Novel clinical trial to test if wolbachia-infected mosquitoes reduce dengue

A female Aedes aegypti mosquito acquiring a blood meal from a human.
A female Aedes aegypti mosquito acquiring a blood meal from a human. (Photo by James Gathnay, courtesy of CDC PHIL)

A clinical trial is underway to determine if mosquitoes that harbor an infection-blocking bacteria can help break the transmission cycle of certain viral diseases to people. Two UF researchers are contributing to the study in Belo Horizonte, Brazil. The goal is to test the safety and efficacy of this method in reducing dengue, chikungunya and Zika virus infections in people.

Researchers with the EVITA Dengue trial are releasing mosquitoes that have been intentionally colonized with a bacteria called Wolbachia. These naturally occurring bacteria exist in harmony with many insects.  However, mosquitoes infected with Wolbachia possess a crucial characteristic — they are much less likely to transmit dengue and chikungunya virus.

The mechanism is unclear. It may be that the Wolbachia bacteria and viruses compete inside the mosquito which limits their ability to make more of themselves. Or the bacteria may trigger an immune response that inhibits the viruses.

The research team is releasing the Wolbachia-infected mosquitoes within 29 one-square-kilometer patches in Belo Horizonte, centered around schools. Researchers will compare rates of infection for dengue, chikungunya, and Zika viruses in school-aged children in areas with and without mosquito releases.

“One of the advantages of this intervention is that it is sustainable over multiple seasons,” says UF researcher Derek Cummings, who is a co-principal investigator on the study.

Wolbachia-infected mosquitoes have been released in other settings and remained at high levels for many years. A separate study using the Wolbachia approach reported a 77% reduction of dengue disease.

“If it works in this setting, it could be a low cost, sustainable intervention to reduce the burden of disease of all these viruses,” says Cummings, who is a professor of biology in UF’s College of Liberal Arts and Sciences and a faculty member in the UF Emerging Pathogens Institute.

Cummings and UF assistant professor of biostatistics, Matt Hitchings, in the College of Public Health and Health Professions and the College of Medicine, are working with collaborators from the Federal University of Minas Gerais, São José do Rio Preto School of Medicine, Emory and Yale Universities. Hitchings and Cummings helped design the study and the study’s statistical analysis plan.

“There’s a lot of existing evidence for the benefits of deploying these mosquitoes. By focusing on children, this trial will really allow us to see the specific benefit in reducing dengue, chikungunya and Zika infections in a population that spends a lot of their time around home or in school,” Hitchings says.

Advancing earlier Wolbachia work

Another principal investigator on the study with Cummings, Srilatha Edupuganti, M.D., of the Emory Vaccine Center, says: “We are excited to have been able to launch this impactful study and start the intervention implementation in the middle of the COVID-19 pandemic.”

Earlier efforts that laid the groundwork for the EVITA trail were promising across multiple mosquito-borne diseases.

“Our preliminary observational data show a 60% reduction in the number of chikungunya cases in Niterói,” says Luciano Moreira, a researcher and World Mosquito Program leader in Brazil. “We are excited to gather more epidemiological data from the EVITA Dengue trial to support the results from the study in Niterói.”

To carry out this unique, cluster-randomized trial, Belo Horizonte, the sixth-largest city in Brazil, was divided into 58 school-based clusters, half of which were randomly assigned to receive the Wolbachia-infected mosquito intervention. More than 3,000 school-aged children who represent all 58 clusters were enrolled in the trial and will be assessed annually for the next three years to see how many are infected with dengue, Zika or chikungunya. Researchers will compare rates of infection in clusters where Wolbachia-infected mosquitoes were released to rates in untreated clusters where Wolbachia-infected mosquitoes were not released. All clusters will continue to undergo routine, standard mosquito control practices set by Brazil’s government.

A brief history of the Wolbachia method

The team behind the EVITA Dengue trial are collaborating with the World Mosquito Program, a global nonprofit organization that developed the Wolbachia method. This technique takes Aedes aegypti mosquitoes, which spread viral infections including dengue, Zika, and chikungunya, and modifies them to harbor the Wolbachia bacteria.

Once released into the environment, these mosquitoes breed with native mosquitoes and begin passing Wolbachia to subsequent offspring. The goal is for the proportion of mosquitoes infected with Wolbachia to naturally increase in the environment over time, making the mosquitoes in that area less able to spread dengue. Wolbachia-infected mosquitoes may also prevent transmission of Zika and chikungunya, which cause large epidemics resulting in congenital birth defects and debilitating joint pain, respectively.

Wolbachia-infected mosquitoes, developed by the World Mosquito Program, were first released in Australia in 2011 and the program is now active in 11 countries. In August of 2020, results from an experimental trial conducted in Yogyakarta City, Indonesia, showed a 77% reduction in dengue disease incidence in Wolbachia-treated communities.

Additional large-scale trials using the Wolbachia method, like the EVITA Dengue trial, will be important for providing supporting evidence for the use of a safe, natural, and self-sustaining intervention in regions of the world where mosquito-borne diseases are endemic.

This study’s Brazilian principal investigator, Dr. Mauro Teixeira, remarks that “The geography and climate in Belo Horizonte is very different from that of Yogyakarta and these differences have a significant impact on transmission of arboviral infections. Our study will, therefore, be fundamental for understanding the general applicability of the Wolbachia method in our region.”

Acknowledgments: This clinical trial is funded by the National Institute of Allergy and Infectious Diseases, part of the National Institutes of Health, under contract HHSN272201300018I. The study is being carried out in collaboration with the Federal University of Minas Gerais led by Dr. Mauro Teixeira, the Virology Research Lab of the São José do Rio Preto School of Medicine, and the municipality of Belo Horizonte with leadership from Dr. Srilatha Edupuganti from the Emory University Vaccine and Treatment Evaluation Unit, Derek Cummings, PhD from the University of Florida, and Dr. Albert Ko from the Yale School of Public Health. The implementation of the World Mosquito Program’s Wolbachia Method in Belo Horizonte is conducted by Oswaldo Cruz Foundation (Fiocruz), in partnership with the local health authorities and funded by the Brazilian Ministry of Health. The trial is scheduled to conclude in 2024.

Adapted from a press release originally prepared by Emory University and revised by DeLene Beeland, science writer for the UF Emerging Pathogens Institute.

Written by: DeLene Beeland