Respiratory Syncytial Virus (RSV), a common respiratory viral infection presents itself as a cold but can become severe in young children, older adults, and immunocompromised patients. Annually, about 58,000 children are hospitalized in the United States, accounting for 100 and 500 deaths among children below five years.
Since its discovery in 1956, despite several attempts to develop and run clinical trials for the treatment of RSV, the virus-strain in it continues to evade vaccines and it continues to be a burden in the health care system.
Decades later, scientists learned about the detailed structure of the RSV virus. Specifically, a protein called F protein on the viral surface they found changes its shape after viral entry into cells. RSV uses the F ‘prefusion’ protein to enter cells. Thus, producing antibodies against the F protein after it has changed shape is not effective at preventing infection.
These ‘postfusion’ antibodies made after viral entry tend to worsen the situation by triggering the immune system and causing inflammation – the cause for failed clinical trials in the 60s. Identifying the structural differences between the prefusion and postfusion F protein was a turning point in the RSV vaccine story.
Scientists Jason McLellan (at the University of Texas at Austin) and Barney Graham (at Morehouse School of Medicine) used X-ray crystallography to determine the structures of F protein in different conformations. They compared different structural conformations of the F protein to determine changes after fusing to the host cell. X-ray crystallography can provide atomic-level resolution of proteins. When a protein changes its shape or conformation during its function, the X-ray structure of the altered protein will also look different.
Understanding this shift in protein conformation helped scientists identify the correct antigen conformation that could induce antibodies before the F protein facilitates virus entry. Vaccine design based on protein conformation has also been used for SARS-CoV-2 and in the development of the COVID vaccine by Moderna and Pfizer.
Thanks to the advanced methods developed to determine protein structures, structure-based vaccine designs are becoming more significant in vaccine development. For example, knowing the F protein conformation was a crucial piece in solving the puzzle of the RSV vaccine.
The US FDA has now approved two RSV vaccines for 60 and older by Pfizer and GlaxoSmithKline. More vaccine trials for RSV are on the way awaiting FDA approval this year. Barney Graham, who has been studying RSV throughout his career and a key contributor to RSV vaccine development say, “The first twenty years of my career were spent trying to understand why the RSV vaccine safety problem occurred back in the mid-sixties… So now, getting to this point where we think we can make a vaccine for RSV safely and now have the efficacy is very exciting.”