Group A streptococcus (Strep A) surface M protein, an a-helical coiled-coil dimer, is a vaccine target as well as a major determinant of virulence. The sequence-variable N-terminal region of the M protein defines the M type and also contains protective epitopes that promote opsonophagocytic killing of the bacteria. Recent reports demonstrate considerable cross-reactivity among different M types, leading to the prospect of identifying cross-protective epitopes that would constitute a broadly protective multivalent vaccine against Strep A. We have used a combination of immunological assays, structural biology and cheminformatics to construct a recombinant M protein-based vaccine that included six Strep A M peptides and was predicted to cross-react with an additional 15 non-vaccine M types of Strep A. Rabbit antisera against the recombinant vaccine cross-reacted with 10 of the 15 non-vaccine M types. Two of the five non-vaccine M types that did not cross-react shared high sequence identity (50%) with the vaccine peptides, implying that high sequence identity alone was not sufficient for cross-reactivity among the M peptides.  Using additional structural analyses, we discovered that the sequence identity at corresponding helical-wheel heptad sites was found to accurately distinguish cross-reactive from non-cross-reactive peptides.  Based on these observations, we developed a comprehensive scoring algorithm that combined linear sequence identity with heptad sequence identity that, when applied to all epidemiologically important M types, should enable the selection of a minimal number of M peptide-based vaccine candidates that will elicit broadly protective immunity against Strep A.

Structure-based group A streptococcal vaccine design: Helical wheel homology predicts antibody cross-reactivity among streptococcal M proteins

Macromolecular Chemistry: The Second Century

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ACS Spring 2020 National Meeting & Expo

The official archive and repository for all ACS Meetings & Expositions abstracts and select posters or presentations.