Background: Multivalent vaccines containing N-terminal M peptides elicit opsonic antibodies which are associated with protection. A perceived limitation of M peptide vaccines is reduced coverage in some geographic regions. Previous studies have shown that there is significant immunological cross-reactivity among sequence-related M proteins. In the present study, we have used a three-tiered structure-based algorithm to identify M peptides most likely to generate antibodies cross-reactive with heterologous M types to incorporate into a multivalent vaccine predicted to have broad global coverage.
Methods: Vaccine design was based on the analysis of 117 N-terminal 50aa M peptides from Strep A with the highest global prevalence. We used a combination of peptide sequence identity, heptad sequence homology, and coiled-coil propensity in a comprehensive pairwise analysis to select peptides predicted to contain cross-protective epitopes.
Results: Based on the in-silico analysis of predicted cross-reactivity, together with the updated global prevalence of M types, we selected 19 vaccine M peptides predicted to cross-react with 37 non-vaccine M types, to which were added 13 type-specific M peptides. The new 32-valent vaccine could theoretically achieve 78% global coverage of Strep A infections with regional coverage ranging from 63-92%. Rabbits immunized with the vaccine developed significant levels of antibodies (>8-fold) against 31/32 vaccine M peptides and 28/37 non-vaccine M peptides. Analysis of functional OPK activity is on-going.
Conclusions: Structure-based assessment of M peptides guided by results of antibody cross-reactivity when combined with global Strep A M type prevalence could result in a broadly protective multivalent M protein-based vaccine.