The structure of a human monoclonal antibody which, strongly neutralizes a type of the potentially lethal dengue virus in an animal model has been determined by researchers at Vanderbilt University and the National University of Singapore.
The finding could pave the way to the first effective therapies and vaccines against dengue.
Dengue fever is a complex of four related but distinct mosquito-borne viruses. They infect about 390 million people each year and are one of the leading causes of illness and death in the tropics.
Co-corresponding author James Crowe Jr., M.D., said:
“Scientists in the antibody discovery group of the Vanderbilt Vaccine Center continue to make great strides in developing novel antiviral drugs, such as this human antibody that not only kills dengue virus but also prevents enhanced dengue disease."
Different antigens, or proteins on the viral envelope that elicit immune responses, distinguish dengue’s four “serotypes”. Antibodies created to battle one serotype do not protect against the others, one of the reasons that dengue is so challenging and dangerous.
Antigens can actually can enhance infection by a second serotype, in a process known as antibody-dependent enhancement (ADE) of infection. The risk for dengue hemorrhagic fever and dengue shock syndrome, characterized by fever, vomiting, internal bleeding and potentially fatal circulatory collapse, is increased by sequential infections.
Previously, the research team had generated human monoclonal antibodies in the lab against a complex epitope, or antigenic portion of the viral envelope. In the new study, cryo-electron microscopy was used to freeze samples at very low temperatures, to enable visualization of antibody-antigen binding nearly down to the atomic level.
They were able to identify a human monoclonal antibody against dengue virus type 2 (DENV2) that “locked” across an array of envelope proteins. In a mouse model, this prevented the virus from fusing to its target cell, preventing infection.
This particular portion of the envelope protein elicits a specific immune response, so it is a potential target for the development of dengue vaccines and therapeutics, researchers wrote.
Guntur Fibriansah, Kristie D. Ibarra, Thiam-Seng Ng, Scott A. Smith, Joanne L. Tan, Xin-Ni Lim, Justin S. G. Ooi, Victor A. Kostyuchenko, Jiaqi Wang, Aravinda M. de Silva, Eva Harris, James E. Crowe Jr., Shee-Mei Lok Cryo-EM structure of an antibody that neutralizes dengue virus type 2 by locking E protein dimers Science 3 July 2015: Vol. 349 no. 6243 pp. 88-91 DOI: 10.1126/science.aaa8651