A cocktail of four engineered antibodies is effective in neutralizing a recently discovered variant of the deadly Hendra virus, the researchers report.
The antibodies made form the basis of a monoclonal antibody treatment to be used after exposure to the virus. They include a new one that neutralizes a crucial viral protein.
Hendra virus is carried by Australian fruit bats known as flying foxes. Horses are susceptible to infection if exposed to bat body fluids, such as under their roosts in pasture. Seven human cases have also been reported, resulting from exposure to bodily fluids from infected horses. Four of them turned out to be fatal.
The latest study focused on protection against a recently emerged Hendra variant virus, which, along with Nipah virus, has been responsible for deadly outbreaks of animal and human infections in the Eastern Hemisphere.
The variant, identified in two fatally ill horses and bats in Australia, had dramatic genetic changes from the original virus, creating a sense of urgency among scientists to find out how existing countermeasures stacked against the restructured pathogen.
Researchers have examined and determined in cell studies that several previously developed monoclonal antibodies designed to neutralize the original virus are also effective against the variant. They also designed an additional antibody that could join three others in a potent cocktail that would leave the virus with minimal ability to mutate further out of antibody recognition.
“These four antibodies can bind simultaneously, which is important to prevent future mutants from escaping,” said study co-lead author Kai Xu, an assistant professor of veterinary biosciences at Ohio State University.
“If you only have one or two antibodies, the virus can easily develop a mechanism to evade antibody recognition. If you have more antibodies in a cocktail developed as a therapeutic, it will reduce a mutant’s chance of escape by several orders of magnitude.
The results of the study were published online recently in the Proceedings of the National Academy of Sciences.
Hendra and Nipah viruses can cause severe respiratory symptoms and brain inflammation that lead to death in up to 95% of those infected.
“People initially thought that these viruses might not mutate as much – their genome is largely stable, so it turned out that a countermeasure like an antibody, drug or vaccine could totally prevent them,” said said Xu.
“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.
In a series of experiments in a viral system lacking the pathogenic gene, researchers first found that the variant, known as HeV-g2, attaches to the same receptor as the original Hendra virus to enter in host cells, and with the same force. The variant, like the original, uses two proteins to enter.
A total of six monoclonal antibodies – three for each input protein – that were previously developed to attach to corresponding “fingerprints” on the viral surface proteins Hendra and Nipah were found to neutralize the HeV-g2 variant almost as well. that they blocked the original viruses. In previous studies, post-infection treatment with these antibodies protected many animal species against lethal doses of Hendra and Nipah viruses.
To offer even more protection, the researchers developed an additional antibody to combine with three others that neutralize one of the two viral proteins that gain access to host cells.
“We know from precise atomic modeling and binding studies 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 vaccine candidate against Hendra virus 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-g2 variant.
“These findings are proof of principle that antibodies are effective against the new variant and we can combine multiple antibodies for multivalent drug development,” Xu said. “And most importantly, we found that although the mutation is significant, the existing countermeasures are still effective.”
Xu co-directed the research with Christopher Broder of Uniformed Services University and David Veesler of the University of Washington. Xu was co-first author of the study. Other co-authoring institutions include the Henry M. Jackson Foundation for the Advancement of Military Medicine; the United States Public Health Services Commissioned Corps; the University of Sydney; Commonwealth Scientific and Industrial Research Organization; equine veterinarian; Epidemiology One Health; 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 & Translational Science, the National Institute of Allergy and Infectious Diseases, a Pew Biomedical Scholars Award, the Burroughs Wellcome Fund, the University of Washington, the National Institutes of Health, and the Australian Government’s Department of Agriculture, Water and Environment.
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