Dual antibody cocktail offers complete Nipah virus protection

Scientists have developed the first fully human monoclonal antibody cocktail to provide complete protection against the deadly Nipah and Hendra viruses in preclinical testing, marking a significant advance in the search for treatments for two of the world’s most dangerous emerging infectious diseases.

The international study, led by researchers in the Department of Microbiology at the Icahn School of Medicine at Mount Sinai, found the antibody combination protected hamsters from otherwise lethal Nipah virus infection, even when treatment was given after infection had begun.

The research identifies two fully human antibodies that target different stages of the virus’s infection process, creating multiple barriers that make it much harder for the virus to evade treatment.

Tackling a deadly virus

Nipah virus and the closely related Hendra virus belong to the henipavirus family, pathogens that can spread from animals to humans and cause severe respiratory and neurological disease. Although outbreaks are uncommon, they can be devastating, with reported mortality rates ranging from 40 percent to more than 75 percent. There are currently no approved vaccines or treatments for infected patients.

Nipah virus and the closely related Hendra virus belong to the henipavirus family, pathogens that can spread from animals to humans 

“One of the biggest challenges in developing treatments for henipaviruses is that human survivor samples are extremely rare,” said Axel Guzman-Solis, a graduate student in the Department of Microbiology at the Icahn School of Medicine and lead author of the study. “We wanted to determine whether we could create fully human antibodies that target the virus in multiple ways at once, making it much more difficult for the virus to evolve resistance.”

To overcome the shortage of human samples, the research team used genetically engineered humanised mice capable of producing fully human antibodies. This allowed them to identify promising candidates without the need for the additional engineering usually required to adapt animal antibodies for use in people.

Dual approach blocks infection

Henipaviruses rely on two proteins to infect human cells: one binds to the cell while the other enables the virus to fuse with and enter it. Previous approaches have generally targeted only one of these proteins, allowing the virus to develop resistance.

The researchers identified two particularly effective antibodies. The first, known as 8G3, targets a highly conserved region of the virus involved in attaching to human cells. According to the researchers, the virus would probably need to develop several genetic mutations simultaneously to escape its effects.

The second antibody, called 2A1, works in a different way by targeting the viral fusion protein. High-resolution structural imaging revealed an unexpected mechanism in which the antibody stabilises a sugar-containing structure on the protein rather than displacing it.

“We were surprised to find that the antibody essentially embraces a structure on the virus that many antibodies try to move out of the way,” said Dr Benhur Lee, MD, Ward-Coleman Chair in Microbiology at the Icahn School of Medicine and a senior author of the study. “The finding suggests that stabilising a viral protein can sometimes be just as effective – or even more effective – than disrupting it.”

Preparing for future outbreaks

When combined, the two antibodies completely protected hamsters from lethal Nipah virus infection, even when treatment was administered after infection had occured. The researchers believe the dual-targeting approach could also prove valuable against other emerging viruses.

“This work provides a blueprint for developing antibody therapies that are more resistant to viral evolution,” said Dr Lee. “Rather than relying on a single target, we can attack a virus at multiple vulnerable points simultaneously.”

When combined, the two antibodies completely protected hamsters from lethal Nipah virus infection, even when treatment was administered after infection had become established

While the findings are based on laboratory and animal studies, researchers say they represent an important step towards the first antibody-based therapy for Nipah virus. Further work, including studies in non-human primates and additional safety testing, will be required before human clinical trials can begin.

“As zoonotic outbreaks continue to emerge around the world there is an urgent need for therapies that can be deployed quickly against high-consequence pathogens,” said Dr Lee. “Our long-term goal is to translate these discoveries into practical tools that help protect people during future outbreaks.”