Evaluation of novel Streptococcus pyogenes vaccine candidates incorporating multiple conserved sequences from the C-repeat region of the M-protein

Bauer, Michelle, Georgousakis, Melina, Vu, Therese, Henningham, Anna, Hoffman, Andreas, Rettell, Mandy, Hafner, Louise M., Sriprakash, Kadaba, & McMillan, David (2012) Evaluation of novel Streptococcus pyogenes vaccine candidates incorporating multiple conserved sequences from the C-repeat region of the M-protein. Vaccine, 30(12), pp. 2197-2205.

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A major challenge for Streptococcus pyogenes vaccine development is the identification of epitopes that confer protection from infection by multiple S. pyogenes M-types. Here we have identified and characterised the distribution of common variant sequences from individual repeat units of the C-repeat region (CRR) of M-proteins representing 77 different M-types. Three polyvalent fusion vaccine candidates (SV1, SV2 and SV3) incorporating the most common variants were subsequently expressed and purified, and demonstrated to be alpha-helical by Circular Dichroism (CD), a secondary conformational characteristic of the CRR in the M-protein. Antibodies raised against each of these constructs recognise M-proteins that vary in their CRR, and bind to the surface of multiple S. pyogenes isolates. Antibodies raised against SV1, containing five variant sequences, also kill heterologous S. pyogenes isolates in in vitro bactericidal assays. Further structural characterisation of this construct demonstrated the conformation of SV1 was stable at different pHs, and thermal unfolding of SV1 a reversible process. Our findings demonstrate that linkage of multiple variant sequences into a single recombinant construct overcomes the need to embed the variant sequences in foreign helix promoting flanking sequences for conformational stability, and demonstrates the viability of the polyvalent candidates as global S. pyogenes vaccine candidates.

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17 citations in Scopus
18 citations in Web of Science®
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ID Code: 47929
Item Type: Journal Article
Refereed: Yes
Keywords: Streptococcus pyogenes, Vaccines
DOI: 10.1016/j.vaccine.2011.12.115
ISSN: 0264-410X
Subjects: Australian and New Zealand Standard Research Classification > BIOLOGICAL SCIENCES (060000) > MICROBIOLOGY (060500) > Infectious Agents (060502)
Divisions: Past > Schools > Cell & Molecular Biosciences
Current > QUT Faculties and Divisions > Faculty of Health
Current > Institutes > Institute of Health and Biomedical Innovation
Copyright Owner: Copyright 2012 Elsevier
Copyright Statement: This is the author’s version of a work that was accepted for publication in <Vaccine>. Changes resulting from the publishing process, such as peer review, editing, corrections, structural formatting, and other quality control mechanisms may not be reflected in this document. Changes may have been made to this work since it was submitted for publication. A definitive version was subsequently published in Vaccine, Vol 30, Issue 12, (2012).DOI: http://dx.doi.org/10.1016/j.vaccine.2011.12.115
Deposited On: 04 Jan 2012 22:29
Last Modified: 12 Nov 2013 11:20

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