The virus is so effective at entering human cells, thanks in large part to the special proteins that coat its outer surface. These proteins are important targets for vaccine development. To study these, scientists usually create a laboratory version to see how the immune system responds. However, these simplified versions often omit important sections that are normally located within the outer membrane of the virus. As a result, antibodies don’t always behave the same way they would during an actual infection, making it difficult to understand how antibodies actually recognize and stop the virus.
Scripps Research researchers, in collaboration with IAVI and other collaborators, have developed a new platform that allows them to study these viral proteins in a more natural form. Their method uses nanodisc technology, which places proteins inside tiny particles made of lipids. This setup mimics the outer membrane of the virus and helps preserve the natural structure and behavior of the proteins. This approach provides a clearer picture of how antibodies interact with the virus and could guide future vaccine design.
Nanodisk technology that mimics viral membranes
This study nature communicationstested the platform using proteins from HIV and Ebola. These viruses have long posed a challenge for vaccine development because their surface proteins are particularly difficult to target by the immune system. The researchers believe the same method could be applied to other viruses with similar membrane-bound proteins, such as influenza and SARS-CoV-2.
“For years, we’ve had to rely on versions of viral proteins that are missing critical parts,” says co-senior author William Sieff, a professor at the Scripps Research Institute and executive director of vaccine design at the IAVI Center for Neutralizing Antibodies. “Our platform allows us to study these proteins in an environment that better reflects their natural environment, which is critical if we want to understand how protective antibodies recognize viruses.”
In real viruses, surface proteins are embedded within a lipid membrane and arranged in a specific shape. In contrast, in most laboratory studies, the membrane-anchored portion of the protein is removed to make it easier to handle. Although this simplifies experiments, it can mask important details, especially for antibodies that target regions near the bases of proteins close to the membrane.
To overcome this limitation, the research team incorporated vaccine candidate proteins into nanodiscs. These small, stable lipid patches hold proteins in place and are much like the outer layer of a virus. This setup allows scientists to study how antibodies interact with proteins in a more realistic setting. The platform also supports standard vaccine research tools such as antibody binding tests, immune cell sorting, and high-resolution imaging.
“Integrating all these components into one reliable system was key,” said first author Kimmo Rantalainen, a senior scientist in the Seeff lab. “The individual parts already existed, but making them work together in a reproducible and scalable way opens up new possibilities for how vaccines can be analyzed and designed.”
New insights into antibody responses
Using HIV as an example, the researchers focused on stable regions of the virus’s surface proteins located near the membrane. This region is targeted by a group of antibodies that can block a wide range of HIV variants. These antibodies are particularly valuable for vaccine research because they recognize parts of the virus that remain consistent even as the virus mutates.
Using the Nanodisc platform, the research team obtained a detailed structural picture of how these antibodies interact with viral proteins in their natural membrane environment. This revealed features not visible when studying proteins alone. The findings also shed light on how certain antibodies neutralize viruses by disrupting the structures they use to infect cells, providing useful clues for designing better vaccines.
“This structure gives us a level of detail that was previously inaccessible,” Rantalainen said. “It showed new interactions at the membrane interface and suggested why they are important for antibody function.”
Applications beyond HIV and Ebola
To demonstrate the widespread utility of the method, the researchers applied it to Ebola proteins. The results confirmed that antibodies can successfully recognize and bind to these proteins within the same membrane-like environment.
This platform is not limited to structural analysis. It can also be used to study immune responses to vaccine candidates. By using nanodiscs as molecular “decoys”, scientists can isolate immune cells that respond to specific viral proteins. This provides a clearer understanding of how the body responds to different vaccine designs. Additionally, the system is efficient. A process that previously took more than a month can now be completed in as little as a week, making it easier to compare multiple vaccine candidates.
Tools to accelerate vaccine development
Although the platform itself is not a vaccine, it serves as a powerful tool to support vaccine research. This is especially important for viruses that are difficult to target using traditional methods.
“This gives the field a more realistic and accurate way to test ideas at an early stage,” Seef emphasizes. “By improving the way we study viral proteins and antibody responses, we hope this platform will help advance next-generation vaccines against the world’s most challenging viruses.”
In addition to Shieff and Rantarainen, the authors of the study, “Viral Glycoprotein Nanodisc Platform for Vaccine Analysis,” include Alessia Liguori, Gabriel Ozorovsky, Claudia Flynn, John M. Steichen, Olivia M. Swanson, Patrick J. Madden, Sabyasachi Babu, Swastik Poorela, Ananth Gharpure, Danny Lu, and Oleksandr. Karyujiny, Patrick Skog, Sierra Terrada, Monolina Sil, Jolene K. Diedrich, Eric Jorgeson, Ryan Tingle, Saman Eskanderzadeh, Wenxin Li, Noushin Alavi, Diana Goodow. Yin, Michael Kubitz, Sonya Amirzeni, Devin Sok, Jeong-Hyun Lee, John R. Yates III, James C. Paulson, Shane Crotty, and Mr. Schiffner and Mr. Andrew B. Ward of the Tauben Scripps Research Institute. and Sunny Himansu of Moderna Inc.
This research was supported by funding from the National Institute of Allergy and Infectious Diseases of the National Institutes of Health (grants UM1 AI144462, R01 AI147826, R56 AI192143 and 5F31AI179426-02). Bill & Melinda Gates Foundation Collaboration for AIDS Vaccine Discovery (grants INV-007522, INV-008813, INV-002916); IAVI Neutralizing Antibody Center (INV-034657 and INV-064772). and the Alexander von Humboldt Foundation.
