Immunogenicity in mice and non-human primates of the Group A Streptococcal J8 peptide vaccine candidate conjugated to CRM197

Vaccine development for Group A streptococcal (GAS) infection has been extensively focused on the N-terminal hypervariable or the C-terminal conserved regions of the M protein, a major virulence factor of GAS. We evaluated the immunogenicity and functional activity of the conserved C-terminal peptide vaccine candidate, J8, conjugated to CRM197, in two mouse strains: C3H (H2k) and Balb/c (H2d), and in rhesus macaques. Mice were immunized with J8-CRM197 formulated with Amorphous Aluminum Hydroxyphosphate Sulfate Adjuvant (AAHSA), and non-human primates were immunized with J8-CRM197 formulated with AAHSA, ISCOMATRIXTM adjuvant, or AAHSA/ISCOMATRIX adjuvant. J8-CRM197 was immunogenic in mice from both H2k and H2d backgrounds, and the antibodies generated bound to the surface of four different GAS serotypes and had functional bacterial opsonic activity. Mice immunized with J8-CRM197/AAHSA demonstrated varying degrees of protection from lethal challenge. We also demonstrated that J8-CRM197 is immunogenic in non-human primates. Our data confirm the utility of J8 as a potential GAS vaccine candidate and demonstrate that CRM197 is an acceptable protein carrier for this peptide.

[1]  T. Penfound,et al.  New 30-valent M protein-based vaccine evokes cross-opsonic antibodies against non-vaccine serotypes of group A streptococci. , 2011, Vaccine.

[2]  J. Heinrichs,et al.  Comparison of rhesus and cynomolgus macaques in a Streptococcus pyogenes infection model for vaccine evaluation. , 2011, Microbial pathogenesis.

[3]  R. Rappuoli,et al.  Evaluation of a Group A Streptococcus synthetic oligosaccharide as vaccine candidate. , 2010, Vaccine.

[4]  H. Shinefield.  Overview of the development and current use of CRM(197) conjugate vaccines for pediatric use. , 2010, Vaccine.

[5]  L. Guilherme,et al.  A vaccine against S. pyogenes: design and experimental immune response. , 2009, Methods.

[6]  J. Carapetis,et al.  Global emm type distribution of group A streptococci: systematic review and implications for vaccine development. , 2009, The Lancet. Infectious diseases.

[7]  H. Goossens,et al.  Increasing telithromycin resistance among Streptococcus pyogenes in Europe. , 2008, The Journal of antimicrobial chemotherapy.

[8]  G. Hermanson,et al.  Chapter 21 – Immunotoxin Conjugation Techniques , 2008 .

[9]  J. Musser,et al.  A non-human primate model of acute group a Streptococcus pharyngitis. , 2008, Methods in molecular biology.

[10]  R. Hepler,et al.  Amino acid analysis of peptide loading ratios in conjugate vaccines: a comparison of direct electrochemical detection and 6-aminoquinolyl-N-hydroxysuccinimidyl carbamate pre-column derivatization methods. , 2008, Bioconjugate chemistry.

[11]  H. McClure,et al.  Toxic shock due to Streptococcus pyogenes in a rhesus monkey (Macaca mulatta). , 2006, Journal of the American Association for Laboratory Animal Science : JAALAS.

[12]  Mei-Fong Ho,et al.  Immunization with a tetraepitopic lipid core peptide vaccine construct induces broadly protective immune responses against group A streptococcus. , 2006, The Journal of infectious diseases.

[13]  M. Juliano,et al.  Towards a Vaccine Against Rheumatic Fever , 2006, Clinical & developmental immunology.

[14]  G. S. Chhatwal,et al.  Vaccination equally enables both genetically susceptible and resistant mice to control infection with group A streptococci. , 2006, Microbes and infection.

[15]  Fredric Carlsson,et al.  Binding of human plasma proteins to Streptococcus pyogenes M protein determines the location of opsonic and non‐opsonic epitopes , 2006, Molecular microbiology.

[16]  J. Carapetis,et al.  The global burden of group A streptococcal diseases. , 2005, The Lancet. Infectious diseases.

[17]  J. Langley,et al.  Safety and immunogenicity of 26-valent group a streptococcus vaccine in healthy adult volunteers. , 2005, Clinical infectious diseases : an official publication of the Infectious Diseases Society of America.

[18]  A. Bisno,et al.  Prospects for a group A streptococcal vaccine: rationale, feasibility, and obstacles--report of a National Institute of Allergy and Infectious Diseases workshop. , 2005, Clinical infectious diseases : an official publication of the Infectious Diseases Society of America.

[19]  G. Kronvall,et al.  M Protein Gene (emm Type) Analysis of Group A Beta-Hemolytic Streptococci from Ethiopia Reveals Unique Patterns , 2005, Journal of Clinical Microbiology.

[20]  M. Davies,et al.  Preclinical evaluation of a vaccine based on conserved region of M protein that prevents group A streptococcal infection. , 2004, The Indian journal of medical research.

[21]  M. Davies,et al.  Protection against group A streptococcus by immunization with J8-diphtheria toxoid: contribution of J8- and diphtheria toxoid-specific antibodies to protection. , 2003, The Journal of infectious diseases.

[22]  B. M. Schroeder.  Diagnosis and management of group A streptococcal pharyngitis. , 2003, American family physician.

[23]  A. Bisno,et al.  Practice guidelines for the diagnosis and management of group A streptococcal pharyngitis. Infectious Diseases Society of America. , 2002, Clinical infectious diseases : an official publication of the Infectious Diseases Society of America.

[24]  M. Good,et al.  Protection of mice from group A streptococcal infection by intranasal immunisation with a peptide vaccine that contains a conserved M protein B cell epitope and lacks a T cell autoepitope. , 2002, Vaccine.

[25]  I. Toth,et al.  A Lipid Core Peptide Construct Containing a Conserved Region Determinant of the Group A Streptococcal M Protein Elicits Heterologous Opsonic Antibodies , 2002, Infection and Immunity.

[26]  E. Wald,et al.  Erythromycin-resistant group A streptococci in schoolchildren in Pittsburgh. , 2002, The New England journal of medicine.

[27]  Dwight R. Johnson,et al.  Dynamic epidemiology of group A streptococcal serotypes associated with pharyngitis , 2001, The Lancet.

[28]  D. Jackson,et al.  New multi-determinant strategy for a group A streptococcal vaccine designed for the Australian Aboriginal population , 2000, Nature Medicine.

[29]  M. Good,et al.  Mapping the minimal murine T cell and B cell epitopes within a peptide vaccine candidate from the conserved region of the M protein of group A streptococcus. , 1997, International immunology.

[30]  R. Anders,et al.  Mapping a conserved conformational epitope from the M protein of group A streptococci. , 1996, Peptide research.

[31]  N. Frimodt-Møller,et al.  Experimental Streptococcus pneumoniae infection in mice for studying correlation of in vitro and in vivo activities of penicillin against pneumococci with various susceptibilities to penicillin , 1995, Antimicrobial agents and chemotherapy.

[32]  C. Phornphutkul,et al.  Towards a vaccine for rheumatic fever: identification of a conserved target epitope on M protein of group A streptococci , 1994, The Lancet.

[33]  R. Houghten,et al.  Conserved T and B cell epitopes on the M protein of group A streptococci. Induction of bactericidal antibodies. , 1992, Journal of immunology.

[34]  V. Fischetti,et al.  Synthetic peptide vaccine against mucosal colonization by group A streptococci. I. Protection against a heterologous M serotype with shared C repeat region epitopes. , 1990, Journal of immunology.

[35]  V. Fischetti,et al.  Protection against streptococcal pharyngeal colonization with a vaccinia: M protein recombinant , 1989, Science.

[36]  V. Fischetti,et al.  Mapping the immunodeterminants of the complete streptococcal M6 protein molecule. Identification of an immunodominant region. , 1988, Journal of immunology.

[37]  G. Perlmann,et al.  PREPARATION AND PROPERTIES OF TYPE-SPECIFIC M ANTIGEN ISOLATED FROM A GROUP A, TYPE 1 HEMOLYTIC STREPTOCOCCUS , 1952, The Journal of experimental medicine.

[38]  B. Seegal,et al.  Incidence of Hemolytic Streptococci and Pneumococci in the Pharyngeal Flora of Normal Rhesus Monkeys , 1936 .