Scientists at the Centers from Disease Control and Prevention have created a synthetic version of the Ebola virus circulating in the Democratic Republic of the Congo, part of an effort to determine whether diagnostic tests and experimental treatments being used in the field are effective.
The research, conducted in the agency’s most secure laboratories — BSL4 — showed that even though the tests and two of the treatments being used in the field were developed based on earlier variation of Ebola viruses, they continue to be effective against the virus causing the current outbreak, the second largest on record.
The results, reported Tuesday in the journal Lancet Infectious Diseases, are encouraging, but also raise questions about why outside research groups have not received direct access to viral specimens from the DRC and instead had to create a synthetic version. The paper noted that there have been no Ebola samples available to the scientific community from the past four outbreaks in the DRC. Those outbreaks occurred in 2014, 2017, and 2018.
The current one, which has involved more than 2,400 cases and 1,600 deaths, began last summer.
Ebola scientists who were not involved in the work praised the CDC’s effort, saying it is important to test the tools being used against the virus in the outbreak. But they noted it would be easier, faster, and potentially more accurate to use actual viruses rather than those recreated from genetic codes logged in an online database.
“I don’t know anyone who has isolates from this outbreak,” said Tom Geisbert, of the University of Texas Medical Branch in Galveston.
“They did a great job here in a short period of time, but man, that takes a lot of resources and a lot of money and a lot of energy to make a cloned virus by reverse genetics. And it would be so much easier if somebody had just sent the isolate.”
Gary Kobinger, who led the work to develop the Ebola treatment ZMapp — one of the therapies the CDC group tested against the synthesized virus — said it is becoming increasingly difficult to get pathogens to study. It’s a global trend, he said, and one that threatens the world’s ability to conduct surveillance and develop diagnostic tests for disease-causing pathogens.
“A lot of the science that is benefiting them, including diagnostics, is because previous isolates were shared,” Kobinger, who is director of the Infectious Disease Research Center at Laval University in Quebec, said of the DRC.
He noted that during the West African outbreak of 2014-2016, Guinea quickly agreed to share virus samples. The Canadian national laboratory, where Kobinger worked at the time and where the Ebola vaccine currently deployed in the DRC was developed, used the virus samples to test whether the vaccine should protect against the viruses causing that outbreak. It did.
Laura McMullan, the lead author of the CDC study, was uncertain if the agency had asked for virus samples from this outbreak. Pressed for a more precise answer, the CDC said the agency has on several occasions offered to assist DRC’s National Biomedical Research Institute with specimen analysis, virus sequencing, and diagnostic support. INRB, as the lab is known, has not asked for help.
“These things are tricky,” said McMullan, who is a research scientist with the CDC’s viral special pathogens branch, said of the processes involved in sharing viral samples. “To get material out … you’ve got to have someone who’s willing to ship, you’ve got to have the appropriate cold chain [equipment]. So it’s often a logistical issue. And you have to have permission and everyone working together.”
A spokeswoman for the DRC health ministry, Jessica Ilunga, said she would look into the country’s policy on sharing of viruses from this outbreak.
McMullan noted that high-quality sequence data generated by INRB and by scientists from the United States Army Medical Research Institute of Infectious Diseases working with the national lab has been posted online. Access to that data enabled the CDC team to recreate the virus.
The Congolese team that generated the data analyzed the sequences to try to gauge whether the tests being used to detect cases and the drugs being used to treat them should be effective against the outbreak, publishing their work in Lancet Infectious Diseases in early June. But they were using computer programs to do the analysis; the CDC team took that work a step further by making and using actual virus.
Conducting that work is important, McMullan said, because genetic sequences can’t necessarily predict how a virus will actually behave.
For example, study of the sequence data showed several points where the tests in use appeared to be potentially mismatched to the outbreak virus.
“One of the changes we thought was going to be an important change,” McMullan said. “We noticed the difference and we were ‘Oh, this could really be a problem.'”
In fact, the tests detected the virus from this outbreak as well as it detected the virus that caused the West African outbreak of 2014-2016. While both are variants of the Ebola Zaire species, they are slightly different genetically.
Kobinger said this work is useful, but actual viruses from the outbreak would be even more precise than one that was recreated from sequence data. “The best is to have the real deal,” he said.
The CDC team found that two of four therapeutics being used on patients in this outbreak appear to be on target for the outbreak virus. They tested Gilead’s antiviral drug Remdesivir and the monoclonal antibody cocktail ZMapp, which is being developed by Mapp Biopharmaceuticals.
McMullan said the team didn’t have access to the two other therapies, which are also monoclonal antibodies — mAb114, which is being developed by the National Institute of Allergy and Infectious Diseases, and REGN 3470-3471-3479, made by Regeneron.