The rise of super-insecticide-resistant Aedes aegypti mosquitoes adds to a new threat and another layer of complexity to the ongoing battle against dengue fever in Asia. The release of Wolbachia mosquitoes is effective yet may not be sustainable in the long term. New candidate vaccines have promising efficacy and results in trials.
Dengue: A Rising Global Health Threat
Globally, dengue fever is on the rise. The United States reported 1,957 cases in 2020, while the EU saw 1,820 cases. In Southeast Asia, dengue is endemic and the situation is even more alarming. Over 5 million cases and 5,000 deaths were reported in 2020. This increase points to a major public health crisis.
Climate Change and Urbanisation: Fuelling the Dengue Outbreak
The primary vector of the dengue virus is the Aedes aegypti mosquito, which thrives in tropical regions. As global temperatures rise, these mosquitoes have expanded their territories, leading to more frequent dengue outbreaks. The increase in dengue outbreaks correlates strongly with rising global temperatures due to climate change. Additionally, rapid urbanisation and increase in human traffic provide the primary vector of the virus, the A. aegypti mosquito, with abundant breeding grounds and a vast pool of human blood. These factors combine to create a perfect storm for the spread of dengue.
Although innovative technologies like sterile and transgenic mosquitoes offer promise in preventing dengue transmission, they are not yet viable for widespread use. Primary concerns include the unknown long-term impact of releasing these genetically modified organisms to the environment. Consequently, pyrethroid insecticides remain the primary method for managing dengue outbreaks in most Asian countries.
The Decline of DDT and the Rise of Pyrethroids
In the early 80s, Dichlorodiphenyltrichloroethane (DDT) was commonly used to control dengue and malaria. However, due to its adverse environmental effects and health concerns, its use has largely been restricted and even outrightly banned in many countries. This led to adopting pyrethroid insecticides, such as permethrin and deltamethrin, introduced in the late 80s and early 2000s.
The Emergence of Super-Insecticide-Resistant Mosquitoes
Unfortunately, many A. aegypti mosquito populations have evaded and survived these treatments, developing pyrethroid resistance. Mutations in the voltage-gated sodium channel (Vgsc) gene are a key mechanism behind this resistance. In Asia, specific mutations in the gene where amino acid valine (V) at position 1016 is replaced by glycine (G) and phenylalanine (F) at position 1534 is replaced by cysteine (C), V1016G and F1534C respectively, are recognised as major mutations. However, newer studies have discovered more mutations and one major mutation exacerbating the resistance to pyrethroids.
A study testing 23 A. aegypti populations from four countries identified a new highly potent L982W mutation that exacerbates the resistance to permethrin. Further, the authors also found that 63% of the Phnom Penh A. aegypti population in Cambodia and 73.1% of the Vietnamese population had this potent L982W mutation. Using molecular modeling, they found that this mutation creates an obstacle to preventing permethrin from approaching the docking site, impeding the effectiveness of permethrin and allowing the mosquitoes to survive treatments.
Currently, it remains uncertain if other A. aegypti populations outside of Cambodia and Vietnam have developed this mutation. Nevertheless, given the increasing urbanisation and human mobility, proactive measures are imperative to curb the spread of these mosquitoes.
Singapore’s Proactive Approach to Combat Dengue
Singapore’s Project Wolbachia began as a small-scale project involving the release of male mosquitoes that carry a natural parasite called Wolbachia, which prevents the eggs of female mosquitoes from hatching. This approach led to a dramatic 90% reduction in the A. aegypti mosquito population and a 77% decrease in dengue cases in the targeted areas. The project has been expanding steadily since its inception.
Recently, with a striking increase in dengue cases over the past ten weeks, Singapore’s government has urged for immediate action. In just the past week, the project released a further 350,000 Wolbachia-carrying males in an area and are planning to extend this initiative to four more regions within this first quarter. This means stepping up to produce a whopping 11 million male Wolbachia mosquitoes weekly and coverage from 26% to 35% of all households in Singapore.
Over $300M Saved in Economic Costs
By controlling the mosquito population, the project helps in mitigating the burden of dengue fever. Fewer dengue cases translate into decreased demand on healthcare resources, including hospital beds, blood transfusion services, and medical personnel. This is particularly crucial for Singapore, a densely populated city-state where the rapid spread of infectious diseases can strain healthcare resources. With hospitalisations and patients requiring time off work or having to find alternative care arrangements, the impact translates to economic costs. Another recent study estimated $329.40 million may be saved in economic costs in 10 years with this project. While the project’s success is evident, the sustainability of continuously producing millions of male Wolbachia-carrying mosquitoes and the balance between long-term production feasibility and economic benefits warrant careful consideration.
Strategies to Combat Dengue in Asia
Asian countries are employing various strategies to combat dengue. These include vector control measures like environmental sanitation and the use of insecticides, biological agents, and genetic modifications. Continual surveillance on the occurrence and distribution of dengue cases and outbreaks in the country also help guide the planning and evaluation of control measures. Importantly, community engagement is essential to control the spread as raising awareness and having everybody play their part is vital to enhance the effectiveness and sustainability of vector control and other interventions.
Vaccinations also play a crucial role, though their use is sometimes controversial. Dengvaxia was the first dengue vaccine developed by Sanofi Pasteur for people with previous dengue infection.
Some key considerations for Dengvaxia use are:
- Prior Dengue Infection Confirmation: Essential to conduct blood tests to confirm past dengue infection due to increased severe dengue risks in naïve individuals.
- Age and Endemicity Considerations: The World Health Organisation (WHO) advises its use for individuals 9-45 years in dengue-endemic regions.
- Country-Specific Approvals: Adherence to local health authority guidelines is crucial, as vaccine approval varies globally.
- Regional Dengue Prevalence: In areas with high transmission, the vaccine’s benefits are potentially more substantial.
These points underscore the nuanced approach required in dengue vaccination strategies.
Additionally, two new vaccine candidates have emerged, Qdenga (TAK-003) by Takeda and Butantan-DV by the Butantan Institute in Brazil. These have shown promising efficacy and safety results in phase III trials. Both vaccines provide broader protective effects as the vaccines can be administered to those who have not previously been infected with dengue. As of 2023, Qdenga has received approval in several countries including the EU and Indonesia, and Malaysia having conditional approval. Butantan-DV is expected to obtain approval in 2025.
In comparison to Dengvaxia, the newer vaccines have favourable safety profiles. However, as with any new vaccine, long-term safety and efficacy data are essential to fully understand its impact. Qdenga is still undergoing the regulatory review process in various countries. The approval status and recommendations for its use might vary depending on the country’s regulatory guidance and the latest ongoing research data.
A United Front Against Dengue
The fight against dengue fever is a global challenge, requiring a multifaceted approach. Climate change and urbanisation are key drivers of the spread, which necessitates international cooperation and innovation. The threat and emergence of super-insecticide-resistant mosquitoes adds urgency to developing new strategies. Countries like Singapore are leading the way with groundbreaking initiatives, but continuous vigilance and adaptation are still essential. As we face this growing threat, commitment to research, public health initiatives, and community involvement are crucial in turning the tide to overcome dengue fever.
References
- Time. (2021, December 22). Dengue Fever Is Soaring Worldwide: What to Know and How to Protect Yourself. Retrieved from https://time.com/6429963/dengue-fever-cases-symptoms-prevention-explainer/
- Hu, Z., Zhou, J., Jiang, F., Chen, M., Zhang, D., Wang, X., … & Zhou, D. (2022). Discovery of a knockdown resistance mutation associated with permethrin resistance in the dengue vector Aedes aegypti in Asia. Science Advances, 8(51), eabq7345. https://doi.org/10.1126/sciadv.abq7345
- Channel NewsAsia. (2022, June 30). Dengue: Project Wolbachia mosquitoes to be released at five more sites in south Singapore. Retrieved from https://www.channelnewsasia.com/singapore/dengue-project-wolbachia-mosquitoes-five-sites-south-singapore-3935836
- Channel NewsAsia. (2021, August 28). Wolbachia-Aedes mosquitoes released at Clementi site as part of project expansion to fight dengue: NEA. Retrieved from https://www.channelnewsasia.com/singapore/wolbachia-aedes-mosquitoes-clementi-dengue-nea-4135106
- Thomas, S. J. (2023). Is new dengue vaccine efficacy data a relief or cause for concern? npj Vaccines, 8, Article 55. https://doi.org/10.1038/s41541-023-00658-2
- Hadinegoro, S. R., Arredondo-García, J. L., Capeding, M. R., Deseda, C., Chotpitayasunondh, T., Dietze, R., … & Rivera-Medina, D. M. (2015). Efficacy and Long-Term Safety of a Dengue Vaccine in Regions of Endemic Disease. New England Journal of Medicine, 373(13), 1195-1206. https://doi.org/10.1056/NEJMoa1506223
- Sáez-Llorens, X., Tricou, V., Yu, D., Rivera, L., Jimeno, J., Villarreal, A. C., … & Rauscher, M. (2021). Three-year Efficacy and Safety of Takeda’s Dengue Vaccine Candidate (TAK-003). Clinical Infectious Diseases, 74(8), 1421-1429. https://doi.org/10.1093/cid/ciab864
- Soh, S., Ho, S. H., Seah, A., Ong, J., Dickens, B. S., & others. (2021). Economic impact of dengue in Singapore from 2010 to 2020 and the cost-effectiveness of Wolbachia interventions. PLOS Global Public Health, 1(10), e0000024. https://doi.org/10.1371/journal.pgph.0000024
