The work illustrates how vaccine development can advance by probing the physical architecture of viruses and finding the parts needed to prime the immune system.
Rotavirus, which causes severe diarrhea and vomiting, infects most children, causes gastroenteritis that sometimes requires hospitalization, and kills about 440,000 children each year. The only licensed vaccine, RotaShield, was discontinued following reported cases of a condition causing bowel obstruction.
Research team leader Philip Dormitzer says of the outside layer of rotavirus that “its job is to get the innermost portions inside the cell.”
From the outer layer project clusters of VP4 molecules, which Dormitzer’s team trimmed down, crystallized, and diffracted using X-ray diffraction to determine their structures. VP4 undergoes shape changes that allow it to breach the membrane of the cell it’s trying to infect.
First, when rotavirus arrives in the intestine, the VP4 molecules prime the virus to attack the cell. Then, VP4 breaks a hole in the cell membrane, letting the virus enter.
“The work is a clear example of the way in which structural studies can contribute to new good ideas about strategies for vaccines,” says Senior Investigator Stephen Harrison, Ph.D.