image: A plaque assay was used to test how much virus (visualized by the blue spots) was present in the blood of the mice. The placebo-treated mice were not protected and had virus in the blood, whereas the mice immunized with weakened MTase mutant virus were protected and had no virus in the blood. view more
Credit: A*STAR SIgN
1. A new strategy that cripples the ability of the dengue virus to escape the host immune system has been discovered by A*STAR's Singapore Immunology Network (SIgN). This breakthrough strategy opens a door of hope to what may become the world's first universal dengue vaccine candidate that can give full protection from all four serotypes of the dreadful virus. This research done in collaboration with Singapore's Novartis Institute of Tropical Diseases (NITD) and Beijing Institute of Microbiology and Epidemiology is published in the Plos Pathogens journal, and is also supported by Singapore STOP Dengue Translational and Clinical Research (TCR) Programme grant [1].
2. Early studies have shown that a sufficiently weakened virus that is still strong enough to generate protective immune response offers the best hope for an effective vaccine. However, over the years of vaccine development, scientists have learnt that the path to finding a virus of appropriate strength is fraught with challenges. This hurdle is compounded by the complexity of the dengue virus. Even though there are only four different serotypes, the fairly high rates of mutation means the virus evolve constantly, and this contributes to the great diversity of the dengue viruses circulating globally. Furthermore, in some cases, the immune response developed following infection by one of the four dengue viruses appears to increase the risk of severe dengue when the same individual is infected with any of the remaining three viruses. With nearly half the world's population at risk of dengue infection and an estimated 400 million people getting infected each year [2] , the need for a safe and long-lasting vaccine has never been greater.
3. The new strategy uncovered in this study overcomes the prevailing challenges of vaccine development by tackling the virus' ability to 'hide' from the host immune system. Dengue virus requires the enzyme called MTase (also known as 2'-O-methyltransferase) to chemically modify its genetic material to escape detection. In this study, the researchers discovered that by introducing a genetic mutation to deactivate the MTase enzyme of the virus, initial cells infected by the weakened MTase mutant virus is immediately recognised as foreign. As a result, the desired outcome of a strong protective immune response is triggered yet at the same time the mutant virus hardly has a chance to spread in the host.
4. Animal models immunised with the weakened MTase mutant virus were fully protected from a challenge with the normal dengue virus. The researchers went on to demonstrate that the MTase mutant dengue virus cannot infect Aedes mosquitoes. This means that the mutated virus is unable to replicate in the mosquito, and will not be able to spread through mosquitoes into our natural environment. Taken together, the results confirmed that MTase mutant dengue virus is potentially a safe vaccine approach for developing a universal dengue vaccine that protects from all four serotypes.
5. The team leader, Dr Katja Fink from SIgN said, "There is still no clinically approved vaccine or specific treatment available for dengue, so we are very encouraged by the positive results with this novel vaccine strategy. Our next step will be to work on a vaccine formulation that will confer full protection from all four serotypes with a single injection. If this proves to be safe in humans, it can be a major breakthrough for the dengue vaccine field."
6. Associate Professor Leo Yee Sin, Clinical Director of Communicable Diseases Centre and Institute of Infectious Disease and Epidemiology at Tan Tock Seng Hospital who heads the Singapore STOP Dengue Translational and Clinical Research (TCR) Programme said, "We are into the seventh decade of dengue vaccine development, this indeed is an exciting breakthrough that brings us a step closer to an effective vaccine."
7. Acting Executive Director of SIgN, Associate Professor Laurent Rénia said, "Dengue is a major public health problem in many of the tropical countries. We are very delighted that our collaborative efforts with colleagues in Singapore and China have made a promising step towards a cost-effective and safe dengue vaccine to combat the growing threat of dengue worldwide."
Footnote:
[1]http://www.nmrc.gov.sg/content/nmrc_internet/home/grant/compgrants/tcrinfec.html
[2] Nature, 2013 Apr 25;496(7446):504-7, "The global distribution and burden of dengue" http://www.nature.com/nature/journal/vaop/ncurrent/full/nature12060.html#access
Notes for editor:
The research findings described in this media release can be found in the 2 August online issue of Plos Pathogens under the title, "Rational design of a live attenuated dengue vaccine: 2'-O-methyltransferase mutants are highly attenuated and immunogenic in mice and macaques" by Roland Züst1#, Hongping Dong2#, Xiao-Feng Li3#, David C. Chang2, Bo Zhang4, Thavamalar Balakrishnan1, Ying-Xiu Toh1, Tao Jiang3, Shi-Hua Li3, Yong-Qiang Deng3, Brett R Ellis5, Esther M Ellis5, Michael Poidinger1, Francesca Zolezzi1, Cheng-Feng Qin3*, Pei-Yong Shi2, 6*, Katja Fink1*
1Singapore Immunology Network (SIgN), Agency for Science, Technology and Research (A*STAR), 138648, Singapore.
2Novartis Institute for Tropical Diseases, Singapore.
3State Key Laboratory of Pathogen and Biosecurity, Beijing Institute of Microbiology and Epidemiology, Beijing, China
4State Key Laboratory of Virology, Wuhan Institute of Virology, Chinese Academy of Sciences, Wuhan 430071, China
5Duke Graduate Medical School, Singapore
6Wadsworth Center, New York State Department of Health, Albany, New York 12208, USA.
*Corresponding Authors
Full text of the article can be accessed from http://www.plospathogens.org/article/info:doi/10.1371/journal.ppat.1003521
AGENCY FOR SCIENCE, TECHNOLOGY AND RESEARCH (A*STAR)
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About the Singapore Immunology Network (SIgN)
The Singapore Immunology Network (SIgN), officially inaugurated on 15 January 2008, is a research consortium under the Agency for Science, Technology and Research (A*STAR)'s Biomedical Research Council. The mandate of SIgN is to advance human immunology research and participate in international efforts to combat major health problems. Since its launch, SIgN has grown rapidly and currently includes 250 scientists from 26 different countries around the world working under 28 renowned principal investigators. At SIgN, researchers investigate immunity during infection and various inflammatory conditions including cancer and are supported by cutting edge technological research platforms and core services. Through this, SIgN aims to build a strong platform in basic human immunology research for better translation of research findings into clinical applications. SIgN also sets out to establish productive links with local and international institutions, and encourage the exchange of ideas and expertise between academic, industrial and clinical partners and thus contribute to a vibrant research environment in Singapore. For more information about SIgN, please visit http://www.sign.a-star.edu.sg.
About the Agency for Science, Technology and Research (A*STAR)
The Agency for Science, Technology and Research (A*STAR) is Singapore's lead public sector agency that fosters world-class scientific research and talent to drive economic growth and transform Singapore into a vibrant knowledge-based and innovation driven economy. In line with its mission-oriented mandate, A*STAR spearheads research and development in fields that are essential to growing Singapore's manufacturing sector and catalysing new growth industries. A*STAR supports these economic clusters by providing intellectual, human and industrial capital to its partners in industry.
A*STAR oversees 20 biomedical sciences and physical sciences and engineering research entities, located in Biopolis and Fusionopolis as well as their vicinity. These two R&D hubs, house a bustling and diverse community of local and international research scientists and engineers from A*STAR's research entities as well as a growing number of corporate laboratories. Please visit http://www.a-star.edu.sg
About STOP Dengue Programme
The 5-year STOP Dengue programme is funded by the National Medical Research Council's S$25 million Translational and Clinical Research (TCR) flagship grant. Started in December 2008, the programme aims to overcome major gaps in the treatment and management of dengue diseases through the translation of our recent research findings. The goal of STOP Dengue TCR is to target zero death from dengue infection in Singapore adults. For more information, please visit http://www.stopdengue.sg.
Journal
PLoS Pathogens