Group a streptococcal vaccines

Abstract

The present invention provides methods for eliciting an immune response against Group A streptococci, comprising use of recombinant fusion polypeptides, and compositions thereof, that include a multivalent immunogenic portion of at least two immunogenic polypeptides from Group A streptococci M proteins (which are capable of stimulating a protective immune response against Group A streptococci), and a reiterated polypeptide from the immunogenic portion carboxy-terminal to the immunogenic portion, wherein the carboxy-terminal polypeptide is not required to stimulate an immune response against Group A streptococci.

1 . A hybrid fusion polypeptide, comprising:
 (a) a multivalent portion that comprises at least two immunogenic amino-terminal polypeptides of Group A streptococcal M protein from at least two different Group A streptococcal serotypes; and   (b) a carboxy-terminal reiterated immunogenic polypeptide, which is carboxy-terminal to the multivalent portion and is a reiteration of a polypeptide from the amino-terminal region of the multivalent portion.   
     
     
         2 . The hybrid fusion polypeptide according to  claim 1  wherein at least one of said immunogenic amino-terminal polypeptides of the fusion polypeptide is from a Group A streptococcal serotype selected from the group consisting of 1, 2, 3, 4, 5, 6, 11, 12, 13, 14, 18, 19, 22, 24, 28, 30, 48, 49, 52, and 56. 
     
     
         3 . The hybrid fusion polypeptide according to  claim 1  wherein the multivalent immunogenic portion of the fusion polypeptide consists of six immunogenic amino-terminal polypeptides of Group A streptococcal M protein from six different Group A streptococcal serotypes. 
     
     
         4 . The hybrid fusion polypeptide according to  claim 3  wherein the six different Group A streptococcal serotypes are 1, 3, 5, 6, 19, and 24. 
     
     
         5 . The hybrid fusion polypeptide according to  claim 1  wherein the multivalent portion of the fusion polypeptide consists of ten immunogenic amino-terminal polypeptides of Group A streptococcal M protein from ten different Group A streptococcal serotypes. 
     
     
         6 . The hybrid fusion polypeptide according to  claim 5  wherein the ten different Group A streptococcal serotypes are 1, 3, 5, 6, 18, 19, 22, 24, 28, and 30. 
     
     
         7 . The hybrid fusion polypeptide according to  claim 1  wherein at least one of the immunogenic amino-terminal polypeptides of the fusion polypeptide is from a Group A streptococcal serotype 1. 
     
     
         8 . The hybrid fusion polypeptide according to  claim 1  wherein at least one of the immunogenic amino-terminal polypeptides of the fusion polypeptide is from a Group A streptococcal serotype 2. 
     
     
         9 . The hybrid fusion polypeptide according to  claim 1  wherein at Currently Amended one of the immunogenic amino-terminal polypeptides of the fusion polypeptide is from a Group A streptococcal serotype 11. 
     
     
         10 . The hybrid fusion polypeptide according to  claim 1  wherein at least one of the immunogenic amino-terminal polypeptides of the fusion polypeptide is from a Group A streptococcal serotype 13. 
     
     
         11 . The hybrid fusion polypeptide according to  claim 1  wherein at least one of the immunogenic amino-terminal polypeptides of the fusion polypeptide is from a Group A streptococcal serotype 19. 
     
     
         12 . The hybrid fusion polypeptide according to  claim 1  wherein at least one of the immunogenic amino-terminal polypeptides of the fusion polypeptide is from a Group A streptococcal serotype 22. 
     
     
         13 . The hybrid fusion polypeptide according to  claim 1  wherein at least one of the immunogenic amino-terminal polypeptides of the fusion polypeptide is from a Group A streptococcal serotype 28. 
     
     
         14 . The hybrid fusion polypeptide according to any one of  claims 1  to  3  wherein the hybrid fusion polypeptide elicits an immune response comprising opsonic antibodies against Group A streptococcal M protein that do not cross-react with human tissue. 
     
     
         15 . The hybrid fusion polypeptide according to  claim 1  further comprising a marker encoded by an expression vector. 
     
     
         16 . The hybrid fusion polypeptide according to  claim 15  wherein the marker encoded by the expression vector is a His-tag. 
     
     
         17 . The hybrid fusion polypeptide according to  claim 15  wherein the encoded marker binds to nickel resin. 
     
     
         18 . The hybrid fusion polypeptide according to  claim 1  wherein the immunogenic polypeptides of the fusion polypeptide are joined by amino acids specified by a restriction enzyme site. 
     
     
         19 . The hybrid fusion polypeptide according to  claim 1  further formulated with an adjuvant. 
     
     
         20 . The hybrid fusion polypeptide according to  claim 19  wherein the adjuvant is alum. 
     
     
         21 . The hybrid fusion polypeptide according to  claim 19  further formulated with an immunomodulatory cofactor. 
     
     
         22 . A composition comprising a hybrid fusion polypeptide according to  claim 1 , and a pharmaceutically acceptable excipient, carrier, stabilizer or diluent. 
     
     
         23 . The composition according to  claim 22  further comprising with an adjuvant. 
     
     
         24 . The composition according to  claim 23  wherein the adjuvant is alum. 
     
     
         25 . The composition according to  claim 22  wherein the pharmaceutically acceptable excipient, carrier, stabilizer or diluent comprises at least one of a buffer, antioxidant, carbohydrate, and chelating agent. 
     
     
         26 . The fusion polypeptide according to  claim 22  wherein the composition further comprises an immunomodulatory cofactor. 
     
     
         27 . The fusion polypeptide according to  claim 26  wherein the immunomodulatory cofactor is selected from the group consisting of IL-4, IL-10, γ-IFN, IL-2, IL-12, and IL-15.