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Recent molecular discoveries offer new details about how the Nipah and Hendra viruses attack cells, and the immune responses that attempt to counter this assault. The findings point to multi-pronged tactics to prevent and treat these deadly diseases.
This research is reported today in Science as the first peer-reviewed article, published quickly online.
Both Nipah virus and Hendra virus are carried by bats native to certain parts of the world. These henipaviruses are species hopping and can infect many other mammals, including humans. Viruses cause brain inflammation and respiratory symptoms. People who contract either of these diseases have a 50% to 100% chance of dying.
There is a vaccine approved for use in horses and a modified version has entered a human clinical trial.
Horses can spread Hendra, possibly contracted by eating fruit contaminated by bats, to their keepers through saliva and nasal secretions. An experimental, but not yet approved, cross-reactive antibody that should work against both Nipah and Hendra viruses was given to fifteen people who had a high-risk exposure. This was done under emergency compassionate use guidelines. This antibody is undergoing a clinical trial in Australia, where it has just completed phase 1 testing. There are no vaccines or therapies approved for use in humans against these henipaviruses, other than supportive care in the limited hope that the patient can overcome the virus.
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New attempts to design preventive agents and life-saving treatments have become even more urgent after the discovery of a new strain of Hendra a few months ago. Nipah virus outbreaks have appeared almost every year for the past two decades in Bangladesh. The disease has also been observed in India and the Philippines. Henipavirus antibodies have been detected in humans and Pteropus bats in Africa. An estimated 2 billion people live in areas of the world where henipavirus spillovers from bats, or intermediate animal vectors, could pose a threat.
The senior author of the latest henipavirus article in Science is David Veesler, associate professor of biochemistry at the University of Washington School of Medicine and medical researcher Howard Hughes. He studies bat immunity to many dangerous viruses and conducts studies on the molecular structure and function of the infectivity machinery of coronaviruses, other related viruses, and henipaviruses. His lab also studies the interactions between antibodies and viruses which hold clues for the design of antivirals and vaccines for these two families of viruses.
The lead author is Zhaoqian Wang, a UW graduate student in biochemistry. Christopher Broder’s lab has collaborated on research at the University of Uniformed Services and the Henry M. Jackson Foundation for the Advancement of Military Medicine.
The researchers explained that the Nipah and Hendra viruses enter cells through attachment and fusion glycoproteins, which work in a coordinated fashion. These glycoproteins are the key targets of the antibody defense system.
Using cryo-electron microscopy, scientists were able to determine the structure of a critical component of the infection mechanism of Nipah viruses in an interaction with a fragment of a broadly neutralizing antibody. They also observed that a mixture or “cocktail” of antibodies works best together to disarm Nipah viruses. Similar synergistic effects were observed in a set of antibodies against Hendra viruses. This combination of forces also helped prevent escaped mutants from emerging to circumvent the antibody response.
Examination of the antibody response in laboratory animals inoculated with a critical section of the Nipah virus infection machinery has provided vital information. The analysis indicated which area of the virus’s receptor-binding protein was dominant in triggering an immune response.
Prior to this study, the researchers said, nothing was available about the structure of a critical part of henipaviruses responsible for driving the antibody response, called the HNV G protein. This lack of information has been an obstacle to the understanding of immunity and improving the design of candidate vaccines.
Now that researchers have uncovered the 3D organization and some of the conformational dynamics of the HNV G protein, science may be closer to creating a template for building new and improved vaccines.
In a simplified description of the more complex finds, a significant part of the attachment structure has a neck and four heads. Only one of the four heads rotates its receptor binding site towards the potential host cell; the other three divert to the virus membrane. This gives the viral structure freedom to reorient the leader domain to engage with the host receptor.
The scientists noted that the architecture “then adopts a unique two-headed up and two-headed down conformation that is unlike any other paramyxovirus attachment glycoprotein.” Paramyxovirus is a large family of single-stranded RNA viruses. They cause several distinct types of disease, most of which are transmitted by respiratory droplets. These include measles, mumps, distemper, parainfluenza, and henipavirus diseases that have more recently passed from animals to humans.
Investigating the nature of antibody responses to Nipah virus and Hendra virus binding protein G, the scientists examined two animals immunized with this glycoprotein. A potent and diverse neutralizing antibody response ensued. The leader domain was found to be the primary, if not exclusive, target of immunization-induced neutralization of antibodies, even though the full tetramer was used. This indicated that the antibody response narrowed in the receptor binding area.
These findings, the researchers noted, “provide a blueprint for designing next-generation vaccine candidates with improved stability and immunogenicity.” The s would focus on the main domain vulnerability. They anticipate a design approach like that used for the new computer-designed 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 leader domain rather than the full G protein could also simplify the manufacture of large quantities of vaccines.