The challenges of treating and preventing Dengue fever

Dengue fever, a mosquito-borne viral disease, is surging to record levels worldwide. With four genetically distinct serotypes, each capable of causing severe illness, the virus presents unique challenges for both treatment and prevention. With half the world’s population already at risk from this disease, the need for an effective antiviral is growing increasingly urgent.

Why do the four serotypes matter?

Note: A serotype is a distinct subgroup within a species of bacteria or viruses.

The dengue virus presents a challenge for both treatment and prevention because it exists as four distinct serotypes (DENV-1 through DENV-4), each one capable of causing infection and severe disease.

Each serotype is genetically and structurally distinct, to the extent that they can be considered different viruses. This diversity complicates both drug and vaccine development, as something that is effective against one serotype may not work against the others.

The four dengue serotypes also differ in their impact on patients, with some more likely to cause severe illness than others.

DENV-2 and DENV-3 are often associated with more severe cases, including dengue hemorrhagic fever and dengue shock syndrome, especially in secondary infections. DENV-4 is generally linked to milder disease but can still cause significant health issues.

For any therapeutic to be truly effective against Dengue, it must work equally well against all four serotypes. Due in no small part to the complexities caused by this situation, there is currently no approved antiviral treatment for dengue, and this painful, debilitating, and sometimes deadly virus continues to ravage communities around the globe.

Understanding primary vs. secondary infection

A primary infection with one serotype typically causes classic dengue symptoms and results in lifelong immunity to that serotype. However, if a person is later infected with a different serotype (secondary infection), the risk of severe disease increases due to a phenomenon called antibody-dependent enhancement (ADE).

In ADE, antibodies from a previous dengue infection can bind to the virus and actually help it enter immune cells. This increases the number of infected cells and boosts viral replication, leading to higher levels of virus in the blood (viremia) and a stronger inflammatory response in the body. These cases are more likely to progress to the more severe forms of dengue, which can be fatal.

 ADE is also a problem in dengue vaccine development, as vaccines that don’t provide balanced protection against all four serotypes could increase the risk of severe disease if a vaccinated person is later exposed to a different serotype.

Dengue vaccine drawbacks

The experience of Dengvaxia, the first licensed dengue vaccine, highlights the dangers of uneven efficacy.

Dengvaxia showed an overall efficacy of about 80% against symptomatic, laboratory-confirmed dengue, but its effectiveness varied significantly against each serotype, and other variables such as the person’s age, and the prior dengue exposure of the vaccine recipient.

 This imbalance meant that recipients were not equally protected against all dengue types, leaving gaps in their immunity, and creating greater risk for individuals who had never been infected with dengue before.

When these individuals later encountered dengue in its natural form (via the bite of disease-carrying mosquitoes), they were unknowingly at higher risk of severe disease and hospitalisation. Dengvaxia has now been withdrawn from most markets, including USA, and its use is now highly restricted

What about antivirals?

In the case of antiviral drugs, achieving equal activity across all four dengue serotypes is technically demanding due to the variance between them. Each serotype differs from the others by about 30 to 35% in their amino acid sequences, making them substantially different in their protein structure and surface features.

This can affect not only how immune system antibodies recognise the virus but also how small-molecule antivirals or inhibitors bind and function, meaning that any drug designed to bind or inhibit a viral protein in one serotype may not fit or work as well against the same protein in another serotype.

Can we succeed where others have failed?

The lack of a dengue-specific antiviral is a major gap in global health, and one that Kimer Med is committed to addressing by taking a fundamentally different approach from traditional antiviral drug development.

Instead of designing drugs to bind to specific viral proteins, which can differ significantly between the four dengue serotypes, Kimer Med’s platform targets a process all viruses (with one possible exception) have in common: the production of long double-stranded RNA (dsRNA) that occurs within virus-infected cells during lytic replication.

This approach reduces the risk that the differences between serotypes will limit or prevent the drugs’ effectiveness. It also lowers the likelihood of resistance developing, since the targeted process is essential to viral survival.

Kimer Med’s leading antiviral drug candidate has shown very high levels of efficacy in vitro against all four dengue serotypes. In total, our positive antiviral results span 21 viruses across nine virus families. This breadth of activity is rare, and directly addresses the challenge of serotype diversity that hampers traditional antiviral and vaccine strategies.

Kimer Med’s broad-spectrum antiviral platform overcomes the technical barriers posed by the diversity among dengue serotypes by targeting a shared and common viral process, not variable proteins. This approach gives Kimer Med a strong chance of developing a single, broadly effective antiviral capable of treating any dengue infection - something traditional, more specific drugs have struggled to achieve.