Structure-based design of broadly protective group a streptococcal M protein-based vaccines

James Dale, Pierre R. Smeesters, Harry Courtney, Thomas A. Penfound, Claudia M. Hohn, Jeremy C. Smith, Jerome Y. Baudry

Research output: Contribution to journalArticle

12 Citations (Scopus)

Abstract

Background 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 175 M 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. Methods 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 E4G AS. Results The synthetic vaccine rabbit antisera reacted with all 17 E4 M peptides and demonstrated bactericidal activity against 15/17 E4G AS. A recombinant hybrid vaccine containing the same E4 peptides also elicited antibodies that cross-reacted with all E4 M peptides. Conclusions 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.

Original languageEnglish (US)
Pages (from-to)19-26
Number of pages8
JournalVaccine
Volume35
Issue number1
DOIs
StatePublished - Jan 3 2017

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Vaccines
peptides
Synthetic Vaccines
vaccines
Peptides
proteins
antibodies
synthetic vaccines
Proteins
Antibodies
Immune Sera
Streptococcal Vaccines
antiserum
Rabbits
rabbits
Subunit Vaccines
streptococcal M protein
subunit vaccines
recombinant vaccines
Antibody Formation

All Science Journal Classification (ASJC) codes

  • Molecular Medicine
  • Immunology and Microbiology(all)
  • veterinary(all)
  • Public Health, Environmental and Occupational Health
  • Infectious Diseases

Cite this

Dale, J., Smeesters, P. R., Courtney, H., Penfound, T. A., Hohn, C. M., Smith, J. C., & Baudry, J. Y. (2017). Structure-based design of broadly protective group a streptococcal M protein-based vaccines. Vaccine, 35(1), 19-26. https://doi.org/10.1016/j.vaccine.2016.11.065

Structure-based design of broadly protective group a streptococcal M protein-based vaccines. / Dale, James; Smeesters, Pierre R.; Courtney, Harry; Penfound, Thomas A.; Hohn, Claudia M.; Smith, Jeremy C.; Baudry, Jerome Y.

In: Vaccine, Vol. 35, No. 1, 03.01.2017, p. 19-26.

Research output: Contribution to journalArticle

Dale, J, Smeesters, PR, Courtney, H, Penfound, TA, Hohn, CM, Smith, JC & Baudry, JY 2017, 'Structure-based design of broadly protective group a streptococcal M protein-based vaccines', Vaccine, vol. 35, no. 1, pp. 19-26. https://doi.org/10.1016/j.vaccine.2016.11.065
Dale, James ; Smeesters, Pierre R. ; Courtney, Harry ; Penfound, Thomas A. ; Hohn, Claudia M. ; Smith, Jeremy C. ; Baudry, Jerome Y. / Structure-based design of broadly protective group a streptococcal M protein-based vaccines. In: Vaccine. 2017 ; Vol. 35, No. 1. pp. 19-26.
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abstract = "Background 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 175 M 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. Methods 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 E4G AS. Results The synthetic vaccine rabbit antisera reacted with all 17 E4 M peptides and demonstrated bactericidal activity against 15/17 E4G AS. A recombinant hybrid vaccine containing the same E4 peptides also elicited antibodies that cross-reacted with all E4 M peptides. Conclusions 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.",
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