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

A. Krarup,D. Truan,Polina Furmanova-Hollenstein,L. Bogaert,P. Bouchier,Ilona J. M. Bisschop,M. Widjojoatmodjo,R. Zahn,H. Schuitemaker,J. McLellan,J. Langedijk

Published 2015 in Nature Communications

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. Respiratory syncytial virus (RSV) is a highly contagious childhood pathogen of the respiratory tract for which no vaccine is currently available. Here the authors present a strategy to stabilize the RSV F protein in a prefusion conformation that can elicit a strong protective immune response in animal models.

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