Four antibodies destroy deadly Henipavirus pathogens

Described as “a global biosecurity threat”, the Henipavirus family of pathogens are highly contagious that can cause deaths in humans, animals and mammals. 

In a major scientific breakthrough, scientists have found a countermeasure to contain the virus from spreading further. 

Researchers have come up with a cocktail of four manufactured antibodies that taken together are effective at neutralising a virus from the Henipavirus family. The study is published in Proceedings of the Natural Academy of Sciences of the United States of America (PNAS).

“Of the five identified Henipavirus strains, Hendra virus and Nipah virus are highly virulent emergent pathogens that cause outbreaks in humans and are associated with high case-fatality ratios,” says the US Centers of Disease Control and Prevention.

A variant of the Hendra virus was identified in two fatally diseased horses and sick bats in Australia showed significant genetic alterations from the original virus – which meant that scientists had to scramble to find out whether and how existing countermeasures acted against it.

The Hendra virus, as well as the Nipah virus, have been responsible for deadly animal and human infection outbreaks in the Eastern Hemisphere. The 2011 Steven Soderbergh film Contagion is based on a hypothetical virus outbreak inspired by the Nipah virus.

In the PNAS study, scientists from Australia and the US analysed several previously developed monoclonal antibodies designed to neutralise the original virus and deemed them effective against the variant. The researchers also designed an additional antibody to add to three others in a potent cocktail that would “leave the virus with minimal ability to further mutate its way out of antibody recognition.”

“These four antibodies can bind simultaneously, which is important for preventing future escaping mutants,” said co-lead study author Kai Xu, 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, it will decrease the chances of an escape mutant by many orders of magnitude.”

Hendra and Nipah viruses are both deadly to humans, horses, pigs and other mammals, and can be transferred between humans and animals (that is, they are zoonotic, like the recent coronavirus pandemic).

A bat species called the flying fox is considered the natural host of the viruses. Hendra and Nipah viruses are very similar pathogens which were discovered in the 1990s in Australia and Malaysia respectively. They can result in severe respiratory symptoms and brain inflammation that lead to death in up to 95 percent of those infected.

“Initially people thought these viruses might not mutate so much – their genome is largely stable, so it appeared that a countermeasure like an antibody, drug or vaccine could totally prevent them. But that’s not the case – just like SARS-CoV-2, a vaccine alone can’t win the war. The virus constantly evolves to adapt to a new host,” Xu said.

During experiments using a virus system lacking the pathogenic gene, the researchers discovered that “the variant, HeV-g2, attaches to the same receptor as the original HeV virus to enter host cells, and with the same strength.” The variant and the original both use two proteins to get in.

The researchers reused six monoclonal antibodies – three for each entry protein – that were developed earlier to attack to matching “footprints” on both Hendra and Nipah viral surface proteins. These neutralised the new variant (HeV-g2) almost as well as they blocked the original viruses. In past studies, post-infection treatment with these antibodies protected numerous animal species against lethal doses of Hendra and Nipah viruses.

In addition to these antibodies, the researchers wanted to provide further protection and developed another antibody “to be combined with three others that neutralise one of the two viral proteins that gain access to host cells.”

“We know after precise atomic modelling and binding studies that these four antibodies, the new one plus the three developed previously, are compatible to 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.”

“We show that targeting four nonoverlapping epitopes on the HeV attachment protein simultaneously leads to potent HeV and HeV-g2 neutralisation, supporting the development of a tetravalent monoclonal antibody cocktail,” write the researchers.

The four-antibody cocktail would be used after a person or an animal was exposed to the virus. The researchers tested the effectiveness of an existing Hendra virus vaccine candidate as well, on two rhesus macaques. They found that 28 days after the last of the three injections, the vaccine generated a neutralising antibody response in the animals’ blood 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 important, we found that although the mutation is significant, the existing countermeasures are still effective.”