Hamer reports receiving advisory board consulting honoraria from Takeda and a grant from the CDC’s Travelers’ Health Branch outside the submitted editorial. Sharp and Utarini report no relevant financial disclosures. Please see the studies for all other authors’ relevant financial disclosures.
The release of Wolbachia-infected mosquitoes led to a 77% reduction in the incidence of symptomatic dengue in an Indonesian city, according to researchers, who said the same approach could be used to fight other mosquito-borne diseases.
The study tested a strain of Wolbachia pipientis called wMel that makes Aedes aegypti mosquitoes less susceptible to dengue virus infection. Wolbachia pipientis occurs naturally in many insects but not A. aegypti, the primary vector of dengue, according to Adi Utarini, PhD, MPH, MSc, and colleagues from the nonprofit World Mosquito Program, which has been releasing Wolbachia-infected mosquitoes in the wild since 2011.
“Wolbachia facilitates its own population introgression by manipulating reproductive outcomes between wild-type and Wolbachia-infected mosquitoes: the only viable mating outcomes are those in which the progeny are infected with Wolbachia,” they wrote in the new report, which was published Wednesday in The New England Journal of Medicine.
Dramatic increase in cases
The global incidence of dengue has risen dramatically over the past half-century to an estimated 100 million to 400 million infections each year, according to WHO, which estimates that around half of the world’s population is at risk for the mosquito-borne disease.
In an editorial related to the new study, Davidson H. Hamer, MD, a professor of global health at the Boston University School of Public Health, said the incidence of dengue has doubled every decade since 1990.
“Rising global temperatures due to climate change, widespread distribution of the mosquito vector Aedes aegypti, increasing urbanization, population growth, environmental conditions that are conducive to mosquito breeding, and limited or nonexistent surveillance have all contributed to making dengue a worldwide threat,” Hamer wrote.
Protecting people has mostly depended on controlling mosquitoes. Dengue vaccine development has been a challenge because an effective vaccine needs to protect against all four serotypes of the virus. People who are infected with one serotype face a higher risk of developing more severe symptoms if they are infected with another.
There is an approved vaccine, Dengvaxia (Sanofi Pasteur), that protects against all four serotypes. The FDA approved the vaccine in 2019 for use in children aged 9 to 16 years who live in areas where dengue is endemic, including Puerto Rico, but recommendations for its use are still pending. (The CDC’s Advisory Committee on Immunization Practices is scheduled to vote on recommendations later this month.) The vaccine is approved only for children with confirmation of a past infection because it can act as an initial infection, putting them at risk for more serious disease if they are then infected naturally.
Although dengue is common in U.S. territories like Puerto Rico, the U.S. Virgin Islands and America Samoa, most cases that occur in the contiguous U.S. are imported, according to the CDC. However, local outbreaks do sometimes occur, including one in Texas in 2013 that involved dozens of cases.
Hamer called the southern U.S. “an ideal setting” for dengue, given its climate, large number of travelers from Latin America and the Caribbean and its population of A. aegypti mosquitoes.
A second report published Wednesday in The New England Journal of Medicine detailed a fatal case of dengue in a woman in Miami in 2019. According to CDC epidemiologist Tyler M. Sharp, PhD, and colleagues, the woman was one of 18 people locally infected with dengue in Florida that year. Her infection was likely caused by a strain imported by travelers who had recently returned from Cuba, they said.
“This case shows the potential hazards of dengue — introduction by travelers from dengue-endemic regions into areas in which dengue is not endemic, local transmission, and severe disease leading to death,” Hamer wrote.
Findings from a study presented at a tropical medicine conference in 2019 showed that cases of dengue plummeted in areas of four countries, including Indonesia, where lab-grown mosquitoes carrying Wolbachia were released.
Wolbachia has been approved by the Environmental Protection Agency for use in the United States since 2017. Other novel methods for mosquito control, including the use of genetically modified mosquitoes, have been explored.
The study by Utarini and colleagues took place in Yogyakarta, Indonesia, an urban area of approximately 16 square miles with a population of around 311,000 people. After obtaining community consent from the leaders of 37 urban villages, Utarini and colleagues divided the area into 24 clusters and assigned them in a 1:1 ratio to receive deployments of open-label Wolbachia-infected mosquito eggs or no mosquitoes from March through December 2017.
“In intervention clusters,” they wrote, “most community members were unaware of the cluster assignment because release containers were placed discretely in a minority of residential properties for a limited time.”
The researchers screened almost 54,000 patients at 18 government-run primary care clinics between Jan. 8, 2018, and March 18, 2020, and enrolled more than 8,000 participants in the study. The analysis included 6,306 people — 2,905 who lived in the 12 clusters where treated mosquitoes were released and 3,401 who lived in control clusters. The median age of study participants was 11.8 years.
According to Utarini and colleagues, 2.3% of participants in the intervention clusters acquired virologically confirmed dengue compared with 9.4% of participants in the control clusters (aggregate OR = 0.23; 95% CI, 0.15-0.35) — a protective efficacy of 77.1% (95% CI, 65.3%-84.9%). The researchers said the result was similar against all four dengue serotypes.
The incidence of dengue-related hospitalization also was lower in intervention clusters — 0.4% vs. 3%, a protective efficacy of 86.2% (95% CI, 66.2%-94.3%), Utarini and colleagues reported.
“Future trials should explore the multivalency of the intervention, since laboratory studies suggest wMel could also attenuate transmission of Zika, chikungunya, yellow fever, and Mayaro viruses by A. aegypti,” they wrote.
In his editorial, Hamer said the study demonstrated the potential of Wolbachia to prevent transmission of dengue.
“Although there is clearly a need for future research to assess the durability of the wMel-infected mosquito populations after introduction and replication of these findings in different contexts — potentially including areas in the southern United States, where the risk of dengue introduction is high — the use of Wolbachia-infected mosquitoes has exciting potential to address the harms associated with dengue,” he wrote. “Predictions from mathematical models have suggested that the reduced infectiousness of wMel-infected A. aegypti could be sufficient to reduce the basic reproductive number to less than 1 and may potentially result in local elimination of disease.”
Anders K, et al. Growing evidence that the World Mosquito Program’s Wolbachia method reduces dengue transmission. Presented at: ASTMH 68th Annual Meeting; Nov. 20-24, 2019; National Harbor, Maryland.
Hamer DH. N Engl J Med. 2021;di:10.1056/NEJMe2107325.
Sharp TM, et al. N Engl J Med. 2021;doi:10.1056/NEJMc2023298.
Utarini A, et al. N Engl J Med. 2021;doi:10.1056/NEJMoa2030243.