October 28, 2021

VUMC researchers a step closer to broad ebolavirus protection


by Bill Snyder

A combination of two broadly acting monoclonal antibodies isolated by researchers at Vanderbilt University Medical Center protected non-human primates from ebolavirus disease, which causes severe and often-fatal hemorrhagic fever in humans.

Their findings, published this week in the journal Cell, bring closer to development the first clinical therapy effective against all three primary ebolaviruses responsible for repeated outbreaks of the disease in equatorial Africa.

“The infectious diseases community has long wanted a single antibody combination to deal with all of the various strains of ebolaviruses, and now we have finally identified a promising combination that fits the bill,” said James Crowe Jr., MD, director of the Vanderbilt Vaccine Center.

Crowe and his colleagues have developed ultra-fast methods for discovering highly potent human monoclonal antibodies and validating their ability to protect small animals and non-human primates from virulent viral infections, including COVID-19.

They have been working on potential treatments for ebolavirus disease for several years.

Spread by contact with contaminated body fluids, including blood and semen, ebolaviruses can cause massive bleeding. To date, 19 outbreaks of ebolavirus disease infecting more than 30,000 people have been confirmed, with an average reported mortality rate of about 70%, according to the World Health Organization.

The U.S. Food and Drug Administration has approved two monoclonal antibody therapies for clinical use, but these treatments are specific only for the Ebola virus, and are not effective against the Bundibugyo or Sudan viruses, which are also significant sources of ebolavirus disease.

The broadly neutralizing human antibodies isolated by the VUMC researchers, called rEBOV-515 and rEBOV-442, recognize non-overlapping sites on the ebolavirus glycoprotein, a surface protein shared by the three main ebolaviruses.

The two-antibody combination exhibited synergistic neutralizing activity, reduced the ability of the viruses to mutate to evade neutralization, and protected non-human primates from all three ebolaviruses with a high degree of therapeutic effectiveness.

“These findings set the stage for clinical evaluation of pan-ebolavirus combination therapy,” the researchers concluded.

Crowe is the Ann Scott Carell Professor and professor of Pediatrics and Pathology, Microbiology & Immunology at VUMC.

Pavlo Gilchuk, PhD, senior staff scientist in Crowe’s lab, was the paper’s co-first author with Charles Murin, PhD, of the Scripps Research Institute in La Jolla, Calif., and Robert Cross, PhD, MPH, of the Galveston National Laboratory in Galveston, Texas.

Other VUMC co-authors were Seth Zost, PhD, Rachel Nargi, Rachel Sutton, Naveen Suryadevara, PhD, Robin Bombardi, MS, and Robert Carnahan, PhD, associate director of the Vanderbilt Vaccine Center.

The research was supported by National Institutes of Health grants AI109711, AI142785 and AI109762, the U.S. Department of Health and Human Services, the Defense Threat Reduction Agency of the U.S. Department of Defense, Merck KGaA, Darmstadt, Germany, and the Vanderbilt Institute for Clinical and Translational Research.