Media Release
13 August 2013
NEW STRATEGY TO DISARM THE DENGUE VIRUS BRINGS NEW HOPE FOR A
UNIVERSAL DENGUE VACCINE
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 PlosPathogens journal, and is
also supported by Singapore STOP Dengue Translational and Clinical Research
(TCR) Programme grant1.
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 year2, 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
1
http://www.nmrc.gov.sg/content/nmrc_internet/home/grant/compgrants/tcrinfec.html
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
2
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.”
Mice immunised with the weakened MTase
mutant virus or with a placebo were
challenged with a normal dengue virus. 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 immunised with weakened MTase
mutant virus were protected and had no
virus in the blood.
Notes for editor:
The research findings described in this media release can be found in the 2 August
online issue of PlosPathogens 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#, XiaoFeng 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*
1
Singapore Immunology Network (SIgN), Agency for Science, Technology and
Research (A*STAR), 138648, 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 430071, China
5
Duke Graduate Medical School, Singapore
6
Wadsworth Center, New York State Department of Health, Albany, New York 12208,
USA.
*Corresponding Authors
Full
text
of
the
article
can
be
accessed
http://www.plospathogens.org/article/info:doi/10.1371/journal.ppat.1003521
from
AGENCY FOR SCIENCE, TECHNOLOGY AND RESEARCH (A*STAR)
For media queries and clarifications, please contact:
Dr. Sarah Chang
Corporate Communications
Agency for Science, Technology and Research
Tel: (65) 6826 6442
Email: [email protected]
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 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 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.