I recently returned from a Keystone Symposia conference in Rio de Janeiro focused on vaccine development. The meeting attracted leading researchers from around the world and featured some of the latest advances in the vaccine field. A highlight of the conference was a report by Dr. Peter Kwong of the National Institutes of Health regarding the development of a new vaccine approach for Respiratory Syncytial Virus (RSV) infections, a leading cause of hospitalization and death for children under 5 years of age as well as for the elderly. The remarkable feature of Kwong’s presentation was not so much that progress had been made toward a new RSV vaccine, but that it involved a new approach referred to as “structure-based design.”
Vaccines work by producing proteins in the blood called antibodies, which are able to bind to, and inactivate, invading infectious agents. For example, flu vaccines induce our bodies to make antibodies that are highly specific for the flu virus. If flu viruses enter the body, these antibody molecules stick to the surface of the virus, preventing it from entering cells and causing an infection. A key feature of antibodies is that they recognize the “shape” of the viral components. For example, the flu virus features protein spikes on its surface; protective antibodies against flu work by recognizing the shape of these spike proteins.
Most vaccines contain either a killed version or isolated components of the infectious agent. Therefore, vaccination works by educating the body’s immune system about the “shapes” presented by an infectious agent’s surface molecules. The vaccine induces the production of antibodies specific for that agent, thereby preparing the immune system to make an immediate response when the live infectious agent is subsequently encountered. However, this traditional approach to vaccine development has proven problematic for RSV, and no effective vaccines are currently approved.
Some time ago, researchers discovered an antibody that was protective against RSV infection and wondered why this antibody was not readily produced using a traditional vaccination strategy. The antibody in question recognized and bound to a protein referred to as the RSV fusion, or F, protein, which is involved in viral entry into cells in the lung. Using the technique of X-ray crystallography, Kwong and colleagues developed a three-dimensional structure of the antibody bound to the RSV F protein. This structure led to the realization that the F protein is a flexible molecule that changes shape during viral entry into cells from a pre-fusion version to a post-fusion version. Furthermore, the protective antibody bound exclusively to the pre-fusion form of the protein. The fact that the pre-fusion version of the F protein is unstable explained why vaccines containing killed RSV do not elicit protective antibodies.
These findings presented a clear path to developing an effective RSV vaccine — simply develop a vaccine formulation that contains a stable form of the pre-fusion version of the F protein. However, this proved to be difficult given the instability of the pre-fusion version of F protein. It was the solution to this problem that was the breakthrough at the vaccine meeting in Rio de Janeiro. Kwong carefully examined the shape of the pre-fusion F protein bound to the protective antibody. He and his research team then started modifying the F protein’s structure by introducing and removing chemical bonds in an attempt to stabilize the protein in its pre-fusion shape. It took a lot of effort and the testing of more than 100 different F protein variants. However, the team finally identified a structure that was stabilized in the pre-fusion form. Vaccination with this modified protein elicited potent antibodies that were able to bind to pre-fusion F protein and were highly protective against live RSV infection. The excitement at the Rio de Janeiro conference was palpable as these data were presented; this was the first vaccine to be designed based on structural studies of the shape of the antibody targets on a virus’s surface.
The approach holds great promise for developing vaccines against other infectious agents that display “unstable” molecules on their cell surface. Indeed, considerable progress is now being made using this approach to develop vaccines against the human immunodeficiency virus (HIV) that causes AIDS. In this case, researchers are closing in on a stable form of a cell surface protein on HIV that can be used for vaccine studies. Many other examples are in the pipeline.
In the meantime, Kwong and colleagues are moving their candidate vaccine into clinical trials. Let’s hope that this technology will result in new vaccines not only for RSV, but for many other infectious agents that have eluded such a solution.
David L. “Woody” Woodland, Ph.D., is the chief scientific officer of Silverthorne-based Keystone Symposia on Molecular and Cellular Biology, a nonprofit dedicated to accelerating life science discovery by convening internationally renowned research conferences in Summit County and worldwide. Woody can be reached at (970) 262-1230, ext. 131, or firstname.lastname@example.org.
The traditional approach to vaccine development has proven problematic for Respiratory Syncytial Virus, and no effective vaccines are currently approved.