Scientists have reported good news on the pandemic preparedness front: A cocktail of four manufactured antibodies is effective in neutralizing a virus from the Henipavirus family, a group of pathogens considered a threat to global biosecurity.
The study focused on protection against a recently identified variant of Hendra virus that, along with Nipah virus, has been responsible for deadly outbreaks of human and animal infections in the Eastern Hemisphere. The 2011 movie Contagion depicts a fictional viral outbreak traced back to an infected pig that is based on the Nipah virus.
The Hendra variant, identified in two fatally ill horses and sick bats in Australia, featured dramatic genetic changes from the original virus, creating a sense of urgency among scientists to learn how existing countermeasures against the restructured pathogen compare.
The researchers examined and determined in cell studies that several previously developed monoclonal antibodies designed to neutralize the original virus are also effective against the variant. The team also designed an additional antibody that could bind to three others in a powerful cocktail that would leave the virus with minimal ability to further mutate out of antibody recognition.
“These four antibodies can bind simultaneously, which is important for preventing future mutant escapes,” said study co-senior author Kai Xu, an assistant professor of veterinary biosciences at The Ohio State University.
“If you have only one or two antibodies, the virus can easily develop a mechanism to escape antibody recognition. If you have more antibodies in a cocktail developed as a therapeutic, you will lower the chances of a mutant escaping by many orders of magnitude.
The study was recently published online at Proceedings of the National Academy of Sciences.
Both Hendra and Nipah viruses can cause fatal diseases in humans, horses, pigs, and other mammals, and are transmitted between humans and animals. The flying fox, a species of bat, is considered a natural host of the virus. The very similar pathogens, discovered in the 1990s in Australia and Malaysia, respectively, cause severe respiratory symptoms and brain swelling leading to death in up to 95% of infected people.
“Initially, people thought these viruses might not mutate that much: their genome is largely stable, so it seemed like a countermeasure like an antibody, drug or vaccine might prevent them altogether. But that is not the case, just like SARS-CoV-2, a vaccine alone cannot win the war. The virus is constantly evolving to adapt to a new host,” Xu said.
In a series of experiments performed in a virus system that lacks the pathogenic gene, the researchers first found that the variant, known as HeV-g2, binds to the same receptor as the original HeV virus to enter host cells and with the same force. The variant, like the original, uses two proteins to enter.
A total of six monoclonal antibodies, three to each entry protein, that were previously developed to bind to matching “fingerprints” on the viral surface proteins Hendra and Nipah, were found to neutralize the HeV-g2 variant almost as well as they blocked the original viruses. . In previous studies, post-infection treatment with these antibodies protected numerous animal species against lethal doses of Hendra and Nipah viruses.
To provide even more protection, the researchers developed an additional antibody to combine with three others that neutralize one of two viral proteins that gain access to host cells.
“After precise atomic modeling and binding studies, we know that these four antibodies, the new one plus the three previously developed, are compatible with each other and can bind at the same time,” Xu said. “You don’t want them to compete or interfere with each other, and you want that kind of combination as a cocktail for therapeutic development.”
A resulting monoclonal antibody treatment would be used after exposure to the virus. The researchers also tested the efficacy of an existing Hendra virus vaccine candidate in two rhesus macaques and found in blood drawn 28 days after the last of three injections that the vaccine elicited a neutralizing antibody response in the animals against the HeV variant. -g2.
“These findings are proof of principle that antibodies are effective against the new variant and we can combine multiple antibodies for multivalent drug development,” said Xu. “And most importantly, we found that although the mutation is significant, existing countermeasures are still effective.”
Xu co-led the research with Christopher Broder of the Uniformed Services University and David Veesler of the University of Washington. Yan Xu from Ohio State was one of the first authors of the study. Other co-author institutions include the Henry M. Jackson Foundation for the Advancement of Military Medicine; the US Public Health Services Commissioned Corps; and the University of Sydney, the Commonwealth Scientific and Industrial Research Organisation, One Health Equine Veterinary and Epidemiology, and a private veterinary practice, all in Australia.
This work was supported by The Ohio State University Comprehensive Cancer Center, Path to K Grant through The Ohio State University Center for Clinical and Translational Sciences, The National Institute of Allergy and Infectious Diseases, a Pew Biomedical Award Scholars, the Burroughs Wellcome Fund, the University of Washington, the National Institutes of Health, and the Australian Government Department of Agriculture, Water and Environment.
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Source: news.osu.edu