title: Structure-based design of broadly protective group a streptococcal M protein-based vaccines.
abstract: A major obstacle to the development of broadly protective M protein-based group A streptococcal (GAS) vaccines is the variability within the N-terminal epitopes that evoke potent bactericidal antibodies. The concept of M type-specific protective immune responses has recently been challenged based on the observation that multivalent M protein vaccines elicited cross-reactive bactericidal antibodies against a number of non-vaccine M types of GAS. Additionally, a new "cluster-based" typing system of 175M proteins identified a limited number of clusters containing closely related M proteins. In the current study, we used the emm cluster typing system, in combination with computational structure-based peptide modeling, as a novel approach to the design of potentially broadly protective M protein-based vaccines.
  
  
  
  M protein sequences (AA 16-50) from the E4 cluster containing 17 emm types of GAS were analyzed using de novo 3-D structure prediction tools and the resulting structures subjected to chemical diversity analysis to identify sequences that were the most representative of the 3-D physicochemical properties of the M peptides in the cluster. Five peptides that spanned the range of physicochemical attributes of all 17 peptides were used to formulate synthetic and recombinant vaccines. Rabbit antisera were assayed for antibodies that cross-reacted with E4 peptides and whole bacteria by ELISA and for bactericidal activity against all E4GAS.
  
  
  
  The synthetic vaccine rabbit antisera reacted with all 17 E4M peptides and demonstrated bactericidal activity against 15/17 E4GAS. A recombinant hybrid vaccine containing the same E4 peptides also elicited antibodies that cross-reacted with all E4M peptides.
  
  
  
  Comprehensive studies using structure-based design may result in a broadly protective M peptide vaccine that will elicit cluster-specific and emm type-specific antibody responses against the majority of clinically relevant emm types of GAS.
authors.affiliation: Department of Medicine, University of Tennessee Health Science Center, Memphis, TN, United States; Department of Microbiology, Immunology, and Biochemistry, University of Tennessee Health Science Center, Memphis, TN, United States; Department of Veterans Affairs Medical Center, Memphis, TN, United States. Electronic address: jbdale@uthsc.edu.
authors.forename: James B
authors.initials: JB
authors.lastname: Dale
authors.affiliation: Department of Pediatrics, Academic Children Hospital Queen Fabiola, Université Libre de Bruxelles, Brussels, Belgium; Molecular Bacteriology Laboratory, Université Libre de Bruxelles, Brussels, Belgium; Group A Streptococcus Research Group, Murdoch Childrens Research Institute, Melbourne, Australia; Centre for International Child Health, University of Melbourne, Melbourne, Australia.
authors.forename: Pierre R
authors.initials: PR
authors.lastname: Smeesters
authors.affiliation: Department of Medicine, University of Tennessee Health Science Center, Memphis, TN, United States.
authors.forename: Harry S
authors.initials: HS
authors.lastname: Courtney
authors.affiliation: Department of Medicine, University of Tennessee Health Science Center, Memphis, TN, United States.
authors.forename: Thomas A
authors.initials: TA
authors.lastname: Penfound
authors.affiliation: Department of Medicine, University of Tennessee Health Science Center, Memphis, TN, United States.
authors.forename: Claudia M
authors.initials: CM
authors.lastname: Hohn
authors.affiliation: Department of Biochemistry and Cellular and Molecular Biology, University of Tennessee, Oak Ridge, TN, United States; University of Tennessee/Oak Ridge National Laboratory Center for Molecular Biophysics, Oak Ridge, TN, United States.
authors.forename: Jeremy C
authors.initials: JC
authors.lastname: Smith
authors.affiliation: Department of Biochemistry and Cellular and Molecular Biology, University of Tennessee, Oak Ridge, TN, United States; University of Tennessee/Oak Ridge National Laboratory Center for Molecular Biophysics, Oak Ridge, TN, United States.
authors.forename: Jerome Y
authors.initials: JY
authors.lastname: Baudry
mesh_terms: D000818:Animals; D000907:Antibodies, Bacterial / Q000097:blood; D000942:Antigens, Bacterial / Q000737:chemistry / Q000235:genetics / Q000276:immunology*; D001425:Bacterial Outer Membrane Proteins / Q000737:chemistry / Q000235:genetics / Q000276:immunology*; D001770:Blood Bactericidal Activity; D002352:Carrier Proteins / Q000737:chemistry / Q000235:genetics / Q000276:immunology*; D019295:Computational Biology; D004797:Enzyme-Linked Immunosorbent Assay; D008958:Models, Molecular; D011487:Protein Conformation; D011817:Rabbits; D013290:Streptococcal Infections / Q000517:prevention & control*; D022541:Streptococcal Vaccines / Q000008:administration & dosage / Q000235:genetics / Q000276:immunology*; D013297:Streptococcus pyogenes / Q000737:chemistry / Q000235:genetics / Q000276:immunology*; D014614:Vaccines, Synthetic / Q000008:administration & dosage / Q000235:genetics / Q000276:immunology
chemical_list: D000907:Antibodies, Bacterial; D000942:Antigens, Bacterial; D001425:Bacterial Outer Membrane Proteins; D002352:Carrier Proteins; D022541:Streptococcal Vaccines; D014614:Vaccines, Synthetic; C014689:streptococcal M protein
keywords: Broadly neutralizing antibodies; Group A streptococcal vaccine; M protein; Structure-based design