A vaccine candidate that blocks infection and confers protection against all four strains of dengue virus has been uncovered by Katja Fink and Cheng-I Wang from the A*STAR Singapore Immunology Network, in collaboration with colleagues from across the country.
The mosquito-borne dengue virus currently has no specific vaccine or treatment. Originally confined to Southeast Asia, the dengue virus has now spread to southern China, Africa, Indonesia, Australasia, Latin America and the United States. Millions of people are infected by the virus each year and usually develop mild flu-like symptoms and a characteristic skin rash. However, around one in every thousand cases is fatal due to dengue hemorrhagic fever or dengue shock syndrome.
The development of a safe and effective small molecule drug or vaccine against dengue has been elusive, partly due to the complexity of the virus itself. There are four strains or ‘serotypes’ and each produces different immune responses by interacting with antibodies in human blood serum. Fink‘s team have been working to develop a therapeutic agent that is effectively a combination of four treatments.
Their first step was to isolate an antibody (SIgN-3C) produced by a naturally-infected dengue patient that is able to bind to all four dengue virus serotypes and prevent their replication in cells. When administered to mice, SIgN-3C reduced blood-virus levels after exposure to any of the four dengue serotypes. If administered before exposure, it conferred protection against infection.
Similar findings were reported with SIgN-3C-LALA, an intentionally mutated version of the antibody that stops antibody−virus complexes from entering cells, thereby preventing enhancement of dengue infection. This phenomenon known as ‘antibody-dependent enhancement’ helps to explain why patients who have been infected by dengue before are more likely to experience severe symptoms when they are infected subsequently by a different serotype. This is a major barrier for developing therapeutic antibodies against dengue virus.
Fink concedes that they were surprised at the efficiency of SIgN-3C-LALA against all four dengue serotypes. “Usually, very potent neutralizing antibodies are specific against one virus serotype, [while] cross-reactive antibodies are usually less potent,” she explains. The key to this cross-reactivity lies in the unique virus−antibody binding site. SIgN-3C-LALA targets a site that is conserved across serotypes and is crucial for virus integrity.
With a grant from the Global Health Innovative Technology Fund, the team continues to investigate the mechanism of action of the antibody and are working with Chugai Pharmaceuticals to evaluate its suitability for the treatment of dengue in humans.