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Existing Treatments and Vaccines No Longer Effective Against Dengue Virus

Breakthrough discovery reveals that Envelope (E) proteins in dengue virus are able to mutate and change its surface structure to evade detection.

Colour coded alert posters strategically placed near bus stops and void decks in Singapore serve to remind us that the threat of dengue fever is never far away from home. To most of us, dengue fever is a notorious disease that needs no introduction. This deadly mosquito-borne tropical disease is caused by the dengue virus (DENV) and its transmission rate is accelerated by high population densities and rising global temperatures. Just a few decades ago, dengue fever affected less than 10 countries. Today, dengue is endemic in areas that affect nearly half the global population.

Evidently, dengue is well on its way to becoming a global pandemic. Currently, the vaccine CYD-TDV, sold under the brand name Dengvaxia, is the only available dengue vaccine that has been licensed to use for the treatment of dengue. Still, it is far from being a viable treatment. An effective vaccine should simultaneously stimulate antibody responses against all four strains of dengue virus. However, this vaccine is ineffective against the second strain of dengue virus, DENV2, and can cause severe dengue haemorrhagic fever (DHF) and dengue shock syndrome (DSS) if incorrectly used.

A breakthrough discovery on the ability of the DENV2 virus to morph into various forms poses another serious problem to the development of effective vaccines. Researchers from Duke-NUS Medical School, A*STAR Bioinformatics Institute and University of Texas have discovered that at higher temperatures, the Envelope (E) protein in the DENV2 virus is able to undergo various mutations to evade the immune system of its host. The E protein is the major surface protein on the virus. This means that any mutations in the E protein would change the external surface structure of the entire virus, rendering vaccines and therapeutics to be ineffective against the mutated strain.

Using lab adapted DENV2, researchers observed that the virus changes from a smooth compact surface morphology to a loose bumpy surface morphology when the temperature is raised from 28°C to 37°C. Using DENV2 strains extracted from patients, the researchers observed that the majority of DENV2 viruses retained its smooth surface morphology at 37°C, only adopting a bumpy surface morphology at 40°C. This disparity in observations allowed the researchers to conclude that lab adapted DENV2 and clinical strains of DENV2 have different structures and characteristics, and that the clinical strains of DENV2 should be used in future experiments for increased accuracy.

“Our study gives a new direction to vaccine development and treatment for dengue disease.” Said Dr Shee Mei Lok, a Professor in the Emerging Infectious Disease program in Duke-NUS Medical School and corresponding author of this study. “For prevention of disease through vaccines that are administered to the patient before dengue infection, we should use those that are effective against the smooth surface virus. For when it comes to patients displaying fever symptoms, treatment strategies against the bumpy surface particles should be implemented.”

Apart from gaining a deeper understanding of the relationship between DENV2 and the host’s immunological defences, the researchers were also able to make use of computational modelling approaches to discover why certain strains of DENV2 viruses were more susceptible to morphological switches than others.

This study has opened up new possibilities for the future of the dengue disease. Should future vaccine and therapeutics development be able to effectively target both morphological forms of the DENV2 virus, a future free from the grasps of the dengue virus may not be so far away after all. [APBN]