A team of scientists has uncovered the remarkable potential of a human antibody, mAb 3A6, in fighting Ebola virus infections. Sourced from a survivor of the devastating 2014–2016 outbreak, this antibody binds to a key structure on the virus known as the “stalk,” effectively neutralizing it.
Notably, mAb 3A6 provides potent protection even at ultra-low doses, making it cost-effective and easier to manufacture. The study used cutting-edge imaging to reveal how the antibody exploits dynamic protein movements on the virus, giving researchers critical insight into how to design future pan-Ebolavirus treatments and vaccines.
Powerful Antibody Discovery Against Ebola
Scientists at the La Jolla Institute for Immunology (LJI) have uncovered how a human antibody called mAb 3A6 works, and their findings suggest it could play a key role in future Ebola virus treatments.
The antibody was originally isolated from the blood of an Ebola survivor who received care at Emory University Hospital during the 2014-2016 Ebola virus outbreak in West Africa, which resulted in over 11,300 deaths.
In the new study, researchers found that mAb 3A6 can block Ebola infection by binding to a critical part of the virus’s structure known as the “stalk.” This region helps anchor the virus’s glycoprotein to its membrane, a step that is essential for infecting host cells. Collaborators at the National Institute of Allergy and Infectious Diseases (NIAID) showed that mAb 3A6 provided a therapeutic benefit in non-human primates, even in later stages of the disease.
Record-Breaking Protection at Low Doses
“This antibody offers the best protection in primates, at the lowest dose yet seen for any single antibody,” says LJI Professor, President & CEO Erica Ollmann Saphire, Ph.D., MBA, who led the recent Nature Communications study alongside John A. G. Briggs, Ph.D., of Cambridge University and the Max Planck Institute of Biochemistry; Gabriella Worwa, D.V.M., and Jens H. Kuhn, M.D., Ph.D., of NIAID; and Carl W. Davis, Ph.D., and Rafi Ahmed, Ph.D., of the Emory Vaccine Center.
The discovery that mAb 3A6 appears effective at a very low dose is also exciting. “The lower the amount of an antibody you can deliver to someone, the easier it will be to manufacture a treatment—and the lower the cost,” says study first author Kathryn Hastie, Ph.D., LJI Instructor and Director of LJI’s Center for Antibody Discovery.
The Mechanics Behind mAb 3A6
The key to treating the Ebola virus is to find antibodies that anchor tightly to and block the essential machinery of the virus. The researchers zeroed in on mAb 3A6 because it appears to target a structure on the Ebola virus called the “stalk.” The stalk is an important part of the Ebola virus structure because it anchors Ebola’s glycoprotein structure (which drives entry into a host cell) to Ebola’s viral membrane.
The team spearheaded efforts to capture images of mAb 3A6 in action. The researchers used two imaging techniques, called cryoelectron tomography and x-ray crystallography, to show how mAb 3A6 binds to the Ebola virus to interrupt the infection process.
A Clever Exploit of Viral Weakness
The researchers found that mAb 3A6 binds to a site normally concealed by a shifting landscape of viral proteins. “There’s a dynamic movement in these proteins,” says Hastie. “They might kind of wiggle around, move back and forth, maybe lean over a little bit, or go up and down.”
Antibody mAb 3A6 takes advantage of this little protein dance. It has such a strong affinity for its viral target that it can slip between the proteins, lift them up, and latch onto its target.
Implications for Broad-Spectrum Therapies
Hastie says mAb 3A6’s ability to bind to this target is important for several reasons. First, the site is conserved across different species of Ebola virus, making antibodies that target this region an attractive component in “pan-Ebolavirus” therapeutics. Second, the new understanding of how mAb 3A6 “lifts up” proteins in the viral stalk gives scientists a clearer view of Ebola’s weaknesses. MAb 3A6 also shows us how similar antibodies against the stalks of other viruses might work as well.
“This study gives us some hints for how to design vaccines that are specifically against this region of Ebola virus,” says Hastie.
Reference: “Anti-Ebola virus mAb 3A6 protects highly viremic animals from fatal outcome via binding GP(1,2) in a position elevated from the virion membrane” by Kathryn M. Hastie, Zhe Li Salie, Zunlong Ke, Peter J. Halfmann, 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, Jens H. Kuhn, John A. G. Briggs, Gabriella Worwa, Carl W. Davis, Rafi Ahmed and Erica Ollmann Saphire, 3 February 2025, Nature Communications.
DOI: 10.1038/s41467-025-56452-2
Additional authors of the study include Zhe “Jen” Li Salie, who solved the X-ray structure; Zunlong Ke, who performed the 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, Jens H. Kuhn
This study was supported in part by the National Institute of Health’s National Institute for Allergy and Infectious Diseases (grant U19 AI142790, Contract No. HHSN272201400058C, Contract No. HHSN272200700016I, Contract No. HHSN272201800013C), DARPA (contract W31P4Q-14-1-0010), and UK Medical Research Council (grant MC_UP_1201/16), the European Research Council (ERC-CoG-648432 MEMBRANEFUSION), and the Max Planck Society.
