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.
Highlights
Respiratory syncytial virus (RSV) causes acute lower respiratory tract infections and is the leading cause of infant hospitalizations
Most in vitro RSV neutralizing antibodies in human sera are directed against the prefusion conformation[5], but due to its instability the prefusion conformation has a propensity to prematurely refold into the stable postfusion conformation, both in solution and on the surface of the virions[10,19]
These strategies led to the generation of a highly stable prefusion RSV fusion protein (RSV F) that produced in high yields and protected cotton rats against RSV challenge
Summary
Respiratory syncytial virus (RSV) causes acute lower respiratory tract infections and is the leading cause of infant hospitalizations. 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. The stabilization of the RSV F protein has recently been achieved by the introduction of a disulphide bond between residues 155 and 290, introduction of two ‘cavity-filling’ substitutions at positions 190 and 207, and attachment of a heterologous trimerization motif to the C terminus of HRB These modifications led to the generation of a stable prefusion molecule with modest expression levels, but excellent immunogenicity in mice and macaques[10]. These strategies led to the generation of a highly stable prefusion RSV F that produced in high yields and protected cotton rats against RSV challenge
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