Nipah virus and Hendra virus are bat-borne zoonotic pathogens responsible for outbreaks of encephalitis and respiratory illness. Notably, these henipaviruses have fatality rates between 50% and 100%. Over the past two decades, Nipah virus has spilled over into humans almost annually in Bangladesh with other outbreaks occurring in India and the Philippines. There are no approved vaccines or therapeutics for use in people against these infections.
The entry of Henipaviruses into host cells requires the attachment (G) and fusion (F) glycoproteins which are the main targets of antibody responses. To further the understanding of viral infection and host immunity, researchers have determined a cryo-electron microscopy structure of Nipah virus’s G homotetrameric ectodomain in complex with a broadly neutralizing antibody Fab fragment.
These findings offer new details on how Nipah and Hendra viruses attack cells, and the immune responses that try to counter them. The results point toward multi-pronged tactics to prevent and treat these deadly illnesses.
This research is reported in Science in the paper, “Architecture and antigenicity of the Nipah virus attachment glycoprotein.”
Using cryo-electron microscopy, a research team led by David Veesler, PhD, associate professor of biochemistry at the University of Washington School of Medicine and a Howard Hughes Medical investigator, was able to determine the structure of the Nipah virus G homotetrameric ectodomain in complex with the nAH1.3 broadly neutralizing antibody Fab fragment. The scientists went on to show that a cocktail of two non-overlapping G-specific antibodies neutralizes Nipah virus and Hendra virus synergistically. The combination of forces also helped keep escape mutants from emerging to sidestep the antibody response.
Examining the antibody response in laboratory animals provided vital information. More specifically, the analysis of polyclonal serum antibody responses elicited by vaccination of macaques with the Nipah virus G protein indicates that the receptor-binding head domain is immunodominant.
Before this study, the researchers said, no information was available on the structure of the G protein. This lack of information was an obstacle to understanding immunity and to improving the design of vaccine candidates.
The scientists noted that the architecture “adopts a unique two heads up and two heads down conformation that is different from any other paramyxovirus attachment glycoprotein.” The paramyxovirus is a large family of single-strand RNA viruses including measles, mumps, distemper, parainfluenza, and henipavirus.
Now that the researchers have uncovered the 3D organization, and some of the conformational dynamics of the G protein, they may be closer to creating a template for building new and improved vaccines. These findings, the researchers noted, “provide a blueprint for engineering next-generation vaccine candidates with improved stability and immunogenicity,” with a focus on the vulnerability of the head domain. They anticipate a design approach like that employed for newer computer-engineered SARS-CoV-2 and respiratory syncytial virus candidates. A mosaic of head antigens would be presented to the body in an ordered array on a multivalent display. Using only the head domain rather than the full G protein could also make manufacturing large supplies of vaccines simpler.
New attempts to design life-saving preventatives and treatments became even more urgent after a new strain of Hendra was discovered a few months ago. Henipavirus antibodies have been detected in people and Pteropus bats in Africa. It’s estimated that two billion people live in the parts of the world where henipavirus spillovers from bats, or intermediary animal vectors, could be a threat.