A highly stable prefusion RSV F vaccine derived from structural analysis of the fusion mechanism

Anders Krarup, Daphné Truan, Polina Furmanova-Hollenstein, Lies Bogaert, Pascale Bouchier, Ilona J. M. Bisschop, Myra N. Widjojoatmodjo, Roland Zahn, Hanneke Schuitemaker, Jason S. McLellan and Johannes P. M. Langedijk ()
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Anders Krarup: Janssen Infectious Diseases and Vaccines
Daphné Truan: Janssen Infectious Diseases and Vaccines
Polina Furmanova-Hollenstein: Janssen Infectious Diseases and Vaccines
Lies Bogaert: Janssen Infectious Diseases and Vaccines
Pascale Bouchier: Janssen Infectious Diseases and Vaccines
Ilona J. M. Bisschop: Janssen Infectious Diseases and Vaccines
Myra N. Widjojoatmodjo: Janssen Infectious Diseases and Vaccines
Roland Zahn: Janssen Infectious Diseases and Vaccines
Hanneke Schuitemaker: Janssen Infectious Diseases and Vaccines
Jason S. McLellan: Geisel School of Medicine at Dartmouth
Johannes P. M. Langedijk: Janssen Infectious Diseases and Vaccines

Nature Communications, 2015, vol. 6, issue 1, 1-12

Abstract: 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.

Date: 2015
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DOI: 10.1038/ncomms9143

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