An international team of scientists reports that therapeutic antibodies may be the best way to stop the Ebola virus. Their study (“Systematic analysis of monoclonal antibodies against Ebola virus GP defines features that contribute to protection”), published in Cell, suggests new therapies should disable the Ebola virus's infection machinery and spark the patient's immune system to fight the virus.
“Antibodies are promising post-exposure therapies against emerging viruses, but which antibody features and in vitro assays best forecast protection are unclear. Our international consortium systematically evaluated antibodies against Ebola virus (EBOV) using multidisciplinary assays. For each antibody, we evaluated epitopes recognized on the viral surface glycoprotein (GP) and secreted glycoprotein (sGP), readouts of multiple neutralization assays, fraction of virions left un-neutralized, glycan structures, phagocytic and natural killer cell functions elicited, and in vivo protection in a mouse challenge model,” write the investigators.
“Neutralization and induction of multiple immune effector functions (IEFs) correlated most strongly with protection. Neutralization predominantly occurred via epitopes maintained on endosomally cleaved GP, whereas maximal IEF mapped to epitopes farthest from the viral membrane. Unexpectedly, sGP cross-reactivity did not significantly influence in vivo protection. This comprehensive dataset provides a rubric to evaluate novel antibodies and vaccine responses and a roadmap for therapeutic development for EBOV and related viruses.”
“This study presents results from an unprecedented international collaboration and demonstrates how 43 previously competing labs can together accelerate therapeutics and vaccine design,” says Erica Ollmann Saphire, Ph.D., professor at Scripps Research and director of the Viral Hemorrhagic Fever Immunotherapeutic Consortium (VIC).
The VIC researchers aim to understand which Ebola-fighting antibodies are best and why. The hope is that the most effective antibodies can be combined in a therapeutic “cocktail.” Unlike an Ebola vaccine, these cocktails could be given to those already infected, which is important for stopping a disease that tends to emerge unexpectedly in remote locations.
Dr. Saphire and her colleagues in the VIC have published more than 40 studies in the last five years. This study is the first-ever, side-by-side comparison of 171 antibodies against Ebola virus and other related viruses, known as filoviruses. All antibodies in the panel were donated by different labs around the world, and many had not been previously characterized in such extensive detail, according to Dr. Saphire.
“Through the VIC, we could test a larger pool of antibodies in parallel, which increased the potential to detect statistically significant relationships between antibody features and protection,” says Dr. Saphire. “We used this global pool of antibodies to evaluate, and streamline, the research pipeline itself.”
In addition to identifying links between antibody target locations and activity, VIC researchers tested this pool of antibodies to reveal which antibodies neutralized the virus, why neutralization assays so often disagree, and whether or not neutralization in test tubes adequately predicted how well these antibodies would protect live animals from Ebola virus infection. Unexpectedly, neutralization alone was not always associated with the protective ability of an antibody.
The scientists found nine antibodies that protected mice from infection without neutralizing the virus in test tubes. These antibodies likely fight infection by interacting with an infected person's immune system, helping orchestrate a better immune response to the virus.
VIC member and Scripps Research faculty member Kristian Andersen, Ph.D., and his graduate student Karthik Gangavarapu developed a network describing how each antibody feature correlates to protection, which can serve as a guide to predict whether newly identified antibodies will have therapeutic value. Dr. Saphire says the next steps for the VIC are to further test promising antibody cocktails in nonhuman primates. The team will also pursue engineering of antibodies that carry signature features to better drive immune system response.