Research advances therapy to protect against dengue virus

April 8, 2013 by Helen Knight
Research advances therapy to protect against dengue virus
Photo: James Gathany/Centers for disease control and prevention

Nearly half of the world's population is at risk of infection by the dengue virus, yet there is no specific treatment for the disease. Now a therapy to protect people from the virus could finally be a step closer, thanks to a team at MIT.

In a paper published today in the Proceedings of the National Academy of Sciences, the researchers, from MIT's Koch Institute of Integrative , present a novel approach to developing a therapy using mutated .

According to a study by the International on Dengue Risk Assessment, Management and Surveillance, up to 390 million people are infected with the each year. For most people the mosquito-borne virus causes flulike symptoms, including fever, headache and joint pain. But for some, particularly children, the virus can develop into the far more serious dengue hemorrhagic fever, causing severe and even death.

Despite the threat posed by the disease, developing a vaccine against dengue has so far proved challenging, according to Ram Sasisekharan, the Alfred H. Caspary Professor of at MIT. That's because dengue is not one virus but four different viruses, or serotypes, each of which must be neutralized by the vaccine.

Protecting people from only one or some of the four viruses could cause them to develop the more severe form of dengue if they later become infected with one of the other serotypes, in a process known as antibody-dependent enhancement, Sasisekharan says. "That was the motivation for carrying out our study, to generate a fully neutralizing antibody that works for all four serotypes."

Pushing the envelope

Efforts to develop a therapeutic antibody for dengue are focused on a part of the virus called the envelope protein. "This is a very that allows the virus to latch on to the appropriate receptor within the host, to infect them, replicate and spread," Sasisekharan says.

Research advances therapy to protect against dengue virus
This transmission electron micrograph depicts a number of round, dengue virus particles. Credit: Frederick Murphy/Centers for disease control and prevention

The contains two regions of interest, known as the loop and the "A" strand. Research teams have previously attempted to engineer an antibody that targets the loop region of the virus protein, as this is known to be able to attack all four serotypes if targeted in the right way.

However, the antibodies that target the loop region tend to have low potency, meaning they are unable to completely neutralize the virus. This increases the risk of more severe secondary dengue infection.

So a team led by Sasisekharan decided instead to look for antibodies that target the "A" strand region of the protein. Such antibodies tend to have much higher potency, but they are unable to neutralize all four serotypes.

450-fold increase

The researchers chose as their model an antibody known as 4E11, which has been shown in tests to neutralize dengue 1, 2 and 3, but not dengue 4. "We wanted to see if we could get good neutralizing activity to dengue 4, and also tweak the antibody to increase the potency associated with the other subtypes," Sasisekharan says.

The authors mined existing antibody-antigen complexes to analyze the physical and chemical features that play an important role in their interaction, such as hydrogen bonding and ionic attraction. Taking a statistical approach, they then ranked these features in terms of their importance to each of the antibody-antigen interactions.

This significantly narrowed the number of possible changes, or mutations, the researchers needed to make antibody 4E11 in order to improve its ability to neutralize all four viruses, in particular 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," Sasisekharan says.

As a result, the researchers came up with 87 possible mutations, which they were able to reduce to just 10 changes after further investigation.

When they tested their mutated antibody on samples of the four dengue serotypes in the laboratory, they found it had a 450-fold increase in binding to dengue 4, a 20-fold increase in binding for dengue 2, and lesser improvements in binding for dengue 1 and 3, Sasisekharan says.

The MIT researchers are now preparing for potential preclinical trials, and hope to be ready to test the antibody on humans within the next two to three years. In the meantime, they are also investigating other targets for their immunotherapy approach, including the influenza .

Explore further: Human antibody for dengue virus isolated

Related Stories

Human antibody for dengue virus isolated

June 22, 2012
(Phys.org) -- A group of scientists in Singapore and the UK have isolated a human antibody capable of effectively neutralizing the mosquito-borne dengue virus. Dengue fever is currently incurable and infects an estimated ...

TIM and TAM: 2 paths used by the Dengue virus to penetrate cells

October 23, 2012
By demonstrating that it is possible to inhibit the viral infection in vitro by blocking the bonding between the virus and these receptors, the researchers have opened the way to a new antiviral strategy. These works were ...

Researchers identify Achilles heel of dengue virus, target for future vaccines

April 11, 2012
A team of scientists from the University of North Carolina at Chapel Hill and Vanderbilt University have pinpointed the region on dengue virus that is neutralized in people who overcome infection with the deadly pathogen. ...

Recommended for you

Google searches can be used to track dengue in underdeveloped countries

July 20, 2017
An analytical tool that combines Google search data with government-provided clinical data can quickly and accurately track dengue fever in less-developed countries, according to new research published in PLOS Computational ...

MRSA emerged years before methicillin was even discovered

July 19, 2017
Methicillin resistant Staphylococcus aureus (MRSA) emerged long before the introduction of the antibiotic methicillin into clinical practice, according to a study published in the open access journal Genome Biology. It was ...

New test distinguishes Zika from similar viral infections

July 18, 2017
A new test is the best-to-date in differentiating Zika virus infections from infections caused by similar viruses. The antibody-based assay, developed by researchers at UC Berkeley and Humabs BioMed, a private biotechnology ...

'Superbugs' study reveals complex picture of E. coli bloodstream infections

July 18, 2017
The first large-scale genetic study of Escherichia coli (E. coli) cultured from patients with bloodstream infections in England showed that drug resistant 'superbugs' are not always out-competing other strains. Research by ...

Ebola virus can persist in monkeys that survived disease, even after symptoms disappear

July 17, 2017
Ebola virus infection can be detected in rhesus monkeys that survive the disease and no longer show symptoms, according to research published by Army scientists in today's online edition of the journal Nature Microbiology. ...

Mountain gorillas have herpes virus similar to that found in humans

July 13, 2017
Scientists from the University of California, Davis, have detected a herpes virus in wild mountain gorillas that is very similar to the Epstein-Barr virus in humans, according to a study published today in the journal Scientific ...

0 comments

Please sign in to add a comment. Registration is free, and takes less than a minute. Read more

Click here to reset your password.
Sign in to get notified via email when new comments are made.