LA JOLLA, Calif.—Using data collected from a consortium of laboratories on five continents, researchers based at the Scripps Research Ollmann Saphire Laboratory have identified a promising link in immune response to various strains of Ebolavirus. Mining the samples contributed from 43 members of the Viral Hemorrhagic Fever Immunotherapeutic Consortium, or VIC, researchers were able to explore the common actions in immune response to each of the five pathogens in the Ebolavirus genus—suggesting that a single treatment regimen and a single vaccine may be possible.
Members of the genus Ebolavirus include Ebola virus, Sudan virus, Bundibugyo virus, Taï Forest virus and Reston virus. Because each individual virus can present with up to half of its amino acid sequence unique from the next, it was initially thought that scientists would need to develop a unique treatment and vaccine for each one. The latest findings suggest there is a common mechanism that can be targeted to both treat cases of the different strains, and eventually look to the creation of a pan-Ebola vaccine.
“This is like understanding how to kill five or six birds with one stone,” says Dr. Erica Ollmann Saphire, professor at Scripps Research and senior author of two recently published papers—in mBio and the Journal of Infectious Diseases—outlining the discovery. “The different viruses in the Ebolavirus genus vary in their structure, but all these different viruses have the same outbreak potential. We need a therapeutic approach that can target them all.”
For the mBio study, the researchers focused on a human antibody called ADI-15878. This antibody was found in the blood of an Ebola virus survivor and is the only human antibody ever found to neutralize all five members of the Ebolavirus genus. In the other paper, the scientists showed that a mouse which had been sequentially immunized with Ebola virus and then Sudan virus also had a broadly protective antibody response.
Saphire likens the quest to stop Ebolavirus to a military campaign, employing structural biology much like military intelligence to target the virus with laser precision. By studying where the virus is vulnerable, where common antibody behavior could be observed and what didn’t change from one iteration of the virus to another, Saphire and her colleagues were able to map the “viral fusion loop” through which the Ebola viruses bind with cells and initiate infection.
The first major breakthrough came five years ago, when an Ebola survivor was transported to the United States. Like a downed aircraft captured in enemy territory, scientists minutely studied the immune response in order to develop the perfect “bomb” to fight the diseases. After identifying the presence of human antibody ADI-15878, they began to understand how it worked. The protein that Ebola uses to infect a cell wraps itself in sugars that help prevent the immune system from detecting the threat. In the survivor samples, they found that ADI-15878 binds to one of those sugars, and then manages to bypass the virus’s protective subterfuge, finding entry through the “waist” of the virus.
“It’s really cool to see that this antibody has found a way to bind into a cryptic, conserved pocket despite the proximity of sugars and other pieces of the virus that effectively hide this region from the immune system,” commented Dr. Brandyn West, a research associate at Scripps Research.
In studying a mouse infected with both the Ebola virus and the Sudan virus, researchers found another example of an antibody, this time one called 6D6 that would bind to the same region of the virus as ADI-15878 for a broadly protective response against both strains of Ebolavirus. Researchers can use this information in the quest for an effective therapy as a curative treatment against infection in the short-term, and a widely available vaccine in the long-term.
“We are still in the intelligence-gathering phase,” Saphire explained. “We have successful[ly] begun mapping where antibodies attach, which will eventually allow us to design the perfect bomb.”
Members of the VIC collaborate often with researchers tackling issues with similarly mutating viruses such as HIV or the flu, each of which has multiple strains and frequent mutations. Scientists speak frequently to share insights about commonalities in mutating diseases, potentially finding an antibody mechanism that can be applied in other diseases.
The VIC was established in 2014 to develop lifesaving antibody therapeutics against some of the world’s deadliest viruses. The collaboration allows member laboratories to contribute samples and strategies to find long-term solutions to some of the world’s most pervasive viruses. The consortium is funded through a National Institute of Allergy and Infectious Diseases Centers for Excellence in Translational Research program grant.