Sunday, 22 December 2019

Reports of Dengue Infections Plummet in Areas Where Wolbachia Has Been Established in Mosquitoes

Amid a global surge of infections with dengue and fears climate change will make it worse, an international alliance of researchers presented new evidence today showing reports that the disease fell dramatically in communities in Indonesia, Vietnam, Brazil and Australia. The reduction in dengue cases occurred in communities where they had released lab-grown mosquitoes carrying Wolbachia, a naturally occurring bacteria that prevents mosquitoes from transmitting infections when they bite humans.

Presenting today at the Annual Meeting of the American Society of Tropical Medicine and Hygiene (ASTMH), researchers at the World Mosquito Program (WMP) reported a key finding: a 76% reduction in dengue transmission in a community in Indonesia that endures frequent dengue outbreaks and a similar reduction in cases of dengue and chikungunya in an urban area near Rio de Janeiro, Brazil.

“We are very encouraged by the public health impact we are seeing – it highlights the potential of this approach to fight dengue and related mosquito-borne diseases at a global scale,” said Professor Cameron Simmons, Director of Impact Assessment and an expert in the epidemiology of dengue at WMP. “Evidence is rapidly accumulating that areas where Wolbachia-infected mosquitoes have been deployed have fewer reports of dengue than untreated areas.”

Often called break-bone fever for the searing joint pain it produces, dengue also can lead to fatal complications. There are no drugs to treat the disease. The only licensed dengue vaccine has been saddled with safety issues. The ASTMH Annual Meeting will feature a highly-anticipated update from a late-stage trial with a new dengue vaccine, but experts stress that many tools are needed to control the disease.

The WMP Wolbachia trials are ongoing and, given the promising results thus far, are being rapidly expanded to Colombia, Sri Lanka, India and Western Pacific island nations. These trials are driven by a large body of evidence indicating that establishing Wolbachia in local mosquito populations could offer a safe way to reduce dengue infections. Wolbachia-infected mosquitoes can be created in the laboratory by injecting it into their eggs. Wolbachia also has been shown to inhibit chikungunya and Zika.

While presenting at the ASTMH conference today, Katie Anders, PhD, an expert in the epidemiology of dengue at WMP, and her colleagues noted that the work in Indonesia involved an experimental release in 2016 of Wolbachia-infected mosquitoes in an area of about 65,000 people adjacent to Yogyakarta City, Indonesia. The city on the island of Java is home to about 400,000 people who routinely face risks of dengue infections. The 76% reduction represented notifications of dengue among the targeted population recorded by local health authorities, compared with an untreated control area nearby.

Anders reported results from a smaller field study near Nha Trang, Vietnam where very few cases of dengue were reported during the year following the 2018 release of Wolbachia-infected mosquitoes. This low case incidence in the intervention area was documented at a time in which Nha Trang itself was experiencing one of its largest dengue outbreaks ever.

Anders also presented results published earlier this year showing local dengue transmission ceased in Far North Queensland, Australia. Beginning eight years ago, releases of Wolbachia-infected mosquitoes in local communities in this region led to a 96% reduction in cases of dengue-transmission.

The researchers stressed that all of the mosquito releases have been preceded by intensive community outreach and education efforts to inform local communities about the safety of Wolbachia bacteria and the potential impact of the releases on the surrounding ecosystem. Advocates of this approach to fighting dengue noted that it has several advantages over other methods. Wolbachia has none of the toxicity of conventional insecticides and it does not require genetically modifying the mosquitoes. It is also self-sustaining, which should make it highly cost effective.

Wolbachia is naturally present in the majority of insects. But it’s not found in the Aedes aegypti mosquitoes that are the main carriers, or vectors, of dengue, chikungunya and Zika—all of which belong to a class of viruses called arboviruses.

“This is exciting work, carried out in the midst of an explosion in dengue infections that health authorities are finding very difficult to control,” said ASTMH President Chandy C. John, MD, MS, FASTMH. “The combination of advanced science and committed community engagement is impressive—and essential to its success.”

Using Wolbachia to Target Both Chikungunya and Dengue in Brazil

Luciano Moreira, PhD, WMP’s Program Lead in Brazil, reported preliminary results showing cases of dengue and chikungunya fell by more than 70% in 2018 – 2019 among 100,000 people in two different areas Niterói, a city near Rio, following the release of Wolbachia-infected mosquitoes in their neighborhoods.

Moreira and his team at Fundação Oswaldo Cruz (Oswaldo Cruz Foundation) also noted, however, that because dengue incidence was generally low throughout Rio and Niteroi during the field trials, it was more difficult to show a comparative reduction in Wolbachia-treated areas. There was, though, a clear difference compared to untreated areas.

“There has been an epidemic of chikungunya in these areas,” Moreira said. “And disease surveillance by the Ministry of Health is showing there was 75% less chikungunya in Niteró where we released the mosquitoes compared with areas where we are not working.”
Chikungunya is a disease that can lead to chronic, debilitating joint pain and, while native to sub-Saharan Africa, it is becoming a growing problem across Latin America and the Caribbean.

Meanwhile, dengue is once again surging in Brazil, with infections in 2019 up almost 600% and deaths rising by 220%. It’s part of a trend in which, last year, dengue infections globally reached near record highs, with especially large outbreaks in Asia and Latin America. Dengue is common in Puerto Rico, the U.S. Virgin Islands and American Samoa, and local transmission has occurred in Florida, Texas and Hawaii.

Moreira said Brazil’s Ministry of Health is keen to expand efforts to test the capacity of Wolbachia-infected mosquitoes as a tool for controlling outbreaks of dengue and chikungunya. There is also interest in using Wolbachia to help protect people from Zika as well. While the intense Zika outbreak of 2016 is over, there are concerns it could return in Brazil and elsewhere.

Moreira said plans are now underway to target 1.5 million people with releases of Wolbachia-infected mosquitoes in Brazil. Meanwhile, Anders said work is also underway in Yogyakarta City to conduct a gold-standard trial that involves a population of about 350,000.

Existing evidence of reductions in dengue linked to the Wolbachia mosquitoes is entirely consistent with earlier modelling predictions of the likely impact. There have been no safety concerns in any of the communities where Wolbachia has been deployed. “We are very excited that this self-sustaining and cost-effective method has been embraced by communities and is delivering the public health benefits we expected it would,” said the WMP’s Simmons. “Our challenge now is to work with partners and governments to bring the method to 100 million people by 2023.”
With insecticide resistance eroding the life-saving power of bed nets—a major malaria-fighting tool—researchers reported today that in a clinical trial that involved distributing millions of treated nets to households across Uganda, far fewer children showed evidence of malaria parasites after sleeping under nets newly formulated to disarm a mosquito’s key resistance mechanisms.

The results presented today at the Annual Meeting of American Society of Tropical Medicine and Hygiene (ASTMH) emerged from the largest trial ever undertaken to assess the malaria-fighting power of long-lasting insecticidal nets (LLINs), which are credited with playing the dominant role in cutting malaria deaths in half over the last 15 years. But there is concern that rising resistance in mosquitoes to pyrethroids, the key insecticide incorporated into the fabric of the nets, is contributing to a recent stall in the decline of malaria infections and deaths—and to a rise of both in some parts of Africa.

“The results from Uganda show that by using an insecticide formulation that interferes with the mechanisms mosquitoes use to defeat pyrethroids, we are seeing a significant restoration of pyrethroid efficacy—not back to pre-resistance levels, but enough to buy us critically needed time while we develop new insecticides and interventions,” said Martin Donnelly, MSc, PhD, an expert in the genetics of insecticide resistance at the Liverpool School of Tropical Medicine and a co-leader of the LLIN Evaluation in Uganda Project, or LLINEUP.

At the ASTMH session, the LLINEUP study team presented data from blood tests of over 23,000 children 2 to 10 years old. The data show that for the children who slept under nets augmented with piperonyl butoxide (PBO)—a chemical that blocks enzymes mosquitoes employ to “detoxify” pyrethroids—the number testing positive for malaria parasites 12 months after the nets were distributed was 27% lower than for children sleeping under nets that were treated solely with pyrethroid insecticides. Moreover, households supplied with the PBO-treated nets had 80% fewer malaria-carrying mosquitoes compared to households using conventional LLINs.

“We think nets with this new formulation would do a better job of preventing malaria than standard nets, particularly in areas of high-level insecticide resistance, and could reduce the burden of malaria,” said Sarah Staedke, MD, PhD, DTM&H, a Uganda-based malaria epidemiologist with the London School of Hygiene and Tropical Medicine and the Infectious Disease Research Collaboration, a co-leader of the project.

The trial was conducted in close partnership with a bed net campaign led by Uganda’s Ministry of Health and supported by The Against Malaria Foundation that, in the last few years, has distributed millions of bed nets free of charge across a large swath of the country. Both the PBO and non-PBO nets had been treated with pyrethroids, which are safe for humans and were, until recently, lethal to mosquitoes. But their ability to stop the insects is steadily declining.

Donnelly cautioned that while the increased efficacy offered by PBO-treated nets is great news, it’s likely just a matter of time before mosquitoes evolve to evade the compound. He noted that PBO does not shut down all the enzymes mosquitoes employ to overcome pyrethroids. He said that he and other scientists studying the genetic mechanisms of resistance believe mosquitoes will eventually emerge that are increasingly impervious to the effects of PBOs.

But he thinks that the PBO nets could be a very good stopgap for several years. In the meantime, the World Health Organization (WHO) will review the evidence from the Uganda study to determine whether to recommend their adoption while testing continues for a long-term solution. For example, there are newer nets being developed that use two active ingredients or a novel insecticide that employ a different mode of action than pyrethroids to kill mosquitoes. Donnelly said there are efforts underway to conduct trials in Uganda to test this new generation of nets against the PBO nets.

The other good news from the Uganda trial is that despite rising levels of resistance, the study showed nets without PBOs can reduce the prevalence of malaria parasites, even if they are not as effective as when net campaigns were first launched more than a decade ago. Children sleeping under the non-PBO nets had a lower prevalence of malaria parasites than they did before the nets were distributed—though the reduction was not as large as for the children sleeping under the PBO-treated nets. LLINs are now used in half or more of all households in sub-Saharan Africa, which shoulders most of the world’s malaria burden, compared to only about 2% in 2000.

Moses Kamya, M.Med, MPH, PhD, the Executive Director of the Uganda Infectious Disease Research Collaboration (IDRC), a study co-leader, said that “there is still an advantage to using any type of LLIN because when you sleep under either type of net, you’re less likely to contract malaria. But the greater reduction in malaria from the PBO-treated nets is significant and switching to this type of net in national malaria control campaigns should be considered.”

“Keeping up with resistance is a constant battle, and ASTMH researchers from around the world are working hard to stay ahead of it. With mosquitoes continually evolving resistance to insecticides, this research provides valuable data that will help to guide the difficult decisions about how best to deploy LLINs to combat malaria in sub-Saharan Africa,” said ASTMH President Chandy C. John, MD, MS, FASTMH.

Posted by Dr. Tim Sandle, Pharmaceutical Microbiology Resources (

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