Nipah virus—and the closely related Hendra virus—are zoonotic pathogens causing severe respiratory and neurological disease with high mortality rates. Outbreaks are rare but often devastating, with mortality rates ranging from 40 to 75 percent. There are no approved human vaccines or therapeutics for people infected with these viruses.
Now, an international research team led by investigators at the Icahn School of Medicine at Mount Sinai has developed the first fully human monoclonal antibody cocktail shown to provide complete protection against Nipah and Hendra virus infection—even when treatment was given after infection had begun. The findings represent an important step toward developing the first antibody-based therapy for Nipah virus and establish a promising strategy for combating emerging infectious diseases.
This work is published in Science Translational Medicine, in the paper, “A cocktail of human mAbs targeting the henipavirus fusion and receptor binding proteins provides cross-species neutralization.”
“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. “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.”
The researchers used vaccinated humanized mice with the fusion protein (F) and receptor binding protein (RBP) of Nipah virus with the goal of isolating monoclonal antibodies. The investigators discovered two antibodies, 8G3 and 2A1, which targeted the RBP and F proteins, respectively, and together, could neutralize the virus and limit the potential for immune escape. Because the antibodies work through independent mechanisms, they create multiple barriers to infection and make it more difficult for the virus to develop resistance.
Using cryo-EM, the researchers discovered that the 2A1 antibody neutralizes the virus by stabilizing a sugar-containing structure on the viral fusion protein rather than displacing it, as scientists had anticipated. This previously unrecognized strategy may help explain the antibody’s potency and resilience against viral escape.
“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 Benhur Lee, MD, chair in microbiology at the Icahn School of Medicine. “The finding suggests that stabilizing a viral protein can sometimes be just as effective—or even more effective—than disrupting it.”
When administered together, the antibody cocktail completely protected hamsters from lethal Nipah virus infection. The treatment remained effective even after infection was established, an encouraging result for a disease that progresses rapidly and carries a high fatality rate.
The findings may have broader implications for pandemic preparedness. Because many viruses rely on multiple proteins to infect cells, the researchers believe this dual-targeting strategy could be adapted for other high-priority pathogens.
“This work provides a blueprint for developing antibody therapies that are more resistant to viral evolution,” said Lee. “Rather than relying on a single target, we can attack a virus at multiple vulnerable points simultaneously.”
Next steps include studies in nonhuman primates, evaluation of long-term safety, and efforts to optimize the antibodies for clinical use. The team is also exploring next-generation antibody formats, including single molecules capable of targeting multiple viral proteins simultaneously, as well as approaches that could broaden protection against additional members of the henipavirus family.
“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 Lee. “Our long-term goal is to translate these discoveries into practical tools that help protect people during future outbreaks.”
