In an exclusive interview with BioPharma APAC, Professor Ooi Eng Eong, a leading expert in Emerging Infectious Diseases at Duke-NUS Medical School, and Dr. Goh Choo Beng, Head of Medical Affairs for India and Southeast Asia at Takeda Pharmaceuticals, share their perspectives on the alarming rise in dengue cases across Southeast Asia. They delve into Singapore’s current dengue situation, explore critical strategies for prevention and control, and discuss the innovative approaches needed to combat this persistent public health threat.

Professor Ooi Eng Eong

Professor in Emerging Infectious Diseases at Duke-NUS Medical School and also Professor at NUS Saw Swee Hock School of Public Health

Can you explain the current dengue situation in Singapore?

Singapore started the year with high daily number of dengue cases. However, the expected surge in cases that happens in the middle of each calendar year has not happened. It is difficult to forecast dengue outbreaks accurately as multiple factors, including population immunity levels, dengue virus genetics, weather patterns and mosquito abundance all influence the risk of dengue outbreaks. 

Why is dengue outbreak a major public health concern?

Dengue outbreak is a major public health concern as large number of cases can strain our healthcare system. Severe dengue cases, as well as dengue patients that suffer from vomiting and thus cannot be adequately hydrated orally, will require hospitalized care. High number of hospitalized dengue cases could lead to insufficient beds and delay elective in-patient procedures. Hence, the impact of dengue outbreaks could extend beyond dengue patients to those suffering from other treatable conditions.

Why has Singapore’s vector control measures not stopped dengue outbreaks?

Singapore started proactive vector control to prevent dengue in 1970, soon after dengue outbreaks were reported in Singapore. Its main strategy was to reduce breeding sites for Aedes mosquitoes, especially Aedes aegypti, which transmits dengue virus effectively. The vector control programme successfully prevented dengue outbreaks from the mid-1970s to the late 1980s. However, since 1992, Singapore has, with a couple of exceptions in 2007 and 2022, experienced outbreaks once every 5-7 years. The main reason for the re-emergence of dengue outbreaks in Singapore since 1992 is low population immunity to dengue; the successful vector control programme reduced dengue virus transmission and, with time, population immunity. Singapore’s experience in dengue control thus underscores the need for integrated measures to prevent dengue. 

Singapore is now piloting Project Wolbachia, which generates and releases male mosquitoes infected with the Wolbachia bacterium. The infected male mosquitoes transmit Wolbachia to uninfected female Aedes aegypti to produce non-viable larvae, thereby reducing Aedes aegypti population even further. While this approach would reduce transmission even further, elevating the currently low population immunity to dengue will be needed to prevent the cyclical 5-7 yearly outbreaks. Incorporating dengue vaccination to elevate population immunity is thus a necessary element of the equation for preventing dengue sustainably. 

How do climate change and urbanization influence the frequency and intensity of dengue outbreaks in Singapore and Southeast Asia?

The primary drivers of dengue epidemics have been urbanization, as Aedes aegypti is well adapted to the urban environment, globalization that moves dengue viruses via infected travellers from one part of the world to another, and inadequate attention to preventing dengue in most parts of the world. Indeed, unplanned urban development can lead to stagnant water collecting in construction sites, and where water supply may be scarce, the population may resort to storing water in tanks – an ideal breeding site for mosquitoes. Irregular and improper waste management can also produce new breeding sites; research in Dhaka, Bangladesh, for example, has found mosquitos breeding in discarded tires, construction waste, plastic drums, and refrigerator trays.[2] 

These contributory factors could all worsen with climate change. Climate change could not only make places like Southern Europe and North America susceptible to dengue outbreaks, it could also lead to changes in land use and movement of even more people into urbanized cities. For instance, currently productive farming land could become unsuitable for planting crops due to changes in weather patterns. When that happens, workers will have seek alternative employment for income, especially in cities since that is where most jobs are created. The collective effect is that dengue outbreaks are expected to be more frequent and intense. Globally coordinated and sustained dengue prevention are thus urgently needed.

Can you discuss any recent advancements in dengue research that could significantly impact our understanding or management of the disease?

There are multiple complementary directions of research. Studies to discovery antiviral drugs and other treatment to prevent severe disease and fatalities in dengue patients are now in clinical trial stages. One anti-dengue drug is now in phase 3 clinical trial, and another will begin phase 3 trial later this year. Another anti-dengue drug is in phase 2 trial currently. This is an encouraging drug development pipeline as just as recent as 5 years ago, there was no drug candidate at this stage of development. Dengue is now also a vaccine-preventable disease and new vaccine candidates are in various stages of clinical development. Finally, besides Project Wolbachia in Singapore, the World Mosquito Programme is also scaling up the release of Wolbachia infected mosquitoes. Unlike Project Wolbachia, the World Mosquito Programme’s approach is to spread Wolbachia in Aedes mosquitoes to make them resistant to transmitting dengue viruses. 

All these research studies are generating exciting findings and there is thus reason for optimism that dengue can be controlled. However, none of these research works will produce a silver bullet to end dengue. They will produce tools with strengths and weaknesses. Hence, dengue prevention will need to integrate all the tools generated by research such that the strengths of one tool cancels out the weakness of another tool.

What role do community engagement and public awareness play in dengue prevention, and how can these be effectively enhanced in Singapore?

I would refer your question to the NEA for more insights, but what I can say is that community engagement and public awareness are essential pillars of effective dengue prevention throughout the world where dengue is endemic.

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Dr. Goh Choo Beng

Head of Medical Affairs, India and Southeast Asia, Takeda Pharmaceuticals

How critical is the role of integrated dengue management strategies in addressing the current surge in dengue cases across Southeast Asia?

Integrated dengue management is critical. Although many governments have been relying on traditional dengue prevention methods such as spraying insecticide, or fogging, relying solely on individual prevention measures has often proven to be insufficient, especially during a sharp rise in cases. Research, for example, has shown that Aedes aegypti is evolving growing resistance to insecticides in many parts of Asia, which can render fogging and the use of insecticides more or less ineffective.[3] In order to manage dengue sustainably and holistically, we need a comprehensive approach encompassing vector control, surveillance, public education, and potentially, vaccination. Vaccination, therefore, combined with vector control strategies, would provide a streamlined, effective, and sustainable approach towards reducing the burden of dengue – similarly to how community vaccination for COVID-19 was implemented during the pandemic.

What are the main factors driving the alarming rise in dengue cases in Malaysia, Thailand, and other Southeast Asian countries this year?

Like Singapore, the wider region faces challenges from climate change, rapid urbanization, and evolving dengue virus serotypes. These factors, coupled with potential limitations in existing vector control methods, contribute to the alarming rise in cases. The 2024 El Niño, with its potential to bring hotter and drier conditions to Southeast Asia, is raising alarm bells about a surge in dengue fever cases across the region.  Countries with tropical climates are particularly vulnerable, given the consistently warm temperatures and high humidity they experience. Moreover, El Niño-driven temperature rises can lead to accelerated mosquito life cycles rand a faster replication rate of the dengue virus within the insects. Across highly popular tourist destinations in the region, another factor may be the influx of visitors from various regions contributing to the introduction and spread of different dengue serotypes.

This complex combination creates a perfect storm for dengue outbreaks, putting immense pressure on healthcare systems already grappling with the disease's burden. That is why it is important to explore more dengue management options, including vaccines, as recommended by the World Health Organization (WHO) in their position paper published in May.[4] However, we need to note that dengue vaccination is not a silver bullet. Vaccine introduction should be accompanied by a well-designed communication strategy and community engagement, as recommended by WHO.

Can you elaborate on the complexities and challenges involved in managing dengue as a public health issue in the region?

Managing dengue in Southeast Asia presents a complex web of interconnected challenges. The region's tropical climate provides ideal breeding conditions for the Aedes mosquito, making vector control a constant battle. Rapid urbanization, often unplanned, leads to inadequate water management and an abundance of breeding sites. High population density further facilitates transmission. 

Simultaneously, there are challenges in healthcare infrastructure, particularly in resource-limited settings.  Timely diagnosis and access to proper medical care can be limited, especially during large outbreaks. Public awareness campaigns often struggle to compete with misinformation and ingrained behaviors.[5]

Adding to this complexity is the cyclical nature of dengue, with outbreaks influenced by factors like monsoon seasons and El Niño events, making it difficult to maintain constant vigilance.  The presence of multiple dengue virus serotypes further complicates matters, as immunity to one serotype doesn't prevent infection with another and can even increase the risk of severe disease.

Addressing dengue requires a multi-faceted, long-term approach that combines robust surveillance, innovative vector control, accessible healthcare, effective public education, vaccination, and cross-border collaboration to manage this persistent threat to public health in the region.

What is the status of dengue vaccine development, and how close are we to having a widely accessible and effective vaccine?

A second licensed dengue vaccine, TAK-003, which can minimize any potential risk in seronegative persons has been made available increasingly across the globe. We've made progress as a region, with TAK-003 vaccine now available in Indonesia, Thailand, Malaysia, and soon, Vietnam. The focus now is on expanding access, particularly in endemic regions, through partnerships and robust public health infrastructures.

Other vaccines are also in development, with large investments and trials ongoing in Brazil[6] and India,[7] as well as ongoing research into inoculations for other mosquito-borne diseases like chikungunya and zika.

How can vaccines contribute to reducing the dengue burden, and what are the key considerations in their deployment across Southeast Asia?

Dengue vaccines hold the potential to significantly reduce the disease burden in Southeast Asia by providing long-term protection against infection and, crucially, potentially fatal severe symptoms. This translates to fewer hospitalizations, reduced strain on healthcare systems, and ultimately, saved lives. However, successful vaccine deployment requires careful consideration of several factors. Prioritizing high-risk populations in areas with high dengue burden and transmission rates is crucial for maximizing impact. It's essential to integrate vaccination programs with existing vector control and public health measures, ensuring a comprehensive approach.  Affordability and accessibility are paramount to guarantee equitable protection for all, regardless of socioeconomic status.  Finally, building public trust through clear and transparent communication about vaccine safety, efficacy, and importance is vital to overcome potential hesitancy and ensure widespread acceptance.

In what ways can international cooperation and collaboration enhance dengue prevention and control efforts in the region?

International cooperation is paramount in effectively combating dengue in Southeast Asia.  Openly sharing knowledge and best practices on surveillance, vector control strategies, and vaccine deployment can accelerate progress across the region.  Collaborative research and development efforts, particularly in vaccine development, diagnostic tools, and innovative vector control methods, are crucial for achieving breakthroughs.

Providing technical and financial support to countries with limited resources will strengthen their dengue control programs, ultimately contributing to regional success.  Beyond these measures, harmonizing surveillance and outbreak reporting mechanisms can facilitate early warning systems and coordinated responses.  Establishing regional training programs for healthcare professionals can enhance clinical management and diagnostic capabilities.  By working together, nations in Southeast Asia can overcome the complexities of dengue and safeguard public health across borders.

What innovative approaches or technologies are being explored to improve dengue diagnosis, treatment, and prevention?

The fight against dengue is driving innovation across multiple fronts.  Researchers are developing faster, more accurate, and affordable point-of-care diagnostic tests to enable early detection and timely treatment.[8] Novel vector control methods, such as genetically modified mosquitoes designed to suppress populations or reduce their ability to transmit the virus, are being explored. As an important component of holistic preventative tactics, vaccines that can improve efficacy across all dengue stereotypes, be safe and effective for broader age groups, including those who have not been previously exposed to the virus, will remain a critical focus. Simultaneously, scientists are researching effective antiviral drugs for dengue treatment, aiming to reduce disease severity and mortality. [9]

Beyond these advancements, harnessing the power of big data and artificial intelligence for enhanced surveillance, outbreak prediction, and targeted interventions holds immense promise.[10]  Combating dengue requires a multifaceted, collaborative approach that embraces these integrated strategies, prioritizes research and innovation, and fosters international cooperation to move towards a future with a significantly reduced dengue burden in Southeast Asia and beyond.

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[1] St. John, Ashley L., and Abhay PS Rathore. "Adaptive immune responses to primary and secondary dengue virus infections." Nature Reviews Immunology 19.4 (2019): 218-230.

[2] Chandrashekar, V., As Temperatures Rise, Dengue Fever Spreads and Cases Rise, Yale 360, November 30, 2023, Accessed August 2023

[3] The Straits Times, Super-resistant mosquitoes in Asia pose growing threat: Study, https://www.straitstimes.com/asia/east-asia/super-resistant-mosquitoes-in-asia-pose-growing-threat-study, January 11, 2023, Accessed August 2024

[4] World Health Organisation, 2024. WHO position paper on dengue vaccines – May 2024. Available at https://www.who.int/publications/i/item/who-wer-9918-203-224 Accessed August 2024

[5] Gagnon-Dufresne, Marie-Catherine, et al. "Social media and the influence of fake news on global health interventions: implications for a study on Dengue in Brazil." International Journal of Environmental Research and Public Health 20.7 (2023): 5299.

[6] The Conversation, Dengue: Brazilian single-dose vaccine could help turn tide in the fight against fever, https://theconversation.com/dengue-brazilian-single-dose-vaccine-could-help-turn-tide-in-the-fight-against-fever-225398, March 14, 2024, Accessed August 2, 2024

[7] Medigeshi, Guruprasad R., Farzana Islam, and Rakesh Lodha. "Quadrivalent dengue-virus vaccines: challenges and opportunities for India." The Lancet Infectious Diseases (2024).

[8] Macêdo, Jéssica VL, et al. "Systematic review and meta-analysis: assessing the accuracy of rapid immunochromatographic tests in dengue diagnosis." Diagnostic Microbiology and Infectious Disease (2024): 116227.

[9] Lee, Michelle Felicia, Yuan Seng Wu, and Chit Laa Poh. "Molecular mechanisms of antiviral agents against dengue virus." Viruses 15.3 (2023): 705.

[10] Sood, Sandeep Kumar, et al. "An intelligent healthcare system for predicting and preventing dengue virus infection." Computing 105.3 (2023): 617-655.