Stabilized soluble pre-fusion rsv f polypeptides

Abstract

Described are stable pre-fusion respiratory syncitial virus (RSV) F polypeptides, immunogenic compositions comprising the polypeptides and uses thereof for the prevention and/or treatment of RSV infection.

1 .- 27 . (canceled) 
     
     
         28 . A recombinant pre-fusion respiratory syncytial virus (RSV) Fusion (F) polypeptide comprising:
 a mutation of the amino acid residue N/T at position 67 into I,   a mutation of the amino acid residue S at position 215 into P, and   a mutation of the amino acid residue D at position 486 into N,   wherein the amino acid positions are given in reference to the sequence of RSV F protein from the A2 strain (SEQ ID NO: 1).   
     
     
         29 . The recombinant pre-fusion RSV F polypeptide according to  claim 28 , wherein the polypeptide comprises a truncated F1 domain and an F2 domain. 
     
     
         30 . The recombinant pre-fusion RSV F polypeptide according to  claim 29 , wherein the polypeptide comprises a heterologous trimerization domain linked to the truncated F1 domain, wherein the heterologous trimerization domain comprises the amino acid sequence 
       
         
           
                 
                 
               
                     
                   (SEQ ID NO: 4) 
                 
                     
                   GYIPEAPRDGQAYVRKDGEWVLLSTFL. 
                 
             
                
                
               
            
           
         
       
     
     
         31 . The recombinant pre-fusion RSV F polypeptide according to  claim 30 , wherein the trimerization domain is linked to amino acid 513 of the truncated F1 domain by a linker sequence. 
     
     
         32 . The recombinant pre-fusion RSV F polypeptide according to  claim 31 , wherein the linker comprises SEQ ID NO: 5. 
     
     
         33 . The recombinant pre-fusion RSV F polypeptide according to  claim 28 , wherein the F1 domain and/or the F2 domain are from an RSV A strain. 
     
     
         34 . The recombinant pre-fusion RSV F polypeptide according to  claim 28 , wherein the F1 domain and/or the F2 domain are from an RSV B strain. 
     
     
         35 . A composition comprising the recombinant pre-fusion RSV F polypeptide according to  claim 28  and a pharmaceutically acceptable carrier or excipient. 
     
     
         36 . A composition comprising the recombinant pre-fusion RSV F polypeptide according to  claim 30  and a pharmaceutically acceptable carrier or excipient. 
     
     
         37 . A nucleic acid molecule encoding the pre-fusion RSV F mutant polypeptide of  claim 28 . 
     
     
         38 . A vector comprising a nucleic acid molecule encoding a pre-fusion RSV F polypeptide according to  claim 28 , wherein the vector is an adenoviral vector. 
     
     
         39 . The vector according to  claim 38 , wherein the adenoviral vector is an adenovirus serotype 26 (Ad26) vector. 
     
     
         40 . A composition comprising the vector according to  claim 38  and a pharmaceutically acceptable carrier or excipient. 
     
     
         41 . A composition comprising a recombinant pre-fusion RSV F polypeptide according to  claim 28  and a vector comprising a nucleic acid molecule encoding the same. 
     
     
         42 . A composition comprising a recombinant pre-fusion RSV F polypeptide according to  claim 30  and an adenoviral vector comprising a nucleic acid molecule encoding a pre-fusion RSV F polypeptide comprising: a mutation of the amino acid residue N/T at position 67 into I, a mutation of the amino acid residue S at position 215 into P, and a mutation of the amino acid residue D at position 486 into N, wherein the amino acid positions are given in reference to the sequence of RSV F protein from the A2 strain (SEQ ID NO: 1). 
     
     
         43 . A method of inducing an immune response against RSV F protein in a subject, the method comprising administering to the subject a recombinant pre-fusion RSV F polypeptide according to  claim 30  and an adenoviral vector comprising a nucleic acid molecule encoding a pre-fusion RSV F polypeptide comprising: a mutation of the amino acid residue N/T at position 67 into I, a mutation of the amino acid residue S at position 215 into P, and a mutation of the amino acid residue D at position 486 into N, wherein the amino acid positions are given in reference to the sequence of RSV F protein from the A2 strain (SEQ ID NO: 1). 
     
     
         44 . The method according to  claim 43 , wherein the adenoviral vector is an adenovirus serotype 26 (Ad26) vector. 
     
     
         45 . A method of prophylaxing and/or treating RSV infection in a subject, the method comprising administering to the subject the recombinant pre-fusion RSV F polypeptide according to  claim 30  and an adenoviral vector comprising a nucleic acid molecule encoding a pre-fusion RSV F polypeptide comprising: a mutation of the amino acid residue N/T at position 67 into I, a mutation of the amino acid residue S at position 215 into P, and a mutation of the amino acid residue D at position 486 into N, wherein the amino acid positions are given in reference to the sequence of RSV F protein from the A2 strain (SEQ ID NO: 1), to prophylax against and/or treat the subject for RSV infection. 
     
     
         44 . The method according to  claim 45 , wherein the adenoviral vector is an adenovirus serotype 26 (Ad26) vector.