Navigation Links
Research advances therapy to protect against dengue virus
Date:4/8/2013

CAMBRIDGE, MA -- 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 Cancer Research, present a novel approach to developing a dengue therapy using mutated antibodies.

According to a study by the International Research Consortium on Dengue Risk Assessment, Management and Surveillance, up to 390 million people are infected with the dengue virus 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 blood loss 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 Biological Engineering 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 critical protein that allows the virus to latch on to the appropriate receptor within the host, to infect them, replicate and spread," Sasisekharan says.

The envelope protein 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 virus.


'/>"/>

Contact: Sarah McDonnell
s_mcd@mit.edu
617-253-8923
Massachusetts Institute of Technology
Source:Eurekalert

Related biology news :

1. Researchers design drug to restore cell suicide in HPV-related head and neck cancer
2. Researchers shine light on how stress circuits learn
3. Cleveland Clinic researchers discover new link between heart disease and red meat
4. Researcher offers clues on the origins of life
5. SFU researchers help unlock pine beetles Pandoras box
6. Mercyhurst Universitys new DNA sequencer to accelerate scientific research in region
7. Empa researchers join Quantis to open new branch in Switzerland
8. MDC and FMP researchers identify edema inhibitor
9. Barrow researchers identify
10. Nobel Laureate Jules Hoffmann kicks off Annual Drosophila Research Conference
11. Energy Department announces 5-year renewal of funding for Bioenergy Research Centers
Post Your Comments:
*Name:
*Comment:
*Email:
(Date:2/7/2017)... , Feb. 7, 2017   MedNet Solutions ... the entire spectrum of clinical research, is pleased to ... , its innovative, highly flexible and award winning ... customers. iMedNet is a proven Software-as-a-Service ... Electronic Data Capture (EDC), but also delivers an entire ...
(Date:2/6/2017)... , Feb. 6, 2017 According to ... are driving border authorities to continue to embrace ... there are 2143 Automated Border Control (ABC) eGates ... deployed at more than 163 ports of entry ... to 2016 achieving a combined CAGR of 37%. ...
(Date:2/2/2017)... 2017   TapImmune, Inc. (NASDAQ: ... in the development of innovative peptide and gene-based ... and metastatic disease, announced today it has successfully ... a second clinical lot of TPIV 200, the ... The manufactured vaccine product will be used to ...
Breaking Biology News(10 mins):
(Date:2/23/2017)... Baltimore, Maryland (PRWEB) , ... ... ... firm, PathSensors, Inc., announced today that in a published evaluation of multiple ... (PNNL), a U.S. Department of Energy Laboratory, PathSensors’ CANARY® biosensor threat detection ...
(Date:2/23/2017)... ... ... The Greater Gift Initiative, Inc , (GGI) a Winston-Salem, NC 501(c)3 non-profit, ... is to advance global health and highlight the greater good of clinical trial participation ... trial volunteer. The vision of GGI is to serve as a philanthropic connector between ...
(Date:2/23/2017)... and SAN FRANCISCO , ... privately-held regenerative medicine company, and Beyond Type 1, a ... type 1 diabetes, today announced a grant from Beyond ... functional cure for type 1 and other insulin-requiring diabetes.  ... has been developing innovative stem cell-derived cell replacement therapies ...
(Date:2/22/2017)... ... February 22, 2017 , ... Kernel ... Kendall Research Systems, LLC (KRS) clinical development program. KRS is a neurotechnology ... for research and clinical applications. The terms of the transaction were not disclosed. ...
Breaking Biology Technology: