Potent dengue antibody discovered
A reconstructed image of dengue virus serotype 3 bound with antigen-binding fragments of super-potent antibody 5J7
Dengue is making a resurgence worldwide, where the incidence of dengue virus has increased by 30 times over the last five decades. In Singapore, the number of reported dengue cases this year has hit more than 1,900. In view of the worrying trend, the finding of a powerful antibody by Duke-NUS Graduate Medical School Singapore (Duke-NUS) that neutralises the dengue virus is thus good news.
Published online in the journal Nature Communications on 20 February 2015, the study identified a newly discovered antibody 5J7 that kills a strain of the dengue virus efficiently. A mere 10-9 g of the antibody can effectively halt the infection of dengue serotype 3 virus (DENV-3), raising hope for the development of effective dengue treatments. No licensed dengue vaccine or therapeutic agent currently exists because the presence of four circulating virus variants or serotypes (DENV-1 to 4) makes the development of a cure greatly challenging.
Senior author of the study Associate Professor Shee Mei Lok, who is with the Emerging Infectious Diseases Programme at Duke-NUS, has been concentrating on understanding the pathology and structure of the dengue virus to develop effective treatments. Her laboratory has already uncovered antibodies effective against DENV-1. The team's approach to a safe therapeutic combines four antibodies, each binding and inhibiting infection of each of the dengue virus serotypes.
In the latest work, the researchers isolated 5J7 from 200 different candidate antibody molecules by examining dengue-infected blood samples from a patient. Under very high magnification, the virus-antibody complex structure demonstrated that each arm of the antibody strongly grabs three surface proteins on the surface of the virus simultaneously. Furthermore, the antibody binds to the sites on the virus critical for its invasion of cells, thus blocking the virus' activity.
Even though a patient infected by one serotype of the virus produces antibodies which provide lifelong immunity towards that particular serotype, antibodies that bind to the other three serotypes are also produced if the patient is infected by them. Secondary infection may occur and cause a more severe form of the disease.
Assoc Prof Lok revealed plans to test the 5J7 in mouse models first before proceeding to clinical trials, as the remaining two serotypes of dengue virus (DENV-2 and DENV-4) have to be considered. She said: "We are optimistic that we will make a treatment breakthrough within these few years but antibodies against all the other serotypes have to be identified first.
The team, which includes first author Research Fellow Guntur Fibriansah and other researchers from Duke-NUS, collaborated with the University of North Carolina and Vanderbilt University on the study.
