An international research team led by investigators in the Department of Microbiology at the Icahn School of Medicine at Mount Sinai has developed the first fully human monoclonal antibody cocktail shown to provide complete protection against lethal Nipah and Hendra virus infection. The protection was seen even when treatment was given after infection had begun.
Published in Science Translational Medicine, the study identifies two fully human antibodies that target different stages of the Nipah virus infection process. When used together, the antibodies provided complete protection in hamster models exposed to otherwise lethal doses of the virus. 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.
Nipah virus and the closely related Hendra virus belong to a family of pathogens known as henipaviruses, which can spread from animals to humans and cause severe respiratory and neurological disease. Outbreaks are rare but often devastating, with mortality rates ranging from 40 to upwards of 75 percent. There are no approved human vaccines or therapeutics for people infected with these viruses.
"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 scarcity of human samples, the researchers used transgenic humanized mice—genetically engineered mice capable of producing fully human antibodies. This approach enabled the team to identify potent antibodies without requiring the additional engineering steps traditionally needed to adapt animal antibodies for human use.
Henipaviruses use two viral proteins to enter cells—a receptor-binding protein and a fusion protein. Previous therapeutic approaches focused on blocking one or the other in isolation, which gave the virus the opportunity to evolve escape mutations that provide resistance to the treatment.
The investigators discovered two particularly powerful antibodies. One blocks the viral protein responsible for attaching to human cells. The other targets a separate viral protein required for the virus to fuse with and enter those cells. Because the antibodies work through independent mechanisms, they create multiple barriers to infection and make it more difficult for the virus to evade treatment.
The first antibody, known as 8G3, targets a critical region of the virus that appears highly resistant to mutation. Researchers found the virus would likely need to acquire multiple simultaneous genetic changes to evade the antibody, an unlikely event.
The second antibody, known as 2A1, revealed an unexpected mechanism of action. Using high-resolution structural imaging, the researchers discovered that the 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, Ward-Coleman Chair in Microbiology at the Icahn School of Medicine and senior author of the study. "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.
Beyond their immediate therapeutic potential, 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 Dr. Lee. "Rather than relying on a single target, we can attack a virus at multiple vulnerable points simultaneously."
While the results are promising, the therapy remains in preclinical development. The current findings are based on laboratory and animal studies, and additional testing will be required before human clinical trials can begin. Planned 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 Dr. Lee. "Our long-term goal is to translate these discoveries into practical tools that help protect people during future outbreaks."
The study was conducted by researchers from the Icahn School of Medicine at Mount Sinai in collaboration with investigators from Fred Hutchinson Cancer Center, the University of Oxford, the University of Texas Medical Branch, and other partner institutions.
About the Icahn School of Medicine at Mount Sinai
The Icahn School of Medicine at Mount Sinai is internationally renowned for its outstanding research, educational, and clinical care programs. It is the sole academic partner for the seven member hospitals* of the Mount Sinai Health System, one of the largest academic health systems in the United States, providing care to New York City's large and diverse patient population.
The Icahn School of Medicine at Mount Sinai offers highly competitive MD, PhD, MD-PhD, and master's degree programs, with enrollment of more than 1,200 students. It has the largest graduate medical education program in the country, with more than 2,700 clinical residents and fellows training throughout the Health System. The Graduate School of Biomedical Sciences offers 12 degree-granting programs, conducts innovative basic and translational research, and trains more than 470 postdoctoral research fellows.
Ranked 11th nationwide in National Institutes of Health (NIH) funding, the Icahn School of Medicine at Mount Sinai is among the 90th percentile of U.S. private medical schools in Sponsored Programs Direct Expenditures per Principal Investigator, according to the Association of American Medical Colleges. More than 6,900 scientists, educators, and clinicians work within and across dozens of academic departments and multidisciplinary institutes with an emphasis on translational research and therapeutics. Through Mount Sinai Innovation Partners (MSIP), the Health System facilitates the real-world application and commercialization of medical breakthroughs made at Mount Sinai.
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* Mount Sinai Health System member hospitals: The Mount Sinai Hospital; Mount Sinai Brooklyn; Mount Sinai Morningside; Mount Sinai Queens; Mount Sinai South Nassau; Mount Sinai West; and New York Eye and Ear Infirmary of Mount Sinai.
About the Lieber Institute for Brain Development
The mission of the Lieber Institute for Brain Development and the Maltz Research Laboratories is to translate the understanding of basic genetic and molecular mechanisms of schizophrenia and related developmental brain disorders into clinical advances that change the lives of affected individuals. LIBD is an independent, not-for-profit 501(c)(3) organization and a Maryland tax-exempt medical research institute affiliated with the Johns Hopkins University School of Medicine. The Lieber Institute's brain repository of nearly 5,000 human brains is the largest collection of postmortem brains for the study of neuropsychiatric disorders worldwide.
