Predicted Coverage and Immuno-Safety of a Recombinant C-Repeat Region Based Streptococcus pyogenes Vaccine Candidate.
The C-terminal region of the M-protein of Streptococcus pyogenes is a major target for vaccine development. The major feature is the C-repeat region, consisting of 35-42 amino acid repeat units that display high but not perfect identity. SV1 is a S. pyogenes vaccine candidate that incorporates five 14mer amino acid sequences (called J14i variants) from differing C-repeat units in a single recombinant construct. Here we show that the J14i variants chosen for inclusion in SV1 are the most common variants in a dataset of 176 unique M-proteins. Murine antibodies raised against SV1 were shown to bind to each of the J14i variants present in SV1, as well as variants not present in the vaccine. Antibodies raised to the individual J14i variants were also shown to bind to multiple but different combinations of J14i variants, supporting the underlying rationale for the design of SV1. A Lewis Rat Model of valvulitis was then used to assess the capacity of SV1 to induce deleterious immune response associated with rheumatic heart disease. In this model, both SV1 and the M5 positive control protein were immunogenic. Neither of these antibodies were cross-reactive with cardiac myosin or collagen. Splenic T cells from SV1/CFA and SV1/alum immunized rats did not proliferate in response to cardiac myosin or collagen. Subsequent histological examination of heart tissue showed that 4 of 5 mice from the M5/CFA group had valvulitis and inflammatory cell infiltration into valvular tissue, whereas mice immunised with SV1/CFA, SV1/alum showed no sign of valvulitis. These results suggest that SV1 is a safe vaccine candidate that will elicit antibodies that recognise the vast majority of circulating GAS M-types.
Bacterial Pathogenesis Laboratory, QIMR Berghofer Medical Research Institute, 300 Herston Rd, Herston, QLD, 4006, Australia.
Celia
C
McNeilly
Bacterial Pathogenesis Laboratory, QIMR Berghofer Medical Research Institute, 300 Herston Rd, Herston, QLD, 4006, Australia.
Samantha
S
Cosh
Bacterial Pathogenesis Laboratory, QIMR Berghofer Medical Research Institute, 300 Herston Rd, Herston, QLD, 4006, Australia.
Therese
T
Vu
Inflammation and Healing Research Cluster, School of Health and Sport Sciences, University of the Sunshine Coast, Maroochydore, QLD, 4558, Australia.
Jemma
J
Nichols
Australian Infectious Disease Research Centre and School of Chemistry and Molecular Biosciences, The University of Queensland, St Lucia, QLD, 4072, Australia.
Anna
A
Henningham
Structural Chemistry Program, Eskitis Institute for Cell and Molecular Therapies, Griffith University, Nathan, and Queensland Tropical Health Alliance, Smithfield, QLD, Australia.
Andreas
A
Hofmann
Australian Institute of Tropical Medicine, James Cook University, Townsville, QLD, 4811, Australia.
Anne
A
Fane
Laboratoire de Génétique et Physiologie Bactérienne, Institut de Biologie et de Médecine Moléculaires, Faculté des Sciences, Université Libre de Bruxelles, Gosselies, Belgium, and Murdoch Children Research Institute, Melbourne, VIC, 3052, Australia.
Pierre R
PR
Smeesters
Australian Institute of Tropical Medicine, James Cook University, Townsville, QLD, 4811, Australia.
Catherine M
CM
Rush
School of Biomedical Sciences, Faculty of Health & Institute of Health and Biomedical Innovation (IHBI), Queensland University of Technology, Brisbane, QLD, 4001, Australia.
Louise M
LM
Hafner
Australian Institute of Tropical Medicine, James Cook University, Townsville, QLD, 4811, Australia.
Natkuman
N
Ketheesan
Bacterial Pathogenesis Laboratory, QIMR Berghofer Medical Research Institute, 300 Herston Rd, Herston, QLD, 4006, Australia.
Kadaba S
KS
Sriprakash
Bacterial Pathogenesis Laboratory, QIMR Berghofer Medical Research Institute, 300 Herston Rd, Herston, QLD, 4006, Australia.|Inflammation and Healing Research Cluster, School of Health and Sport Sciences, University of the Sunshine Coast, Maroochydore, QLD, 4558, Australia.
David J
DJ
McMillan
D000276:Adjuvants, Immunologic / Q000008:administration & dosage; D000534:Alum Compounds / Q000008:administration & dosage; D000818:Animals; D000907:Antibodies, Bacterial / Q000096:biosynthesis*; D000942:Antigens, Bacterial / Q000235:genetics / Q000276:immunology*; D003094:Collagen / Q000235:genetics / Q000378:metabolism; D005260:Female; D015870:Gene Expression; D006351:Heart Valves / Q000187:drug effects / Q000276:immunology / Q000382:microbiology / Q000473:pathology; D051379:Mice; D008807:Mice, Inbred BALB C; D009218:Myosins / Q000235:genetics / Q000378:metabolism; D051381:Rats; D011917:Rats, Inbred Lew; D020449:Repetitive Sequences, Amino Acid; D012214:Rheumatic Heart Disease / Q000276:immunology / Q000382:microbiology / Q000473:pathology / Q000517:prevention & control*; D013154:Spleen / Q000187:drug effects / Q000276:immunology / Q000382:microbiology / Q000473:pathology; D013290:Streptococcal Infections / Q000276:immunology / Q000382:microbiology / Q000473:pathology / Q000517:prevention & control*; D022541:Streptococcal Vaccines / Q000008:administration & dosage* / Q000096:biosynthesis / Q000276:immunology; D013297:Streptococcus pyogenes / Q000187:drug effects / Q000235:genetics / Q000276:immunology*; D013601:T-Lymphocytes / Q000187:drug effects / Q000276:immunology / Q000382:microbiology / Q000473:pathology; D014614:Vaccines, Synthetic
D000276:Adjuvants, Immunologic; D000534:Alum Compounds; D000907:Antibodies, Bacterial; D000942:Antigens, Bacterial; D022541:Streptococcal Vaccines; D014614:Vaccines, Synthetic; C041524:aluminum sulfate; D003094:Collagen; D009218:Myosins