greater throughput is demanded from read aligners. The full-text minute index is often used to make alignment very fast and memory-efficient, but the approach is ill-suited to finding longer, gapped alignments. Bowtie 2 combines the strengths of the full-text minute index with the flexibility and speed of hardware-accelerated dynamic programming algorithms to achieve a combination of high speed, sensitivity and accuracy.
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              The global emergence/resurgence of arboviral diseases as public health problems.

              During the past 20 years there has been a dramatic resurgence or emergence of epidemic arboviral diseases affecting both humans and domestic animals. These epidemics have been caused primarily by viruses thought to be under control such as dengue, Japanese encephalitis, yellow fever, and Venezuelan equine encephalitis, or viruses that have expanded their geographic distribution such as West Nile and Rift Valley fever. Several of these viruses are presented as case studies to illustrate the changing epidemiology. The factors responsible for the dramatic resurgence of arboviral diseases in the waning years of the 20th century are discussed, as is the need for rebuilding the public health infrastructure to deal with epidemic vector-borne diseases in the 21st century.

                Author and article information

                Role: Editor
                PLoS Pathog
                PLoS Pathog
                PLoS Pathogens
                Public Library of Science (San Francisco, USA )
                August 2013
                August 2013
                1 August 2013
                : 9
                : 8
                : e1003521
                [1 ]Singapore Immunology Network, Agency for Science, Technology and Research, Singapore
                [2 ]Novartis Institute for Tropical Diseases, Singapore
                [3 ]State Key Laboratory of Pathogen and Biosecurity, Beijing Institute of Microbiology and Epidemiology, Beijing, China
                [4 ]State Key Laboratory of Virology, Wuhan Institute of Virology, Chinese Academy of Sciences, Wuhan, China
                [5 ]Duke Graduate Medical School, Singapore
                [6 ]Wadsworth Center, New York State Department of Health, Albany, New York, United States of America
                University of Washington, United States of America
                Author notes

                We have read the journal's policy and have the following conflicts: HD, DC and PYS are currently or have been under the employment of Novartis, which provided funds and equipment to conduct the studies and where they receive salary, benefits and stock. This does not alter our adherence to all PLoS Pathogens policies on sharing data and materials.

                Conceived and designed the experiments: PYS KF CFQ RZ. Performed the experiments: KF RZ HD XFL DCC BZ TB YXT TJ SHL YQD BRE EME. Analyzed the data: PYS KF CFQ RZ HD BRE FZ MP. Wrote the paper: KF RZ PYS CFQ.


                This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.

                : 8 October 2012
                : 10 June 2013
                Page count
                Pages: 13
                KF's group was supported by the Agency for Science, Technology and Research, Singapore. BZ's group was supported by the National Basic Research Program of China (2012CB518904) and the National Natural Science Foundation of China (31170158). CFQ's group was supported by the National Basic Research Program of China (2012CB518904) and the National Natural Science Foundation of China (31270974). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.
                Research Article
                Clinical Immunology
                Infectious Diseases

                Infectious disease & Microbiology
                Infectious disease & Microbiology


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