New research from scientists at La Jolla Institute for Immunology has revealed important insights into how a human antibody, mAb 3A6, works to combat Ebola virus infections. This groundbreaking discovery emerged from blood samples taken from an Ebola survivor treated at Emory University Hospital during the devastating West African outbreak of 2014-2016, which resulted in over 11,300 fatalities.
In their latest study published in Nature Communications, the researchers demonstrated that mAb 3A6 plays a crucial role by binding to an essential part of the Ebola virus structure known as the “stalk.” Collaborators at the National Institute of Allergy and Infectious Diseases (NIAID) found that treatment with this antibody showed significant benefit in non-human primates suffering from advanced stages of Ebola infection. Professors Erica Ollmann Saphire, John A. G. Briggs, Gabriella Worwa, Jens H. Kuhn, Carl W. Davis, and Rafi Ahmed were among the leaders of this international team.
“This antibody offers the best protection in primates to date at an incredibly low dose,” explained Dr. Erica Ollmann Saphire from La Jolla Institute for Immunology. “The lower the required dosage, the more feasible it is to manufacture on a large scale and distribute widely at affordable prices.” The study’s first author, Dr. Kathryn Hastie, underscored this advantage: “Lower manufacturing costs make mAb 3A6 particularly promising for treating Ebola virus infection in resource-limited settings.
The mechanism behind mAb 3A6’s effectiveness centers on its ability to target the ‘stalk’ of the Ebola virus structure. The stalk anchors the glycoprotein, which is crucial for the virus’s entry into host cells, to its viral membrane. Drs. Hastie and her colleagues employed advanced imaging techniques—cryoelectron tomography and x-ray crystallography—to capture detailed images showing how mAb 3A6 binds to Ebola virus molecules.
“There’s dynamic movement among the viral proteins,” explained Dr. Hastie, “but mAb 3A6 can navigate these fluctuations by attaching itself above the membrane level.” This unique binding strategy is significant for several reasons: It targets a conserved site across various types of Ebola viruses, making it ideal for developing broad-spectrum therapies. Moreover, understanding how mAb 3A6 interacts with the viral stalk offers new perspectives on designing vaccines against this dangerous pathogen.
Additional authors contributing to this research included Zhe “Jen” Li Salie, who resolved the X-ray structure; Zunlong Ke, responsible for cryoelectron tomography imaging; Lisa Evans DeWald, Sara McArdle, Ariadna Grinyó, Edgar Davidson, Sharon L. Schendel, Chitra Hariharan; Michael J. Norris and Xiaoying Yu performed other key experimental work alongside Chakravarthy Chennareddy and Xiaoli Xiong in the lab.
This research was supported by several grants from institutions including the National Institutes of Health (NIH), DARPA, UK Medical Research Council (MRC), European Research Council (ERC-CoG-648432 MEMBRANEFUSION), and Max Planck Society. Their collaborative effort has advanced our understanding of Ebola virus therapeutics, paving the way for more effective treatments to protect global health.
