The World Health Organization (WHO) considers the deadly Nipah virus a research priority due to its potential to cause a future pandemic (1). Despite the risk it poses to global health, it has no FDA-approved treatment or vaccine (2). Now in a study in Science, researchers reported the structure of key Nipah virus surface proteins and used it to design a vaccine candidate against the virus (3).

The Nipah virus originated in southeast Asia in the 1990s and causes outbreaks there almost every year. It has an estimated 40-75% fatality rate, making it as lethal as the Ebola virus. Symptoms of infection include brain swelling, seizures, and respiratory illness (4,5). Nipah virus’s entry into the cell requires fusion of both the virus and the host cell membrane, and the virus contains built in tools to do this: attachment and fusion glycoproteins. 

“These are probably going to work together to initiate the viral fusion to the host cell. This is the innovation of the virus, and this mechanism has never been described in great detail,” said Zhaoqian Wang, a structural biologist at the University of Washington and author of the study.

Using cryoelectron microscopy (cryo-EM), Wang and his colleagues determined the full tetrameric structure of the attachment glycoprotein. Previously, researchers had only mapped one portion of the protein, known as the head domain. Using this structural knowledge, the team determined where two different previously discovered antibodies bind to the attachment glycoprotein. They found that the antibodies worked synergistically to prevent viral entry into cells by each binding to an opposite side of the head of the attachment glycoprotein. The antibody cocktail reduced the emergence of viral escape mutants, which evade immune detection by carrying changes to the sites where antibodies bind.

Wang’s team then tested how well the attachment glycoprotein tetramer worked as a vaccine against Nipah virus infection in macaques. They found that the macaques developed a potent antibody response toward the attachment protein’s head domain. Wang emphasized that his map of the attachment protein structure would inform future structure-based designs of Nipah virus vaccines that target the attachment protein.

“This is the best you can do with the current technology of cryoelectron microscopy,” said Hong Zhou, a structural biologist at the University of California, Los Angeles who was not affiliated with the study. “They really reached beyond the structure, which is basic study. They worked with a team of immunologists. Then they not only pushed beyond the molecule, they pushed into the cell. They pushed into animals.” 

Nipah virus outbreaks primarily occur in Bangladesh and India. Nipah is one of the most lethal diseases on the radar of the world’s disease control agencies with potential to spread not only between humans, but also from animals to people (6). Fruit bats serve as a viral host reservoir, and some livestock like pigs transmit the disease too. Fruit bats can initiate “spillover” events, where humans consume fruits or sap contaminated by fruit bats and introduce new points of infection into the population. 

With the risks that Nipah virus poses, Wang and his team hope to improve the knowledge base needed to generate better therapies for this disease. Wang is interested in conducting further studies to generate a structure-based vaccine design. “We know as far as the structure has been solved, it’s going to help a lot, for both antibody drug discovery, the vaccine study for these viruses, and so on.”

References

1. Prioritizing diseases for research and development in emergency contexts. WHO (2022). Available at: https://www.who.int/activities/prioritizing-diseases-for-research-and-development-in-emergency-contexts
2. Nipah Virus Treatment. Centers for Disease Control and Prevention (2020). Available at: https://www.cdc.gov/vhf/nipah/treatment/index.html#:~:text=Currently%20there%20are%20no%20licensed,of%20symptoms%20as%20they%20occur.
3. Wang, Z. et al. Architecture and antigenicity of the Nipah virus attachment glycoprotein. Science  375, 1373-1378 (2022). 
4. Mortality analyses. Johns Hopkins Coronavirus Resource Center (2022). Available at: https://coronavirus.jhu.edu/data/mortality (2022).
5. Nipah Virus Signs and Symptoms. Centers for Disease Control and Prevention (2020). Available at: https://www.cdc.gov/vhf/nipah/symptoms/index.html
6. Gurley, S. E., et al. Twenty Years of Nipah Virus Research: Where Do We Go From Here?. J. Infect. Dis.  221, S359-S362 (2020).