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. 2017 Jan 3;35(1):19-26.
doi: 10.1016/j.vaccine.2016.11.065. Epub 2016 Nov 24.

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

James B Dale  1 , Pierre R Smeesters  2 , Harry S Courtney  3 , Thomas A Penfound  3 , Claudia M Hohn  3 , Jeremy C Smith  4 , Jerome Y Baudry  4
Affiliations

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

James B Dale et al. Vaccine. .

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 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.

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 E4GAS.

Results: 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.

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.

Keywords: Broadly neutralizing antibodies; Group A streptococcal vaccine; M protein; Structure-based design.

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Conflict of interest statement

JBD is the inventor of certain technologies related to the development of group A streptococcal vaccines. The University of Tennessee Research Foundation has licensed the technology to Vaxent, LLC, of which JBD is the Chief Scientific Officer and a member. All other authors have no conflicts.

Figures

Fig 1
Fig 1
Relatedness of physicochemical properties of E4 peptides calculated from structures derived using de novo 3-D peptide structure prediction and represented in principal component space. Peptides selected to represent all E4 peptides are indicated by solid symbols.
Fig. 2
Fig. 2
Schematic representation of the pentavalent E4 synthetic (A) and recombinant hybrid (B) vaccines.
Fig. 3
Fig. 3
E4 peptide-specific and cross-reactive antibodies evoked by pentavalent E4 synthetic peptide vaccine. Each of the three bars represents the titer obtained with serum from one of the three rabbits.
Fig. 4
Fig. 4
Bactericidal activity of pentavalent E4 peptide vaccine antisera against vaccine emm types and non-vaccine emm types of GAS in the E4 cluster. Each data point represents the mean bactericidal killing observed in four independent experiments (+/− S.D.).
Fig. 5
Fig. 5
Association between E4 synthetic peptide vaccine antibody binding to the M protein on the surface of whole streptococci and functional bactericidal activity in human blood. Vaccine emm types are indicated by solid symbols. (R=0.6, p=0.05, Pearson’s correlation coefficient).
Fig. 6
Fig. 6
E4 peptide-specific and cross-reactive antibodies evoked by recombinant pentavalent E4 hybrid peptide vaccine. Each of the two bars represents the titer obtained with serum from one of two immunized rabbits.
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