New research from scientists at La Jolla Institute for Immunology (LJI) has shed light on a human antibody called mAb 3A6, which may play a crucial role in developing treatments against Ebola virus. This particular antibody was isolated from blood samples of an Ebola survivor treated at Emory University Hospital during the deadly 2014-2016 West African outbreak that claimed over 11,300 lives.
In their latest study published in Nature Communications, researchers demonstrated that mAb 3A6 helps prevent infection by binding to a vital part of Ebola’s viral structure known as the “stalk.” Collaborators from the NIH’s National Institute of Allergy and Infectious Diseases (NIAID) further tested this antibody on non-human primates with advanced stages of Ebola virus disease, finding that it offers significant benefits. Lead researcher Erica Ollmann Saphire, Ph.D., MBA, highlighted that mAb 3A6 provides the best protection in primate models at the lowest dose observed for any single antibody to date.
The discovery that this antibody is effective even at low doses is particularly promising. “The lower amount of an antibody needed for treatment means it’s easier and less costly to manufacture,” explained Kathryn Hastie, Ph.D., LJI Instructor and Director of LJI’s Center for Antibody Discovery, who was the first author of the study.
The mechanism by which mAb 3A6 works is key to its potential as an Ebola treatment. The researchers focused on this antibody because it targets a structure called the “stalk” in the Ebola virus. This stalk plays a critical role by anchoring another important viral protein, responsible for entry into host cells, to the virus’s membrane.
To understand how mAb 3A6 functions, the team used advanced imaging techniques such as cryoelectron tomography and x-ray crystallography. These methods revealed that mAb 3A6 binds to Ebola in a manner that interrupts its infection process. Specifically, it attaches itself to an area usually hidden by other moving viral proteins.
“The proteins have a dynamic movement,” Hastie explained. “They might wiggle around or change position.” Despite these movements, mAb 3A6 has such strong affinity for its target that it can fit between the shifting parts of the virus and bind securely to its intended site. This binding is significant because:
1. The targeted region on Ebola’s stalk is similar across different species of Ebola viruses, making antibodies targeting this area attractive components in a “pan-Ebolavirus” treatment.
2. Understanding how mAb 3A6 interacts with these proteins offers insight into the virus’s vulnerabilities.
3. This knowledge might help design vaccines specifically against this part of the Ebola virus.
The research team includes Zhe “Jen” Li Salie, who solved the X-ray structure; Zunlong Ke, who performed cryoelectron tomography; Lisa Evans DeWald, Sara McArdle, Ariadna Grinyó, Edgar Davidson, Sharon L. Schendel, Chitra Hariharan, Michael J. Norris, Xiaoying Yu, Chakravarthy Chennareddy, Xiaoli Xiong, Megan Heinrich, Michael R. Holbrook, Benjamin Doranz, Ian Crozier, Yoshihiro Kawaoka; Luis M. Branco and Jens H. Kuhn.
This study was supported by several funding bodies including the National Institute of Health’s National Institute for Allergy and Infectious Diseases (grants U19 AI142790, Contract No. HHSN272201400058C), DARPA (contract W31P4Q-14-1-0010), the UK Medical Research Council, European Research Council (ERC-CoG-648432 MEMBRANEFUSION), and the Max Planck Society.
