1. A highly stable prefusion RSV F vaccine derived from structural analysis of the fusion mechanism.
- Author
-
Krarup A, Truan D, Furmanova-Hollenstein P, Bogaert L, Bouchier P, Bisschop IJM, Widjojoatmodjo MN, Zahn R, Schuitemaker H, McLellan JS, and Langedijk JPM
- Subjects
- Animals, Antigens, Viral genetics, Blotting, Western, Crystallization, Crystallography, X-Ray, Electrophoresis, Polyacrylamide Gel, Enzyme-Linked Immunosorbent Assay, Mice, Microscopy, Electron, Mutation, Protein Conformation, Respiratory Syncytial Virus Infections immunology, Respiratory Syncytial Viruses genetics, Sigmodontinae, Viral Fusion Proteins genetics, Antibodies, Neutralizing immunology, Antigens, Viral immunology, Respiratory Syncytial Virus Infections prevention & control, Respiratory Syncytial Virus Vaccines immunology, Respiratory Syncytial Viruses immunology, Viral Fusion Proteins immunology
- Abstract
Respiratory syncytial virus (RSV) causes acute lower respiratory tract infections and is the leading cause of infant hospitalizations. Recently, a promising vaccine antigen based on the RSV fusion protein (RSV F) stabilized in the native prefusion conformation has been described. Here we report alternative strategies to arrest RSV F in the prefusion conformation based on the prevention of hinge movements in the first refolding region and the elimination of proteolytic exposure of the fusion peptide. A limited number of unique mutations are identified that stabilize the prefusion conformation of RSV F and dramatically increase expression levels. This highly stable prefusion RSV F elicits neutralizing antibodies in cotton rats and induces complete protection against viral challenge. Moreover, the structural and biochemical analysis of the prefusion variants suggests a function for p27, the excised segment that precedes the fusion peptide in the polypeptide chain.
- Published
- 2015
- Full Text
- View/download PDF