With the nicknames “break-bone fever” and “bone-crusher disease,” you can imagine that the pain caused by dengue fever is pretty unpleasant. Alongside this horrendous symptom, infection can develop into a potentially lethal complication called severe dengue. Worse still, half of the world’s population is at risk of infection, yet there are no vaccines or specific treatments.
While raised hopes were recently dashed following disappointing trial results of a previously promising vaccine, there is still reason to be optimistic as scientists have just revealed a novel viral target which could help in the design of both vaccines and therapeutics. Importantly, an antibody directed against this portion of the virus successfully treated mouse models of severe disease caused by one of the dengue viruses. The study has been published in Science.
There are four different viruses that cause dengue fever, DENV-1–4, which are spread by mosquitoes. Following infection with one, an individual is bestowed with lifetime immunity against that type. But there is a problem with this: the antibodies that protect from future infections actually enhance infection by a different type of dengue virus, a process known as antibody-dependent enhancement (ADE) of infection. This means that subsequent infections with different types come with an increased risk of dengue hemorrhagic fever and dengue shock syndrome, which can be fatal.
This means that in order to be effective and safe, vaccines should elicit antibody responses to all of the different types of dengue virus. While recent vaccine trials have demonstrated good levels of protection against DENV-3 and DENV-4, and some for DENV-1, the same was not observed for DENV-2. This is thought to be because DENV-2’s surface is more dynamic than that of the others, meaning that antibodies lose potency as they try to stick to different bits.
But scientists were offered some encouragement recently following the generation of human antibodies which stick to a complex outer portion of the DENV-2 virus. Importantly, the antibodies were found to protect mice against the virus when administered before or after exposure, suggesting potential for use as both a vaccine and treatment. To probe the antibodies further, researchers from Vanderbilt University and the National University of Singapore used a sophisticated microscopic technique, called cryo-electron microscopy, to provide incredibly detailed images of the antibody bound to its target on two different DENV-2 strains.
This revealed that the antibody latches onto and locks multiple surface proteins, which the researchers propose prevents them from reorganizing into the structures required for entry into target cells. Furthermore, it is capable of neutralizing both DENV-2 strains with equal efficiency. But perhaps the most important finding is that by sticking to the virus in this manner, the antibody actually blocks other dengue virus antibodies from binding and thus prevents ADE.
The researchers therefore believe that this newly identified antibody target could help researchers design both effective vaccines and drugs to treat infection.