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Abstract

Human Antibodies to M-Protein Epitope-Based Vaccines Demonstrate Increased Immunogenicity and Streptococcus pyogenes (StrepA) Bactericidal Activity †

1
Institute for Biomedicine and Glycomics, Griffith University, Gold Coast, QLD 4222, Australia
2
Department of Medicine, Division of Infectious Diseases, University of Alberta, Edmonton, AB T6G 2G5, Canada
3
Li Ka Shing Institute of Virology, University of Alberta, Edmonton, AB T6G 2G5, Canada
4
Department of Medical Microbiology and Immunology, University of Alberta, Edmonton, AB T6G 2G5, Canada
5
Clinical Trials Office, University of Alberta, Edmonton, AB T6G 2G5, Canada
6
Department of Pediatrics, University of Alberta, Edmonton, AB T6G 2G5, Canada
7
Department Laboratory Medicine & Pathology, University of Alberta, Edmonton, AB T6G 2G5, Canada
*
Author to whom correspondence should be addressed.
Presented at the 22nd Lancefield International Symposium on Streptococci and Streptococcal Diseases, Brisbane, Australia, 1–5 June 2025.
Proceedings 2025, 124(1), 18; https://doi.org/10.3390/proceedings2025124018
Published: 18 August 2025
The high antigenic diversity of Streptococcus pyogenes (StrepA) presents extensive challenges to vaccine development; however, cryptic epitopes—conserved across emm types—offer an alternative approach. Our group has developed two promising vaccine candidates combining modified synthetic M-protein epitopes (J8 or p*17) and K4S2, a non-M-protein epitope derived from the anti-neutrophil chemotaxis factor SpyCEP. These epitopes are individually conjugated to the carrier protein CRM197, combined, and then formulated with aluminium hydroxide (Alum). The two final formulations, J8-CRM197+K4S2-CRM197/Alum and p*17-CRM197+K4S2-CRM197/Alum, are currently undergoing a Phase I clinical trial.
The trial was divided into two stages to maximise safety, involving a single-blind test dosing phase, and a placebo-controlled, double-blind, randomised controlled trial. Intramuscular immunisations were administered at 0, 3, and 6 weeks. Following three immunisations with either vaccine, peptide-specific serum IgG titres increased at 2 weeks and 6 months post third vaccination compared to pre-vaccination. Three immunisations with either vaccine also demonstrated induction of bactericidal antibodies against multiple StrepA strains (5448 and 2031) at 2 weeks post third vaccination compared to pre-vaccination, which was sustained and further increased at 6 months post-third vaccination, despite an observed decrease in peptide-specific antibody titres.
Results show our peptide-conjugate vaccines targeting highly conserved regions of the M protein and SpyCEP were safe for use in preclinical studies. Vaccination induced robust peptide-specific serum IgG responses were sustained for at least six months post final vaccination. Notably, the functional activity of vaccine-induced antibodies improved over time, suggesting a potential increase in antibody affinity.

Author Contributions

Conceptualisation, M.P. and M.F.G.; data acquisition, V.M.-S., I.O., A.S., K.K., A.C., V.O., S.R. and C.T.M.S.; data analysis, C.T.M.S., S.R., A.C., V.O., M.P. and M.F.G.; writing—original draft preparation, C.T.M.S.; writing—review and editing, C.T.M.S., M.P. and M.F.G.; clinical trial principal investigators, M.F.G., M.H. (Michael Houghton), D.L.T., M.H. (Michael Hawkes) and G.J.T.; clinical lead, V.M.-S.; scientific lead, M.P.; project administration, V.M.-S., M.P. and M.F.G.; funding acquisition, M.P. and M.F.G. All authors have read and agreed to the published version of the manuscript.

Funding

The trial is sponsored by the University of Alberta and the Li Ka Shing Institute of Virology (Canada). The research is funded through the Canadian Institutes of Health Research (CIHR) Phase 1/2 Clinical Trials Grant program, the Heart Foundation (Australia), the Snow Foundation (Australia), the National Health and Medical Research Council of Australia, the National Foundation for Medical Research and Innovation (Australia) and the Lowitja Foundation (Australia).

Institutional Review Board Statement

This study was conducted in full conformity with the Declaration of Helsinki (1986) and approved by the University of Alberta Health Research Ethics Board – Biomedical Panel (protocol code: PRO 00089919; date of approval: 29 November 2021).

Informed Consent Statement

Written informed consent was obtained from all trial participants. The consent process was initiated at the time of enrolment into the study and continued throughout study participation.

Data Availability Statement

The datasets presented in this article are part of an ongoing study and as such are not yet readily available. Requests to access the datasets should be directed to M.F.G.

Conflicts of Interest

The authors declare no conflicts of interest.
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Share and Cite

MDPI and ACS Style

Short, C.T.M.; Meier-Stephenson, V.; Ozberk, V.; Calcutt, A.; Reynolds, S.; Ogbuehi, I.; Seth, A.; Kim, K.; Hawkes, M.; Tyrrell, G.J.; et al. Human Antibodies to M-Protein Epitope-Based Vaccines Demonstrate Increased Immunogenicity and Streptococcus pyogenes (StrepA) Bactericidal Activity. Proceedings 2025, 124, 18. https://doi.org/10.3390/proceedings2025124018

AMA Style

Short CTM, Meier-Stephenson V, Ozberk V, Calcutt A, Reynolds S, Ogbuehi I, Seth A, Kim K, Hawkes M, Tyrrell GJ, et al. Human Antibodies to M-Protein Epitope-Based Vaccines Demonstrate Increased Immunogenicity and Streptococcus pyogenes (StrepA) Bactericidal Activity. Proceedings. 2025; 124(1):18. https://doi.org/10.3390/proceedings2025124018

Chicago/Turabian Style

Short, Christie T. M., Vanessa Meier-Stephenson, Victoria Ozberk, Ainslie Calcutt, Simone Reynolds, Ijeoma Ogbuehi, Avi Seth, Kelly Kim, Michael Hawkes, Gregory J. Tyrrell, and et al. 2025. "Human Antibodies to M-Protein Epitope-Based Vaccines Demonstrate Increased Immunogenicity and Streptococcus pyogenes (StrepA) Bactericidal Activity" Proceedings 124, no. 1: 18. https://doi.org/10.3390/proceedings2025124018

APA Style

Short, C. T. M., Meier-Stephenson, V., Ozberk, V., Calcutt, A., Reynolds, S., Ogbuehi, I., Seth, A., Kim, K., Hawkes, M., Tyrrell, G. J., Tyrrell, D. L., Houghton, M., Pandey, M., & Good, M. F. (2025). Human Antibodies to M-Protein Epitope-Based Vaccines Demonstrate Increased Immunogenicity and Streptococcus pyogenes (StrepA) Bactericidal Activity. Proceedings, 124(1), 18. https://doi.org/10.3390/proceedings2025124018

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