Around half of the world’s population is now at risk of Dengue fever, and the mosquito-bourne virus is the leading cause of death in some Latin American and Asian countries. But despite a rapid rise in cases and decades of drug development efforts, the field has no specific treatment and only one limited-use vaccine.
There is no antiviral treatment for Dengue fever, and the only approved vaccine–Sanofi’s Dengvaxia–can prove risky. Dengvaxia can reduce the severity of Dengue fever in those who have had a prior infection. However, Dengvaxia may increase the risk of severe Dengue in those who have not yet been infected.
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Experts say poorly coordinated clinical trial efforts, difficulties in animal models and laboratory tests, and a complex, evolving virus have stalled vaccine and antiviral development. Still, by streamlining clinical trial symptom endpoints and pursuing less traditional designs like platforms trials and human challenge studies, experts say manufacturers could make progress towards addressing this neglected disease.
Dengue largely occurs in tropical and sub-tropical climates, but manufacturers should still look toward the FDA and European Medicines Agency (EMA) for regulatory guidance. Many low- and middle-income countries look towards these regulatory bodies, as well as local authorities in Brazil and Singapore, to guide their regulatory approach.
Dengue fever is a viral infection transmitted through mosquito bites. Cases range from asymptomatic to flu-like symptoms to severe Dengue, which can lead to organ impairment, severe bleeding, and death.
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Mosquito-bourne viruses on the rise
There are an estimated 100–400 million yearly Dengue infections, with cases quickly on the rise, according to WHO. However, reported numbers largely underestimate the global prevalence of mosquito-bourne illnesses, says Rajeev Vaidyanathan, PhD, entomologist at Oxitec, a US-owned biotech company developing genetically modified insects to assist in insect control. Many cases are underreported and, in the case of Dengue fever, more than 80% of cases are asymptomatic, he adds.
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By GlobalDataIn the preceding decades, trends in urbanisation and climate change have driven a rise in mosquito-bourne illnesses, Vaidyanathan says. Urbanisation has led to greater human population density, poor sanitation, and more artificial water reservoirs–particularly in neighbourhoods that lack running water and rely on cisterns, he notes. Climate change has created warmer cities and increased reliance on artificial water storage, which makes them more hospitable to mosquitoes, he adds.
Dengue fever and other mosquito-bourne illnesses largely take place in countries with tropical climates. According to GlobalData’s Clinical Trial Database, India and Brazil have the most clinical trial sites with at least one ongoing study in Dengue fever, with 58 and 16 sites respectively. Mosquito-bourne illnesses malaria and Chikungunya fever follow similar global trends. GlobalData is the parent company of Clinical Trials Arena.
Challenges of drug and vaccine development
From a biochemical standpoint, there are two key challenges to developing Dengue fever antivirals and vaccines, says La Jolla Institute for Immunology infectious disease expert Sujan Shresta, PhD. First, Dengue fever has four different serotypes, leading many biologists to see Dengue as four distinct viruses requiring differing approaches. Second, Dengue fever is an RNA virus, which means it constantly evolves as the virus replicates, she explains.
Put together, Dengue fever is a multi-faceted, moving target, and researchers do not fully understand how it evolves in mosquitos and human hosts, Sujan says.
From a clinical trial standpoint, the obstacles loom even larger. There are normally substantial gaps between the time of a mosquito bite, the time symptoms start, and the time someone would seek medical help and get a diagnosis, Vaidyanathan explains.
Additionally, the Dengue field should aim to avoid issues seen during the Covid-19 pandemic: many of the Covid-19 clinical trials in existence are not well designed to determine clinically meaningful effects, adds Drugs for Neglected Disease Initiative (DNDi) discovery director Dr Charles Mowbray.
There are 43 ongoing Phase I–IV trials for Dengue fever, the majority of which are company sponsored. As for the two other most common mosquito-bourne illnesses, there are 138 ongoing trials for malaria and just eight for Chikungunya fever.
Overcoming deficits in early data
Animal models are generally weak for Dengue fever, so many drugs and vaccines enter the human trial stage with a less robust understanding of their mechanisms and effects, says SUNY Upstate Medical University infectious disease expert Dr Stephen Thomas. Primates do not get sick with Dengue viruses and mice require severe alterations to their immune systems to exhibit symptoms, he adds.
To address potential challenges with animal studies, Shresta’s lab at the La Jolla Institute has developed a method for infecting animal cells with Dengue viruses. By using antibody dependent enhancement to prime cells to allow entry to real Dengue viruses, researchers can better observe the effects of Dengue fever in animal models, Shresta explains.
This method has also shown that prior exposure to Dengue virus can provide cross-protection against Zika virus, she adds. As a result, trials targeting Dengue could expand to include patients with or at risk of developing Zika virus infections, she notes.
Nevertheless, clinical trials can counteract potential deficits in preclinical animal models by beginning clinical development programs with human challenge studies, Thomas notes. This entails giving a group of healthy subjects an attenuated Dengue virus to monitor and test the effects of new treatments, he adds. Human study challenges can use an attenuated Dengue virus from the US Army, which gives a mild infection and was derived from earlier attempts to create a vaccine, he notes.
Designing later-stage trials
When designing Dengue fever clinical trials, there are two main types of endpoints: clinical signs and laboratory values, Thomas says. Clinical symptoms include fever, headache, pain behind the eyes, muscle pain, bone pain, and rash. Meanwhile, laboratory values include temporary drop in white blood cell count, drop in platelets, and increase in liver enzymes, as well as longer-term fluctuations in viral replication, he adds.
Later stage trials can prove challenging, as most would require enrolling paediatric populations, which are at the highest risk of contracting Dengue fever, Thomas explains. In addition, Dengue fever trials can draw on lessons learned from Covid-19 studies, Mowbray adds. Many Covid-19 trials tested the same drugs and vaccines but under different names and protocols, complicating the data-sharing process, he explains.
As one potential solution, platform trials can streamline collection of good evidence for multiple drugs across different treatment settings and endemic regions, Mowbray says. Platform trials, which study multiple treatments under a single, durable master protocol, are gaining steam in the rare disease and oncology spaces.
Devising regulatory strategy
Dengue fever is most prevalent in low- and middle-income countries, and so antivirals and vaccines will require regulatory approval in countries throughout Latin America and Asia, Mowbray says. Countries including Mexico, Malaysia, Thailand, and Vietnam have high incidences of Dengue fever but less established regulatory systems, Thomas notes. Dengue fever is less prevalent in Africa, although travelers to the continent can get infections, he adds.
In many cases, low- and middle-income countries with less robust regulatory infrastructure will still look toward highly established regulators like the FDA and EMA for guidance, Thomas says. As a result, manufacturers should still look toward the FDA and EMA for clinical trial success expectations. These regulatory bodies value Dengue treatments because of possible exposure to travelers, expatriates, and military members, he explains.
Outside of Europe and the US, Brazil and Singapore have strong regulatory programs for Dengue fever that other countries look towards, Thomas adds. In particular, Brazil has a high prevalence and strong domestic manufacturing capacities, he notes.
Overall, Mowbray says cooperation between research and regulatory stakeholders is key to making progress: “Dengue fever drug development is typically a collaborative space, and as scientists, we like to do that.”
Takeaways:
- Global warming and urbanisation have driven a surge in Dengue fever, a mosquito-bourne virus that can cause severe shock or death.
- Manufacturers have struggled to develop Dengue antivirals and vaccines due to poorly coordinated clinical research and inadequate understanding of how the virus evolves.
- Clinical trial programs should consider human challenge studies with attenuated viruses to address potential deficits in preclinical data.
- Later-stage trials could use master protocol and platform trial designs to streamline endpoint selection and overcome inconsistencies in data collection.
- Although Dengue fever largely occurs outside the US and Europe, other countries still rely on the FDA and EMA for guidance.
Clarification: This article has been edited to reflect that Mowbray's comments about trials testing the same drugs and vaccines under different protocols were in reference to Covid-19 studies as models for Dengue fever trials, not past Dengue fever trials.
