AsianScientist (Apr. 15, 2013) – Dengue is the most medically relevant mosquito-borne viral illness affecting humans today, with an estimated 390 million people infected each year. For most people, the virus causes relatively mild flu-like symptoms. But for some, particularly children, the infection can develop into dengue hemorrhagic fever, a potentially fatal condition.
Despite the enormous public health burden of the disease, a dengue vaccine has remained elusive. This is because dengue actually exists as four different viruses, known as serotypes, and an effective vaccine must elicit an immune response that neutralizes all of these. Protection against only one or some is not an option – through a phenomenon known as antibody-dependent enhancement, this could in fact cause more severe dengue if patients subsequently become infected with the remaining serotypes.
“That was the motivation for carrying out our study, to generate a fully neutralizing antibody that works for all four serotypes,” said Prof. Ram Sasisekharan, MIT professor and leader of the team, which was a part of the Singapore-MIT Alliance for Research and Technology’s Infectious Diseases Research Program.
Efforts to develop a therapeutic antibody against dengue typically target the viral envelope protein, which adorns the virus surface. “This is a very critical protein that allows the virus to latch on to the appropriate receptor within the host, to infect them, replicate and spread,” said Prof. Sasisekharan.
Two regions of the envelope protein are of interest: the loop region and the “A” strand. Antibodies targeting the loop region can neutralize all four dengue serotypes, but do so with low potency, thus risking antibody-dependent enhancement. On the other hand, antibodies that target the “A” strand are highly potent, but are rarely effective against all four serotypes.
The researchers wanted to engineer an “A” strand-targeting antibody that would potently neutralize all dengue serotypes. They chose antibody 4E11, which neutralizes dengue 1, 2, and 3, but not dengue 4. Many previous attempts at antibody design relied on screening huge libraries of randomly mutated antibodies for the desired properties, a painstaking and expensive process.
Instead, the scientists developed a novel computational method that captures the essential physical and chemical properties of the interactions between antibody and virus. This enabled them to predict the mutations in antibody 4E11 that would increase its affinity for dengue 4.
“So rather than random screening, we used a statistically driven approach so we knew the regions to focus on, and what things we had to change,” Prof. Sasisekharan explained.
The team incorporated five of the most promising mutations into their redesigned 4E11 antibody. This improved its binding affinity for dengue 4 by 450-fold, without compromising its affinity for the other three serotypes. The redesigned antibody also showed antiviral activity in a mouse model of dengue infection.
Publishing their study in the journal Proceedings of the National Academy of Sciences, the researchers hope to be able to test the antibody in humans within the next two to three years, and are also investigating other targets for their approach, including the influenza virus.
Source: MIT. Photo: Sanofi Pasteur/Flickr/CC.
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