Vaccine development against Streptococcus pyogenes (StrepA) faces significant challenges due to M-protein polymorphism (>250 emm-types), safety concerns related to molecular mimicry, and the need for immunity at multiple infection sites, such as skin and respiratory mucosa. Our peptide-based vaccine, IMVax, targets two conserved virulence factors: (i) the M-protein, focusing on p*17, a highly conserved 20-mer peptide from the C3-repeat region of p145, overcoming M-protein diversity; and (ii) SpyCEP, an IL-8 protease, using the conserved B-cell epitope S2 to tackle hypervirulent covR/S mutant strains. These peptides are chemically conjugated to carrier proteins diphtheria toxoid (DT) or Cross-Reactive Material 197 (CRM197). This Alum-formulated vaccine is currently in a Phase I clinical trial (NCT04882514).
We have designed a next-generation vaccine comprising peptide (p*17 and S2) encoding mRNA encapsulated in a novel lipid nanoparticle (LNP), denoted as Combo2mRNA-LNP/dmLNP. This formulation generates robust cytokine responses, mucosal antibodies, and allows for dose sparing. We found that the peptide conjugate and peptide-encoded mRNA platforms, despite generating distinct immune responses, are highly efficacious in protecting against StrepA. We hypothesise that combining these two platforms in a prime-boost regimen will synergistically enhance immune responses leading to higher levels of protection across all primary infection sites. Our preclinical data demonstrate the significant potential of this approach against a covR/S mutant StrepA strain with additional supporting data under development.
By integrating highly conserved antigens, advanced delivery systems, and dual-route administration, our vaccination strategy represents a major advancement in bacterial vaccine design, offering a safe and adaptable solution to combat StrepA globally.