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.
Krarup, Anders; Truan, Daphné; Furmanova-Hollenstein, Polina; Bogaert, Lies; Bouchier, Pascale; Bisschop, Ilona; Widjojoatmodjo, Myra; Zahn, Roland; Schuitemaker, Hanneke; McLellan, Jason; and Langedijk, Johannes, "A Highly Stable Prefusion Rsv F Vaccine Derived from Structural Analysis of the Fusion Mechanism" (2015). Open Dartmouth: Faculty Open Access Articles. 2499.