NEA looking at biological control methods to curb dengue

By Amanda Lee, TODAY, 16 Jun 2014

For the first time, the National Environment Agency (NEA) is considering the use of biological control methods to limit the spread of dengue, by infecting male Aedes mosquitoes with a type of bacteria that results in females producing eggs that do not hatch.

The NEA’s Environmental Health Institute (EHI) has tested the use of the Wolbachia bacteria in the laboratory, but not in the field. A panel of experts has been set up and will convene in August to look into whether the use of the technology — which has been around since the ’60s and is being tested in Vietnam, Indonesia and Australia — is safe.

There was a record 22,170 dengue cases last year. About 7,000 cases have been reported this year, with the traditional peak period — June to October — only beginning.

Announcing the NEA’s plans at the launch of the Do The Mozzie Wipeout campaign yesterday, Second Minister for the Environment and Water Resources, Ms Grace Fu, said the Government had found the Wolbachia method to be interesting and probably applicable. “We are not under any pressure, of course. We want to fight dengue as quickly as we can, but we also want to make sure the study is thorough and safe,” she added.

Wolbachia technology involves infecting Aedes mosquitoes with Wolbachia — a naturally-occurring bacterium found in more than 60 per cent of insect species. When a male Aedes mosquito carrying Wolbachia mates with a female, the eggs produced do not hatch. The aim is to reduce the Aedes population to a level where dengue transmission cannot be sustained.

While the number of dengue cases so far this year is about 25 per cent below that of the same period last year, Ms Fu said this was still too high.

The Dengue Expert Advisory Panel consists of local and foreign experts and is led by epidemiologist and entomologist Professor Duane Gubler, founding director of the Emerging Infectious Diseases Programme at Duke-NUS Graduate Medical School.

Commenting on the Wolbachia method, Prof Gubler said in an email: “The main advantage of this and the other new methods in the pipeline is that they will control the mosquitoes that are breeding in hidden larval habitats that cannot be controlled by current methods.”

Lab studies by the EHI have shown that mosquitoes carrying Wolbachia have lower transmission potential for all dengue serotypes, as well as for the chikungunya virus. Preliminary data has also shown that male Aedes mosquitoes carrying Wolbachia can compete with wild males for female attention.

However, Monash University Dean of Science Scott O’ Neill said although the technology was powerful, releasing only male mosquitoes with the bacteria is not the most effective. Releasing both males and females infected with the bacteria would greatly reduce the ability of resident mosquitoes to transmit dengue between people, he said. He also noted that the approach Singapore was considering could be costly, as it will require continual releases of male mosquitoes to control the wild mosquito population.

Prof Gubler said other new technologies for tackling dengue could become available in the next three to five years. “These include new insecticides, genetically-modified mosquitoes (sterile male release), vaccines, antiviral drugs and therapeutic antibodies. None will likely be totally effective when used in isolation, but all show great promise if used in an integrated and synergistic programme,” he said.

Meanwhile, Ms Fu said the NEA had conducted more than 1.5 million inspections this year and would continue to focus on areas that have higher potential for dengue transmission. As of June 9, the NEA has issued 373 notices to attend court and 34 stop-work orders. There were 16 court prosecutions involving eight contractors.

Next in the war against dengue: Bacteria v virus
Introducing bug into Aedes could render mosquito less virulent
By Salma Khalik, The Sunday Times, 22 Jun 2014

Singapore is mulling over using the Wolbachia bacteria to help wipe out dengue-spreading mosquitoes.

Despite intensive efforts ranging from destroying mosquitoes to eliminating breeding areas, the nation faces a serious dengue problem.

So far this year, more than 7,700 people have come down with the viral infection, with almost one in five needing to be hospitalised, while last year saw the highest number of dengue cases to date.

So, any additional arsenal in fighting the disease should be welcome.

Wolbachia is a bacterium found naturally in many insects - though not the Aedes mosquito, the main dengue carrier.

Professor Duane Gubler, an epidemiologist from Duke-NUS Graduate Medical School who is on the newly appointed Dengue Expert Advisory Panel, sees only benefits in such an experiment.

"All available data suggest the strain of Wolbachia to be introduced will not alter Aedes aegypti genetically, and in fact is not sustainable in the population without continued introduction," he said.

The panel will advise Singapore on the best method of introducing Wolbachia to mosquitoes here.

Wolbachia - introduced into laboratory mosquitoes for the first time about eight years ago - appeared to work miracles.

In females, it either shortens their lives so they die before they can start infecting people with dengue; or blocks the virus from multiplying in their bodies - and from transmitting the disease when they next bite a victim.

In males, it makes them sterile, but still strong and capable of beating their natural peers in mating with female mosquitoes, leaving them to lay eggs that never hatch.

Laboratory and controlled field experiments also appear promising.

But tinkering with the genetic make-up of mosquitoes - or anything for that matter - can have serious consequences, and evolution has a tendency to undermine Man's efforts at thwarting it.

Because the history of Wolbachia in Aedes mosquitoes is less than a decade old, there is no long-term data available.

So many questions remain and, if things go wrong, the dengue situation in Singapore could well end up becoming worse, because none of the Wolbachia interventions is totally foolproof, say experts.

Method 1: Wolbachia is put into male mosquitoes to make them sterile.

What happens if a tiny fraction of male mosquitoes with the bacteria remain potent? Nothing to worry about if they produce normal offspring. But if their progeny turn out to be even more virile, could it actually increase the mosquito population?

Method 2: The bacteria are introduced to female mosquitoes - as it is the females that spread the virus.

What if the virus evolves to overcome the bacteria's ability to stop it from multiplying and spreading? Will it become stronger and more virulent? Evolution could even produce a new strain of the virus to add to the four current ones.

Method 3: Wolbachia is used to shorten the lives of mosquitoes so they do not live long enough to spread the disease.

What if the mosquitoes evolve so that their full life-cycle is crammed into a shorter lifespan?

Even worse, the mosquitoes could evolve to transmit the dengue virus from mother to baby, rather than just getting it after biting an infected person. That would mean a new generation of mosquitoes born with the virus and able to spread it from the first bite.

These negative outcomes might be unlikely, but are not impossible.

Faced with extinction, a species' fight for survival can be fierce.

A paper, Wolbachia Versus Dengue, published at the end of last year in the journal Evolution, Medicine and Public Health noted: "In any regime that kills entire populations, there is intense selection for escape."

The authors, Dr James Bull, professor in molecular biology at the University of Texas, and geneticist Michael Turelli of the University of California, also cautioned: "Evolution may alter the disease control effectiveness of the released Wolbachia for decades to come."

Antibiotic resistance that has transformed easy-to-treat infections into death sentences is a lesson from history.

When antibiotics were introduced to medicine, they were hailed as the holy grail of medicine.

And they have saved hundreds of millions of lives.

Then Nature fought back.

Bacteria evolved into superbugs to beat the best medicine man could produce.

Now, antibiotic-resistance is considered a major health threat worldwide.

In the United States alone, its Centres for Disease Control and Prevention (CDC) says that every year, two million people get infected, and 23,000 die of an antibiotic-resistant bug; and that it adds US$20 billion (S$25 billion) in additional direct health-care costs and US$35 billion in lost productivity.

But keep in mind too, that dengue is a looming and immediate menace.

The World Health Organisation estimates that there are 50 million to 100 million dengue infections a year - up from just over a million cases worldwide in 1998.

The figure just keeps going up.

There is currently no vaccine against the disease, and insecticides have to be continually changed as mosquitoes gain immunity.

Last year, Vietnam released Wolbachia-infested mosquitoes - but did it on Tri Nguyen Island, home to 3,250 people and far enough from the mainland that should things go wrong, the mosquitoes would be contained on the island.

Australia has been field testing them in small batches, since 2011, in northern Queensland where incidence of dengue is high. Scientists there are now calling for larger-scale releases.

Prof Gubler said he supports any means that can contain the disease: sterile males, new insecticides, vaccines, drugs and therapeutic antibodies.

"All are experimental at this point and we do not know which ones will be the most effective. It is unlikely that any of them will be completely effective when used alone," he said.

The Wolbachia experiment may have many positives. But as professors Bull and Turelli point out, the actual risk is largely unknown.

S'pore may be among first in world to get dengue vaccine
Drug giant Sanofi Pasteur's vaccine likely to be ready by end of 2015
By Linette Lai In Angeles City, The Straits Times, 16 Jun 2014

THE world's first dengue vaccine could be ready by the end of next year, and Singapore may be one of the first countries to get it.

The need could not be greater. Dengue is the fastest spreading vector-borne viral disease, says the World Health Organisation, and is endemic in over 100 countries. Four in 10 people are at risk of getting infected.

And more than two-thirds of the world's dengue cases come from Asia, with South-east Asia being a major contributor.

Drug giant Sanofi Pasteur aims to put its vaccine in markets where it is most needed first, and that includes South-east Asia.

"The overall ambition is first to address the disease where it is most severe," said Dr Guillaume Leroy, who heads the company's dengue vaccine unit.

At the two-day Asean Dengue Summit held in Angeles City in the Philippines over the weekend, Dr Leroy announced the success of an Asian clinical trial to test the vaccine's effectiveness.

After the vaccine candidate was administered, dengue cases in the group of about 10,000 - including participants from Indonesia, Thailand and Malaysia - fell by more than half.

Another trial, involving more than 20,000 people, is currently under way in Latin America.

"We are at a very critical milestone," Dr Leroy said. "By the end of the year, we will have a full analysis of all the results."

The outcome of these latest trials brings Sanofi Pasteur one step closer to a goal which has been more than 20 years in the making.

The company's work on a dengue vaccine has been hampered by the fact that dengue has four different strains. All must be effectively subdued before any vaccine can be counted a success - which is what Sanofi Pasteur says it has managed to do.

The disease is on the rise in the region.

In Singapore, dengue cases hit an all-time high last year, with more than 22,000 cases and seven deaths reported.

Across South-east Asia, there were about 100,000 reported cases in 2000. By 2010, this figure had reached 700,000.

Experts say this figure might be only the tip of the iceberg. "Not all the cases come to the attention of the public health authorities," said health economist Donald Shepard.

The disease tends to be under-reported due to poor surveillance, or because it is misdiagnosed as another condition.

Dr Maria Rosario Capeding, who heads the dengue study group in the Philippines' Research Institute for Tropical Medicine, welcomed the progress made towards a working dengue vaccine.

"The worst thing is the uncertainty of the disease," she said. "As a mother whose son has been ill with dengue, I can tell you that it is the worst nightmare."

As soon as its vaccine is approved for use, Sanofi Pasteur will be able to churn out 100 million doses a year. In 2009 - long before the vaccine neared completion - the company invested in a €350 million (S$593 million) production plant located in France.

"It was a big risk," Dr Leroy said. "But imagine not making the investment, getting the results, and then telling countries they have to wait five more years."

* S'pore may release sterile mozzies to combat dengue
These can fight with virile males for mates and weaken Aedes population
By Salma Khalik Senior Health Correspondent, The Straits Times, 18 Jun 2014

IF THE males shoot blanks, female mosquitoes will not be able to create new dengue-spreaders.

That is why Singapore could be releasing millions of sterile male mosquitoes here, if field studies are successful, say experts who have backed the plan.

The special mosquitoes have been genetically modified to contain a form of bacteria that makes them incapable of fertilising eggs. They also cannot spread dengue and are harmless to people.

These special mosquitoes will compete with virile males for mates and hopefully decimate the Aedes mosquito population, which this year alone has landed thousands of people in hospital, killing three.

The National Environment Agency, which tasked a panel with studying the use of the Wolbachia bacteria to fight dengue, yesterday said it will review the details of its recommendations.

It will also continue working with experts and stakeholders to develop the framework for the safe and effective adoption of the technology.

The bacteria is found in many insects but not the dengue- spreading Aedes mosquito.

Panel member Ary Hoffmann, from the departments of zoology and genetics at Australia's University of Melbourne, explained that female mosquitoes breeding with the sterile males will lay eggs that will not hatch, thus reducing the mosquito population.

Dengue, which is endemic in the region, has infected more than 16,000 people in Singapore this year. Roughly one in five patients diagnosed with the disease ends up in hospital, adding to the bed crunch.

Work on genetically modifying the Aedes mosquito has been going on for almost a decade, with five countries - Australia, Vietnam, Indonesia, Brazil and Colombia - doing field tests.

Another panel member, epidemiologist Duane Gubler from Duke-NUS Graduate Medical School, said that releasing the new mosquitoes would not harm people or the environment.

Professor Hoffmann estimates that Singapore has between 250,000 and 500,000 male Aedes mosquitoes. For the plan to be effective, five times those numbers of sterile males will have to be released - and more than once.

But he noted that the country could concentrate on dengue hot spots rather than flooding the whole country at one go.

Professor Gubler stressed that the Wolbachia bacteria is not a magic bullet. Other methods such as removing water that allows breeding must continue, he said.