A highly stable prefusion RSV F vaccine derived from structural analysis of the fusion mechanism.
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.
Janssen Infectious Diseases and Vaccines, Archimedesweg 4-6, Leiden 2333 CN, The Netherlands.
Anders
A
Krarup
Janssen Infectious Diseases and Vaccines, Archimedesweg 4-6, Leiden 2333 CN, The Netherlands.
Daphné
D
Truan
Janssen Infectious Diseases and Vaccines, Archimedesweg 4-6, Leiden 2333 CN, The Netherlands.
Polina
P
Furmanova-Hollenstein
Janssen Infectious Diseases and Vaccines, Archimedesweg 4-6, Leiden 2333 CN, The Netherlands.
Lies
L
Bogaert
Janssen Infectious Diseases and Vaccines, Archimedesweg 4-6, Leiden 2333 CN, The Netherlands.
Pascale
P
Bouchier
Janssen Infectious Diseases and Vaccines, Archimedesweg 4-6, Leiden 2333 CN, The Netherlands.
Ilona J M
IJM
Bisschop
Janssen Infectious Diseases and Vaccines, Archimedesweg 4-6, Leiden 2333 CN, The Netherlands.
Myra N
MN
Widjojoatmodjo
Janssen Infectious Diseases and Vaccines, Archimedesweg 4-6, Leiden 2333 CN, The Netherlands.
Roland
R
Zahn
Janssen Infectious Diseases and Vaccines, Archimedesweg 4-6, Leiden 2333 CN, The Netherlands.
Hanneke
H
Schuitemaker
Department of Biochemistry, Geisel School of Medicine at Dartmouth, Hanover, New Hampshire 03755-3844, USA.
Jason S
JS
McLellan
Janssen Infectious Diseases and Vaccines, Archimedesweg 4-6, Leiden 2333 CN, The Netherlands.
Johannes P M
JPM
Langedijk
D000818:Animals; D057134:Antibodies, Neutralizing / Q000276:immunology*; D000956:Antigens, Viral / Q000235:genetics / Q000276:immunology*; D015153:Blotting, Western; D003460:Crystallization; D018360:Crystallography, X-Ray; D004591:Electrophoresis, Polyacrylamide Gel; D004797:Enzyme-Linked Immunosorbent Assay; D051379:Mice; D008854:Microscopy, Electron; D009154:Mutation; D011487:Protein Conformation; D018357:Respiratory Syncytial Virus Infections / Q000276:immunology / Q000517:prevention & control*; D022261:Respiratory Syncytial Virus Vaccines / Q000276:immunology*; D012136:Respiratory Syncytial Viruses / Q000235:genetics / Q000276:immunology*; D016205:Sigmodontinae; D014760:Viral Fusion Proteins / Q000235:genetics / Q000276:immunology*
D057134:Antibodies, Neutralizing; D000956:Antigens, Viral; D022261:Respiratory Syncytial Virus Vaccines; D014760:Viral Fusion Proteins