A modestly titled new study released in the New England Journal of Medicine belies the extraordinary 77% protective efficacy reported for preventing dengue infections with Wolbachia-infected Aedes aegypti mosquitoes.
A cluster-randomized clinical trial, the AWED (“Applying Wolbachia to Eliminate Dengue”) study was conducted in Yogyakarta, Indonesia and led by professors Adi Utarini, MD, PhD, of Gadjah Mada University and Cameron Simmons, PhD, the World Mosquito Program’s Oceana director, in partnership with the Tahija Foundation and Monash University.
Yogyakarta was chosen as the study site in part because it consistently ranks among the top 10 provinces 1in Indonesia for dengue. For the purposes of the study, investigators divided the area of Yogyakarta into geographic clusters. In a random half of those clusters, investigators released A aegypti mosquitoes infected with the wMel strain of Wolbachia pipientis to multiply throughout the area; the other half had no intervention.
Researchers recruited patients aged 3-45 who presented for care because of fever and they tested them for dengue. This type of trial is a variant of a cluster-randomized trial called a test-negative design. Instead of following everyone who lived in the clusters to see who became ill, all patients who presented with fever were compared to see who lived in treated vs untreated communities.
In the control group from untreated areas, 9.4% of the patients were infected with dengue. Infections fell to 2.3% in the patients from communities with Wolbachia treatment, showing a protective efficacy of 77%. The level of protection was similar against all four dengue serotypes. Even more striking were the rates of hospitalization: 0.4% among the treated group compared to 3% among the controls, an 86% protection rate.
Simmons told Medscape Medical News that the WHO’s vector control advisory group has reviewed the trial and, based on such positive results, has concluded that WHO can proceed with a formal policy recommendation supporting the deployment of Wolbachia.
Wolbachia
Wolbachia are naturally occurring bacteria. When introduced into A aegypti mosquitos, Wolbachia prevent dengue. However, researchers don’t know with certainty how this happens. Simmons, one of the principal investigators on the AWED trial, advanced two hypotheses in an interview with Medscape: One is that the bacteria compete with the dengue virus for resources, particularly lipids, inside A aegypti cells. Another is that Wolbachia is triggering innate immune defense mechanisms inside the mosquito tissues that may contribute to viral suppression.
In addition to reducing dengue, the study authors note that lab studies suggest Wolbachia “could also attenuate transmission of Zika, chikungunya, yellow fever, and Mayaro viruses by A. aegypti.”
This type of study and intervention requires considerable community education about biology, mosquitoes, and the natural history of dengue infection. Simmons credits Utarini with much of the successful community relations that made this study possible. “I think that it’s a great testament to the community in many ways and community leadership.”
Impact of Wolbachia on Viral Infections
Dengue infections have doubled every 10 years since 1990. According to the CDC, each year 100 million people become ill from their infection, and 22,000 die.
Timothy Endy, MD, MPH, professor emeritus at SUNY Upstate Medical University in Syracuse, New York, told Medscape that it’s in part due to climate change and in part from urbanization and waste, which favor the A aegypti mosquito. “The risk of dengue and other flavivirus spreading in the United States is fairly low,” he said, because the US does not have the same densely populated urban areas.
Endy did note that there have been periodic outbreaks of dengue in Florida, Texas, and Hawaii. Because of this, he “could see Wolbachia being released in certain specific areas of the United States, especially along the southern border, which is [the area with] the highest risk. Aedes aegypti and Aedes albopictus have been spreading throughout the southern parts of the United States for a number of reasons — with climate change, warmer weathers, higher humidity, and those kinds of factors. All contribute to the spread of this particular vector.”
The World Mosquito Project told Medscape that the “cost of deployment is currently less than $10 per person,” and they are working toward $1 per person. In addition, a modeling study showed the technique is expected to be “highly cost-effective.”
Several strategies are being employed to reduce mosquito-borne infections, including new vaccinations; Oxitec’s genetically modified mosquito, which reduces the population of mosquitoes; and Wolbachia. The latter two technologies are expected to reduce infections caused by chikungunya, Zika, and other viruses, as well as dengue.
Endy was part of a team of consultants for this Wolbachia project more than 5 years ago.
N Engl J Med. Published online June 10, 2021. Full text
Judy Stone, MD, is an infectious disease specialist and author of Resilience: One Family’s Story of Hope and Triumph Over Evil and of Conducting Clinical Research , the essential guide to the topic. You can find her at drjudystone.com or on Twitter @drjudystone .
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