In the tropical and subtropical regions of the world, buzzing Aedes aegypti mosquitoes ferry infectious agents like the dengue virus from person to person. When a mature female — thirsty for blood to nourish her growing eggs — bites an infected human, the dengue virus replicates in her gut and spreads to her salivary glands, where it has the chance to pass to a new host when she bites them for her next meal. The best option to break this cycle is for people in these regions to avoid mosquito bites because there are no antivirals for mosquito-borne viruses currently on the market.
But KU Leuven virologist Leen Delang is optimistic that will change, and she wants to know what effects these antivirals will have when they finally get out into the world. Early in her career, Delang thought a lot about how antivirals prevent or disrupt infections in humans, but these days, she’s more interested in whether these drugs could affect the mosquito itself and the transmission cycle. “If this mosquito is infected with the virus and it ingests via the blood meal this antiviral drug, would it also have an effect there — like an additional bonus?” she wondered.
Delang finally got the chance to address this question when researchers at Johnson & Johnson identified JNJ-A07, which belongs to a new class of molecules capable of inhibiting dengue virus replication in mammals (1, 2). In a recent Science Advances study, she and her team showed that the proposed antiviral both prevented and treated dengue virus infection in mosquitoes (3).
Leen Delang studies how antivirals affect the ability of viruses to replicate in mosquitoes.
Credit: Leen Delang
“Every drug for a mosquito-borne virus should be evaluated before it gets accepted to see if there’s also this additional effect on mosquitoes and if it could reduce transmission,” said Delang.
After acquiring samples of JNJ-A07 from Johnson & Johnson, Delang’s team began by testing it on mosquito cells infected with dengue virus. A quantitative real-time PCR test confirmed that the drug reduced the amount of virus in the cells and that higher doses resulted in bigger reductions. The scientists found similar results when they tested the antiviral on whole mosquito guts, so they decided to give it to living mosquitoes.
Delang and her team created artificial blood containing red blood cells from rabbits and spiked it with dengue virus, JNJ-A07, or both. Then, they gave mosquitoes the opportunity to drink the blood meal from a membrane-covered container and tracked the effects of their consumption of the antiviral.
First, Delang wanted to know if the antiviral would affect the mosquitoes in any way. “We want to kill the virus, but if it will also start killing the mosquito, then maybe the mosquito will find a way to increase the expression of an enzyme that metabolizes the drug,” she said. So, her team gave the insects a high dose of the antiviral and monitored them for about a month and confirmed that the treated mosquitoes did not die in greater numbers than the untreated group. Furthermore, they found that JNJ-A07 had no effect on the number of eggs that the mosquitoes produced. Because the drug did no harm to the insects, Delang felt confident that there would be no unintended consequences arising from its interaction with the mosquitoes themselves.
To see if the antiviral could successfully block dengue infections in mosquitoes, Delang and her team collected organ samples from individual mosquitoes which had been exposed to dengue virus and doses of the antiviral simultaneously. They found that at higher doses, JNJ-A07 completely inhibited infection, and even at lower concentrations, it reduced viral replication to an extent.
That excited Delang, but she realized the experiment didn’t necessarily represent a real-world scenario. “If people are taking the drug, it will probably work quickly, so there will not be much dengue anymore,” said Delang. In other words, mosquitoes are not likely to encounter the virus and the drug within one person’s blood at the same time. So, Delang set up a pair of experiments in which mosquitoes drank the artificial blood twice, six days apart. One group received the virus first and a dose of JNJ-A07 second, and the other got the drug first then the virus. Tracking the insects’ infections over the following week revealed that the therapeutic dose reduced the amount of virus in the insects and that the prophylactic dose prevented viral replication altogether.
“That was really surprising to us, that the drug could stay so long in the mosquitoes that it could have such significant inhibition,” said Delang.
That was really surprising to us, that the drug could stay so long in the mosquitoes that it could have such significant inhibition.
- Leen Delang, KU Leuven
They put the data from their experiments into a mathematical model of dengue infection developed by researchers at Johnson & Johnson, which suggested that exposing mosquitoes to JNJ-A07 could reduce the likelihood of dengue outbreaks in humans. In the future, Delang hopes that public health officials can build on her team’s initial model by using real-world data on interactions between mosquitoes and people in outbreak-prone areas.
George Dimopoulos, a virologist at Johns Hopkins University, appreciated the work that Delang did, but he wondered why she didn’t consider other methods for administering the drug to mosquitoes. He mentioned strategies used in the fight against malaria like doping bug nets with antimalarials and administering the drugs to other animals that mosquitoes might feed on. Dimopoulos was particularly interested in using the antiviral in attractive targeted sugar baits, which are an emerging technology for controlling mosquito populations. “What people typically do is they lace this artificial nectar with an insecticide to kill the mosquito,” said Dimopoulos. “But in theory, you could also lace it with an antiviral compound.”
Now that she knows JNJ-A07 works to inhibit dengue infections in mosquitoes, Delang is open to those other possibilities for administration. But before public health officials can implement any strategy based on her work, the antiviral has to actually make it to market. In October 2024, Johnson & Johnson announced that it had discontinued its Phase 2 field study to evaluate the efficacy of the closely related molecule mosnodenvir, which the company had chosen to move forward with because of its improved safety profile relative to JNJ-A07 (4).
“It’s a very potent drug,” said Delang. “We’ll hope it will be picked up by another company.”
References
- Kaptein, S.J.F. et al. A pan-serotype dengue virus inhibitor targeting the NS3-NS4B interaction. Nature 598, 504-509 (2021).
- Kiemel, D. et al. Pan-serotype dengue virus inhibitor JNJ-A07 targets NS4A-2K-NS4B interaction with NS2B/NS3 and blocks replication organelle formation. Nat Commun 15, 6080 (2024).
- Rosales-Rosas, A.L. et al. The antiviral JNJ-A07 significantly reduces dengue virus transmission by Aedes aegypti mosquitoes when delivered via blood-feeding. Sci Adv 10, eadr8338 (2024).
- Goethals, O. et al. Blocking NS3-NS4B interaction inhibits dengue virus in non-human primates. Nature 615, 678-686 (2023).
