Cross-reactive human monoclonal antibodies isolated by researchers at Vanderbilt University Medical Center prevented, in an animal model, severe illness and death caused by two emerging and deadly viruses called Nipah and Hendra.
Their results, published this week in the journal Cell Reports, suggest the antibodies potentially could be given as a therapeutic combination to treat Nipah and Hendra infections while reducing the risk that the viruses will mutate to evade treatment, the researchers concluded.
“These viruses are very lethal, but we have found sites of vulnerability on the surfaces of the viruses to which human antibodies can take hold and stop the viruses in their tracks,” said the paper’s corresponding author, James Crowe Jr., MD, director of the Vanderbilt Vaccine Center.
“Some of these antibodies inhibit all of the medically important viruses in this family, suggesting we have the opportunity to advance them as antiviral drugs,” he said. Nipah and Hendra are members of the henipavirus family of RNA viruses. Like the COVID-19 virus, they can jump from animals to humans.
Hendra virus was first identified in 1994 during an outbreak of respiratory and neurologic disease in horses and humans in Australia. Nipah virus was identified four years later during an epidemic of encephalitis and respiratory illness among pig farmers in Malaysia and Singapore that killed more than 100 people.
Because of their lethality and potential for rapid spread, the World Health Organization has listed Nipah and Hendra among its “priority diseases” requiring extensive and immediate research and development. Crowe is the Ann Scott Carell Professor of Pediatrics and professor of Pathology, Microbiology & Immunology.
He and his colleagues have developed ultra-fast methods for isolating human monoclonal antibodies for many pathogenic viruses, and they have pioneered the rational design of neutralizing antibody treatments and vaccines, some of which have progressed to clinical trials.
Last month the global biopharmaceutical firm AstraZeneca announced that a combination of antibodies discovered at VUMC and optimized by the company significantly reduced COVID-19 symptoms in a phase 3 clinical trial of immunocompromised and chronically ill adults.
In the past year the Crowe team, working with colleagues across the country, also isolated monoclonal antibodies that in laboratory and animal studies have shown efficacy against:
- Alphaviruses, including the often-lethal Eastern equine encephalitis virus;
- Equally dangerous New World hantaviruses, which can cause the lungs to fill with fluid; and
- Rift Valley Fever Virus, an emerging infection in sub-Saharan and North Africa that causes severe, hemorrhagic illness in livestock and humans, and which has pandemic potential.
Phase 1 clinical trials have begun or are being planned to test the efficacy of antibodies isolated at VUMC against the Marburg virus, which can cause a hemorrhagic fever similar to that caused by Ebola, and chikungunya, a tropical, mosquito-borne virus that can cause headaches, nausea, fatigue and rashes.
In the current study, the researchers isolated a panel of human monoclonal antibodies from the antibody-producing B cells (a type of white blood cell) of a man who was accidentally injected with an experimental Hendra vaccine developed for horses.
The most potent class of these cross-reactive antibodies “neutralized” both Hendra and Nipah by preventing the viruses from attaching to receptors expressed by endothelial and nerve cells in the body.
Another class of antibodies was stimulated to attack the viruses once they had bound to the receptors. In a hamster model of Nipah virus infection, the combination protected the animals from serious illness or death.
A significant concern is the capacity of rapidly evolving, emerging viruses to mutate within a person’s body, and thus evade neutralization by vaccines or even the most “ultrapotent” antibody treatments. Resulting “spillover” variants, like the delta variant of the COVID-19 virus, can frustrate efforts to bring a pandemic under control.
The discovery of protective, cross-reactive antibodies against Nipah and Hendra suggest that it is possible to construct antibody combinations that prevent viruses from escaping through mutation or evolving into rapidly spreading spillover variants, the researchers concluded.
Michael Doyle, PhD, a former graduate student in Crowe’s lab, was the paper’s first author. Other VUMC co-authors were Nurgun Kose, Elad Binshtein, PhD, Marcus Nagel, PhD, Erica Armstrong, Robin Bombardi, Jinhui Dong, PhD, and Kevin Schey, PhD.
The research was supported by National Institutes of Health grants AI142764, AI094660, AI152332 and TR002243.
