Differing Efficacies of Lead Group A Streptococcal Vaccine Candidates and Full-Length M Protein in Cutaneous and Invasive Disease Models.
Group A Streptococcus (GAS) is an important human pathogen responsible for both superficial infections and invasive diseases. Autoimmune sequelae may occur upon repeated infection. For this reason, development of a vaccine against GAS represents a major challenge, since certain GAS components may trigger autoimmunity. We formulated three combination vaccines containing the following: (i) streptolysin O (SLO), interleukin 8 (IL-8) protease (Streptococcus pyogenes cell envelope proteinase [SpyCEP]), group A streptococcal C5a peptidase (SCPA), arginine deiminase (ADI), and trigger factor (TF); (ii) the conserved M-protein-derived J8 peptide conjugated to ADI; and (iii) group A carbohydrate lacking the N-acetylglucosamine side chain conjugated to ADI. We compared these combination vaccines to a "gold standard" for immunogenicity, full-length M1 protein. Vaccines were adjuvanted with alum, and mice were immunized on days 0, 21, and 28. On day 42, mice were challenged via cutaneous or subcutaneous routes. High-titer antigen-specific antibody responses with bactericidal activity were detected in mouse serum samples for all vaccine candidates. In comparison with sham-immunized mice, all vaccines afforded protection against cutaneous challenge. However, only full-length M1 protein provided protection in the subcutaneous invasive disease model.



This set of experiments demonstrates the inherent variability of mouse models for the characterization of GAS vaccine candidate protective efficacy. Such variability poses an important challenge for GAS vaccine development, as advancement of candidates to human clinical trials requires strong evidence of efficacy. This study highlights the need for an open discussion within the field regarding standardization of animal models for GAS vaccine development.
Australian Infectious Diseases Research Centre and School of Chemistry and Molecular Biosciences, The University of Queensland, St. Lucia, Queensland, Australia.
Tania
T
Rivera-Hernandez
Institute for Glycomics, Griffith University, Gold Coast Campus, Southport, Queensland, Australia.
Manisha
M
Pandey
University of California, San Diego, San Diego, California, USA.
Anna
A
Henningham
University of California, San Diego, San Diego, California, USA.
Jason
J
Cole
University of California, San Diego, San Diego, California, USA.
Biswa
B
Choudhury
Australian Infectious Diseases Research Centre and School of Chemistry and Molecular Biosciences, The University of Queensland, St. Lucia, Queensland, Australia.
Amanda J
AJ
Cork
Australian Infectious Diseases Research Centre and School of Chemistry and Molecular Biosciences, The University of Queensland, St. Lucia, Queensland, Australia.
Christine M
CM
Gillen
Australian Infectious Diseases Research Centre and School of Chemistry and Molecular Biosciences, The University of Queensland, St. Lucia, Queensland, Australia.
Khairunnisa Abdul
KA
Ghaffar
Australian Infectious Diseases Research Centre and School of Chemistry and Molecular Biosciences, The University of Queensland, St. Lucia, Queensland, Australia.
Nicholas P
NP
West
Emory Vaccine Center and Yerkes National Primate Research Center, Emory University, Atlanta, Georgia, USA.
Guido
G
Silvestri
Institute for Glycomics, Griffith University, Gold Coast Campus, Southport, Queensland, Australia.
Michael F
MF
Good
Australian Infectious Diseases Research Centre and School of Chemistry and Molecular Biosciences, The University of Queensland, St. Lucia, Queensland, Australia School of Pharmacy, The University of Queensland, St. Lucia, Queensland, Australia.
Peter M
PM
Moyle
Australian Infectious Diseases Research Centre and School of Chemistry and Molecular Biosciences, The University of Queensland, St. Lucia, Queensland, Australia.
Istvan
I
Toth
University of California, San Diego, San Diego, California, USA.
Victor
V
Nizet
Institute for Glycomics, Griffith University, Gold Coast Campus, Southport, Queensland, Australia.
Michael R
MR
Batzloff
Australian Infectious Diseases Research Centre and School of Chemistry and Molecular Biosciences, The University of Queensland, St. Lucia, Queensland, Australia mark.walker@uq.edu.au.
Mark J
MJ
Walker
D000276:Adjuvants, Immunologic / Q000008:administration & dosage; D000534:Alum Compounds / Q000008:administration & dosage; D000818:Animals; D000907:Antibodies, Bacterial / Q000097:blood; D000942:Antigens, Bacterial / Q000276:immunology; D016470:Bacteremia / Q000276:immunology / Q000517:prevention & control*; D001770:Blood Bactericidal Activity; D004195:Disease Models, Animal; D008807:Mice, Inbred BALB C; D017192:Skin Diseases, Bacterial / Q000276:immunology / Q000517:prevention & control*; D013290:Streptococcal Infections / Q000276:immunology / Q000517:prevention & control*; D022541:Streptococcal Vaccines / Q000008:administration & dosage* / Q000276:immunology*; D013297:Streptococcus pyogenes / Q000276:immunology*; D016896:Treatment Outcome; D017778:Vaccines, Combined / Q000008:administration & dosage / Q000276:immunology; D018074:Vaccines, Conjugate / Q000008:administration & dosage / Q000276:immunology
D000276:Adjuvants, Immunologic; D000534:Alum Compounds; D000907:Antibodies, Bacterial; D000942:Antigens, Bacterial; D022541:Streptococcal Vaccines; D017778:Vaccines, Combined; D018074:Vaccines, Conjugate; C041524:aluminum sulfate