Key messages
– People living in areas where Wolbachia-carrying Aedes mosquitoes have been released are less likely to contract dengue than people living in areas with no release.
– People living in areas where Wolbachia-carrying Aedes mosquitoes have been released are less likely to be admitted to hospital due to dengue than people living in areas with no release.
What is dengue?
Dengue is a viral disease transmitted by certain mosquitoes that is found in over 100 countries, with 3.9 billion people at risk of infection. Most dengue infections are mild (fever, headache, and muscle and joint pain), and some people do not have symptoms, but 1 in 20 people will develop a severe form of dengue. In the worst cases, this can cause organ failure and be life-threatening. Therefore, preventing the spread of dengue virus is of high importance.
What is Wolbachia, and how could these bacteria prevent dengue?
Wolbachia is a bacterium that can infect mosquitoes and alter their ability to survive and mate. Mosquitoes carry viruses such as dengue, and infect people with this virus through biting. Some species of mosquitoes, known as Aedes, find it harder to carry and transmit the dengue virus when they have been infected with Wolbachia. Researchers have microinjected Wolbachia extracts into mosquitoes and released Wolbachia-carrying mosquitoes into the wild population, where they have bred with other mosquitoes and passed on the Wolbachia infection. Once a large proportion of mosquitoes in an area become infected with Wolbachia, there is potential to reduce the mosquitoes' ability to spread dengue virus and prevent the frequency of dengue infections in the local human population. Wolbachia can only infect invertebrate organisms (that is, animals without a backbone), therefore, there is no risk that humans will become infected with the bacteria, and risks to humans and the environment associated with releasing Wolbachia-carrying mosquitoes are believed to be minor.
What did we want to find out?
We wanted to determine whether releasing Wolbachia-carrying Aedes mosquitoes into areas where dengue is regularly found could prevent dengue infection in the people who live there.
What did we do?
We searched for any randomized controlled trials (clinical trials where people are randomly put into one of two or more treatment groups) that investigated whether releasing Wolbachia-carrying Aedes mosquitoes into an area where dengue is present prevented the spread or incidence of dengue, compared to areas with no releases.
What did we find?
We identified one completed trial that met our inclusion criteria, and two more that are ongoing. The completed trial was conducted in Yogyakarta, Indonesia, and included people aged three to 45 years. The trial involved releasing mosquito eggs that were infected with Wolbachia into half of the study area until more than 60% of the mosquitoes in that area were carrying Wolbachia. There were no releases in the other half of the study area.
The trial tested all people who presented at their local health facility with a fever to determine how many people had contracted dengue. They compared the results between people living in the areas where Wolbachia-carrying mosquitoes were released and people living in the areas where no new mosquitoes were released over a 27-month period.
The likelihood of people who lived within the area where Wolbachia-carrying mosquitoes were released contracting dengue was probably reduced by 77% compared to people who lived in an area with a wild population of mosquitoes.
About 95.8% of mosquitoes in the population in the areas where Wolbachia-carrying mosquitoes were released became infected with the bacteria. This demonstrates that the bacteria were being passed on to wild mosquitoes via mating after the Wolbachia-infected mosquitoes were no longer being released. There were no reliable data for this in the group of the trial where no new mosquitoes were released.
We also wanted to find out whether releasing the bacteria-carrying mosquitoes into the wild reduced the number of mosquitoes that were carrying the dengue virus, reduced the traces of the dengue virus in the mosquito DNA (a molecule that contains the genetic code that is unique to every organism), reduced the size of the mosquito population, or caused any unwanted effects. Additionally, we were interested in the cost of this intervention, and the community's views towards it. We did not find any data that answered these questions.
What are the limitations of the evidence?
The effectiveness of the Wolbachia strategy will likely depend on factors that are specific to the location in which it is implemented, such as the climate, prevalence of dengue infection, existing vector control strategies, or community views towards the strategy. The ability to successfully achieve and sustain a high prevalence of Wolbachia-carrying mosquitoes in the population is critical to the effectiveness of the intervention, and this may vary in different settings. Since we only identified one completed trial, we do not know if these results will apply to other settings and countries.
How up to date is this evidence?
This evidence is up to date to 24 January 2024.
The included trial demonstrates the potential significant impact of wMel-Wolbachia-carrying Ae aegypti mosquitoes on preventing dengue infection in an endemic setting, and supports evidence reported in non-randomized and uncontrolled studies. Further trials across a greater diversity of settings are required to confirm whether these findings apply to other locations and country settings, and greater reporting of acceptability and cost are important.
Dengue is a global health problem of high significance, with 3.9 billion people at risk of infection. The geographic expansion of dengue virus (DENV) infection has resulted in increased frequency and severity of the disease, and the number of deaths has increased in recent years. Wolbachia, an intracellular bacterial endosymbiont, has been under investigation for several years as a novel dengue-control strategy. Some dengue vectors (Aedes mosquitoes) can be transinfected with specific strains of Wolbachia, which decreases their fitness (ability to survive and mate) and their ability to reproduce, inhibiting the replication of dengue. Both laboratory and field studies have demonstrated the potential effect of Wolbachia deployments on reducing dengue transmission, and modelling studies have suggested that this may be a self-sustaining strategy for dengue prevention, although long-term effects are yet to be elucidated.
To assess the efficacy of Wolbachia-carrying Aedes species deployments (specifically wMel-, wMelPop-, and wAlbB- strains of Wolbachia) for preventing dengue virus infection.
We searched CENTRAL, MEDLINE, Embase, four other databases, and two trial registries up to 24 January 2024.
Randomized controlled trials (RCTs), including cluster-randomized controlled trials (cRCTs), conducted in dengue endemic or epidemic-prone settings were eligible.
We sought studies that investigated the impact of Wolbachia-carrying Aedes deployments on epidemiological or entomological dengue-related outcomes, utilizing either the population replacement or population suppression strategy.
Two review authors independently selected eligible studies, extracted data, and assessed the risk of bias using the Cochrane RoB 2 tool. We used odds ratios (OR) with the corresponding 95% confidence intervals (CI) as the effect measure for dichotomous outcomes. For count/rate outcomes, we planned to use the rate ratio with 95% CI as the effect measure. We used adjusted measures of effect for cRCTs. We assessed the certainty of evidence using GRADE.
One completed cRCT met our inclusion criteria, and we identified two further ongoing cRCTs. The included trial was conducted in an urban setting in Yogyakarta, Indonesia. It utilized a nested test-negative study design, whereby all participants aged three to 45 years who presented at healthcare centres with a fever were enrolled in the study provided they had resided in the study area for the previous 10 nights.
The trial showed that wMel-Wolbachia infected Ae aegypti deployments probably reduce the odds of contracting virologically confirmed dengue by 77% (OR 0.23, 95% CI 0.15 to 0.35; 1 trial, 6306 participants; moderate-certainty evidence). The cluster-level prevalence of wMel Wolbachia-carrying mosquitoes remained high over two years in the intervention arm of the trial, reported as 95.8% (interquartile range 91.5 to 97.8) across 27 months in clusters receiving wMel-Wolbachia Ae aegypti deployments, but there were no reliable comparative data for this outcome.
Other primary outcomes were the incidence of virologically confirmed dengue, the prevalence of dengue ribonucleic acid in the mosquito population, and mosquito density, but there were no data for these outcomes. Additionally, there were no data on adverse events.