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Abstract

Parenteral Vaccination with a Super Immunogen Targeting M-Protein Provides Unprecedented Protection Against Group A Streptococcus (StrepA) Respiratory Infections †

by
Victoria Ozberk
*,
Christie Short
,
Ailin Lepletier
,
Ainslie Calcutt
,
Khushi Jain
,
Simone Reynolds
,
Aroon Supramaniam
,
Jamie-lee Mills
,
Jessica Dooley
,
Jacqualine Kaden
,
Michael F. Good
and
Manisha Pandey
Institute for Biomedicine Glycomics, Southport, QLD 4215, Australia
*
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), 8; https://doi.org/10.3390/proceedings2025124008
Published: 8 August 2025
Versions Notes

Rheumatic heart disease (RHD) is a devastating consequence of group A streptococcus (StrepA) infections, being associated with 15.6 million cases and 233,000 deaths annually. A vaccine is urgently needed to prevent StrepA primary infection, which can lead to RHD. Peptides, with their molecular compactness, offer significant potential as multicomponent vaccines, strategically incorporating epitopes from diverse antigens. Through a series of systematic amino acid substitutions within the highly conserved M-protein epitope p145, we pinpointed a super immunogen, denoted as p*17. Peptide p*17 was conjugated to a universal carrier protein (DT/CRM197) and combined with K4S2 (a minimal epitope from the neutrophil anti-chemotaxis factor, SpyCEP), which was also conjugated to DT/CRM197.
Mice vaccinated intramuscularly with the combination vaccine (p*17/K4S2) formulated with aluminum hydroxide were protected against upper respiratory tract (URT) challenge with covR/S mutant StrepA. Enduring IgG antibody levels in the sera and saliva remained high up to 10 months post last vaccine boost, and protection was observed for up to one year post last vaccine boost. The vaccine lost its efficacy when tested in mice that lacked mature B-cells, indicating that antibodies play a major role in vaccine efficacy. Furthermore, passively transferred, purified, vaccine-specific IgG protected immunosuppressed SCID mice from invasive challenge and also conferred protection against URT challenge with StrepA pre-opsonized with vaccine antisera. In a whole-cell ELISA, we demonstrated that vaccine-induced serum IgG binds to StrepA strains across multiple emm types.
Overall, we identified a super immunogen that enhances StrepA vaccine development by inducing salivary IgG and providing protection against both invasive and URT infections.

Author Contributions

Conceptualization, V.O., M.F.G., and M.P.; methodology, V.O., M.F.G., M.P., C.S., A.L., and A.C.; validation, V.O., M.F.G., and M.P.; formal analysis, V.O., M.F.G., and M.P.; investigation, V.O., M.F.G., M.P., C.S., A.L., A.C., K.J., S.R., A.S., J.-l.M., J.D., and J.K.; resources, M.F.G. and M.P.; data curation, V.O., M.F.G., M.P., C.S., and A.L.; writing—original draft preparation, V.O.; writing—review and editing, V.O., M.F.G., and M.P.; visualization, V.O., M.F.G., and M.P.; supervision, M.F.G., and M.P.; project administration, M.F.G., and M.P.; funding acquisition, V.O., A.L., S.R., M.F.G. and M.P. All authors have read and agreed to the published version of the manuscript.

Funding

This work was supported by the National Health and Medical Research Council (NHMRC), Australia, Program Grant APP1083548 (M.F.G.), NHMRC Project Grant APP1160379 (M.P.), NHMRC Australia, Investigator Fellowship APP1174091 (M.F.G.) and Griffith University Postdoctoral Fellowship (V.O.).

Institutional Review Board Statement

All animal protocols were reviewed and approved by the Griffith University Animal Ethics Committee (GU-AEC) in accordance with the National Health and Medical Research Council (NHMRC) of Australia guidelines. All mice were housed in a PC2-certified animal facility in individually ventilated cages (IVC) with a maximum of 5 mice/cage. The relative humidity ranged between 45–65% and temperature at 20–24 °C. Mice were exposed to a 12-h light–dark cycle.

Informed Consent Statement

Not applicable.

Data Availability Statement

The data presented in this study are available upon request from the corresponding author.

Conflicts of Interest

The authors declare no conflict of interest.
Disclaimer/Publisher’s Note: The statements, opinions and data contained in all publications are solely those of the individual author(s) and contributor(s) and not of MDPI and/or the editor(s). MDPI and/or the editor(s) disclaim responsibility for any injury to people or property resulting from any ideas, methods, instructions or products referred to in the content.

Share and Cite

MDPI and ACS Style

Ozberk, V.; Short, C.; Lepletier, A.; Calcutt, A.; Jain, K.; Reynolds, S.; Supramaniam, A.; Mills, J.-l.; Dooley, J.; Kaden, J.; et al. Parenteral Vaccination with a Super Immunogen Targeting M-Protein Provides Unprecedented Protection Against Group A Streptococcus (StrepA) Respiratory Infections. Proceedings 2025, 124, 8. https://doi.org/10.3390/proceedings2025124008

AMA Style

Ozberk V, Short C, Lepletier A, Calcutt A, Jain K, Reynolds S, Supramaniam A, Mills J-l, Dooley J, Kaden J, et al. Parenteral Vaccination with a Super Immunogen Targeting M-Protein Provides Unprecedented Protection Against Group A Streptococcus (StrepA) Respiratory Infections. Proceedings. 2025; 124(1):8. https://doi.org/10.3390/proceedings2025124008

Chicago/Turabian Style

Ozberk, Victoria, Christie Short, Ailin Lepletier, Ainslie Calcutt, Khushi Jain, Simone Reynolds, Aroon Supramaniam, Jamie-lee Mills, Jessica Dooley, Jacqualine Kaden, and et al. 2025. "Parenteral Vaccination with a Super Immunogen Targeting M-Protein Provides Unprecedented Protection Against Group A Streptococcus (StrepA) Respiratory Infections" Proceedings 124, no. 1: 8. https://doi.org/10.3390/proceedings2025124008

APA Style

Ozberk, V., Short, C., Lepletier, A., Calcutt, A., Jain, K., Reynolds, S., Supramaniam, A., Mills, J.-l., Dooley, J., Kaden, J., Good, M. F., & Pandey, M. (2025). Parenteral Vaccination with a Super Immunogen Targeting M-Protein Provides Unprecedented Protection Against Group A Streptococcus (StrepA) Respiratory Infections. Proceedings, 124(1), 8. https://doi.org/10.3390/proceedings2025124008

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