New research at the molecular level may lead to dengue protection

Creating a vaccine that protects people from all four types of dengue virus has frustrated scientists for decades. But researchers at the University of North Carolina have discovered a new target for human antibodies that could hold the key to a vaccine for the world’s most widespread mosquito-borne disease.

Using an experimental technique new to the dengue field, the labs of Ralph Baric and Aravinda de Silva showed that a molecular hinge where two regions of a protein connect is where natural human antibodies attach to dengue 3 to disable it. The finding, published in the Proceedings of the National Academy of Sciences, shows that after primary infection most human antibodies that neutralize the virus bind to the hinge region.

It’s the first study to demonstrate how these binding sites, composed of just 25 amino acids, can be genetically swapped out for amino acids from another dengue type without disrupting the integrity of the virus.

By re-engineering a tiny chain of amino acids in one type of dengue virus, Baric and de Silva discovered a new path that has the potential to transform vaccine development for other diseases, including SARS and HIV.

“This gives us a lot of insight into how human antibodies work,” said de Silva, a professor of microbiology and immunology in the university’s School of Medicine. “And there could be a lot of translational aspects to this. It could lead to a new way to create vaccines for other diseases.”

De Silva and Baric, also a professor, are now working with vaccine developers at two pharmaceutical companies to test the effectiveness of potential dengue vaccines now in clinical trials. If these vaccines don’t bind to their molecular hinge, then the vaccines will likely prove less effective than researchers would like, especially over time.

Dengue, which infects approximately 390 million people each year, is common in tropical and subtropical regions around the world.

Making a truly effective dengue vaccine has proven difficult because of a phenomenon called antibody dependent enhancement. People infected with one type of dengue usually develop a natural immune response that rids the body of the virus and prevents a repeat infection of that same virus type. But if those people are infected with a second type of dengue, the virus is enhanced because of that first immune response. The result can be severe dengue hemorrhagic fever, which can be deadly.

Consequently, a vaccine that offers immunity for only one type of dengue would make other types of dengue more virulent and dangerous. The first large clinical trial of a dengue vaccine, conducted in Thailand in 2011, contained a cocktail of all four types of dengue. But for reasons that remain unclear, the vaccine was just partially protective. There was no evidence that the vaccine protected people during a dengue 2 outbreak that same year.

To study dengue, de Silva and colleagues have collected samples from infected Sri Lankans and from Americans who had acquired the disease while abroad. Such samples allowed de Silva’s team to find that human antibodies are not the same as mouse antibodies, which had served as the basis for vaccine development.

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