Group A streptococcal vaccines: facts versus fantasy

Purpose of review This review provides an overview of progress of the development of group A streptococcal (GAS) vaccines with a focus on recent advances. Recent findings Historically, GAS vaccine development has focused on the N-terminus of the M protein, which ultimately led to successful phase I/II clinical trials of a 26-valent recombinant M protein vaccine in 2004–2005. More recently, interest in antigens conserved among most, if not all, group A streptococci has increased. However, no vaccines containing these antigens have reached clinical trials. Three strategies have been used to develop conserved antigen vaccine candidates: use of the conserved region of the M protein; use of well described virulence factors as antigens, including streptococcal C5a peptidase, streptococcal carbohydrate, fibronectin-binding proteins, cysteine protease and streptococcal pili; and use of reverse vaccinology to identify novel antigens. Summary Several vaccine candidates against GAS infection are in varying stages of preclinical and clinical development. Although there is great hope that one of these vaccine candidates will reach licensure in the next decade, only one, the multivalent N-terminal vaccine, has entered clinical trials in the last 30 years. Although strong advocacy for GAS vaccine development is important, there remains an urgent need to institute available public health control measures against GAS diseases globally, particularly in developing countries.

[1]  Bart J. Currie,et al.  Surface Analyses and Immune Reactivities of Major Cell Wall-Associated Proteins of Group A Streptococcus , 2005, Infection and Immunity.

[2]  L. Guilherme,et al.  Rheumatic Fever and Rheumatic Heart Disease: Genetics and Pathogenesis , 2007, Scandinavian journal of immunology.

[3]  D. Ohlendorf,et al.  Toxoids of Streptococcal Pyrogenic Exotoxin A Are Protective in Rabbit Models of Streptococcal Toxic Shock Syndrome , 2000, Infection and Immunity.

[4]  E. N. Fox,et al.  Protective study with a group A streptococcal M protein vaccine. Infectivity challenge of human volunteers. , 1973, The Journal of clinical investigation.

[5]  L. Van Melderen,et al.  Differences between Belgian and Brazilian Group A Streptococcus Epidemiologic Landscape , 2006, PloS one.

[6]  V. Fischetti,et al.  Passive acquired mucosal immunity to group A streptococci by secretory immunoglobulin A , 1988, The Journal of experimental medicine.

[7]  L. Rantz GROUP A HEMOLYTIC STREPTOCOCCUS ANTIBODIES III. A STUDY OF THE SIMULTANEOUS INFECTION OF A LARGE NUMBER OF MEN BY A SINGLE TYPE , 1944 .

[8]  E. Kaplan,et al.  Potential Mechanisms for Failure to Eradicate Group A Streptococci From the Pharynx , 1999, Pediatrics.

[9]  K. Schulze,et al.  Intranasal immunization with serum opacity factor (SOF) of Streptococcus pyogenes fails to protect mice against lethal mucosal challenge with a heterologous strain. , 2006, Vaccine.

[10]  S. Olmsted,et al.  Immunization with C5a peptidase from either group A or B streptococci enhances clearance of group A streptococci from intranasally infected mice. , 2004, Vaccine.

[11]  W. Schmidt,et al.  THE DETERMINATION OF ANTIBODY TO GROUP A STREPTOCOCCAL POLYSACCHARIDE IN HUMAN SERA BY HEMAGGLUTINATION , 1965, The Journal of experimental medicine.

[12]  R. Zagursky,et al.  Proteomic Analysis and Identification of Streptococcus pyogenes Surface-Associated Proteins , 2006, Journal of bacteriology.

[13]  J. Carapetis,et al.  Prospective Surveillance of Invasive Group A Streptococcal Disease, Fiji, 2005–2007 , 2009, Emerging infectious diseases.

[14]  M. V. Veldee Purification and Precipitation of the Erythrogenic Factor of Scarlet Fever Streptococcus Toxin and Its Antigenic Value , 1937 .

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

[16]  FAILURE of type specific Streptococcus pyogenes vaccine to prevent respiratory infections. , 1946, United States naval medical bulletin.

[17]  M. Reddish,et al.  Immunogenicity of a 26-Valent Group A Streptococcal Vaccine , 2002, Infection and Immunity.

[18]  E. N. Fox ANTIGENICITY OF THE M PROTEINS OF GROUP A HEMOLYTIC STREPTOCOCCI. , 1966, Journal of immunology.

[19]  F. W. Denny,et al.  Studies on immunity to streptococcal infections in man. , 1953, A.M.A. American journal of diseases of children.

[20]  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.

[21]  N. Khardori Preventing Bacterial Infections with Pilus-Based Vaccines: the Group B Streptococcus Paradigm , 2009 .

[22]  M. Pichichero,et al.  Mucosal antibody response to parenteral vaccination with Haemophilus influenzae type b capsule. , 1983, The Journal of allergy and clinical immunology.

[23]  W. Collis,et al.  INTRAVENOUS VACCINES OF HÆMOLYTIC STREPTOCOCCI IN ACUTE RHEUMATISM IN CHILDHOOD , 1932 .

[24]  G. Stollerman,et al.  Recall of type specific antibodies in man by injections of streptococcal cell walls. , 1962, The Journal of clinical investigation.

[25]  James D. Campbell,et al.  Safety and immunogenicity of a recombinant multivalent group a streptococcal vaccine in healthy adults: phase 1 trial. , 2004, JAMA.

[26]  J. Zabriskie,et al.  Phagocytic, serological, and protective properties of streptococcal group A carbohydrate antibodies. , 1997, Advances in experimental medicine and biology.

[27]  E. N. Fox,et al.  Protective studies with a group A streptococcal M protein vaccine. II. Challange of volenteers after local immunization in the upper respiratory tract. , 1975, The Journal of infectious diseases.

[28]  B. F. Massell,et al.  Rheumatic fever following streptococcal vaccination. Report of three cases. , 1969, JAMA.

[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]  M. Batzloff,et al.  Moving forward: a mucosal vaccine against group A streptococcus , 2009, Expert review of vaccines.

[31]  R. Tanz,et al.  Streptococcal pharyngitis: the case for penicillin therapy. , 1994, The Pediatric infectious disease journal.

[32]  J. Musser,et al.  Sequence variation in group A Streptococcus pili and association of pilus backbone types with lancefield T serotypes. , 2008, The Journal of infectious diseases.

[33]  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.

[34]  V. P. Wasson,et al.  Further studies in immunization against rheumatic fever , 1942 .

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

[36]  V. P. Wasson,et al.  Immunization against rheumatic fever with hemolytic streptococcus filtrate , 1938 .

[37]  Ruihong Zeng,et al.  Similar Ability of FbaA with M Protein to Elicit Protective Immunity Against Group A Streptococcus Challenge in Mice , 2009, Cellular and Molecular Immunology.

[38]  P. Cleary,et al.  Active and Passive Intranasal Immunizations with Streptococcal Surface Protein C5a Peptidase Prevent Infection of Murine Nasal Mucosa-Associated Lymphoid Tissue, a Functional Homologue of Human Tonsils , 2005, Infection and Immunity.

[39]  Mengyao Liu,et al.  Active and Passive Immunizations with the Streptococcal Esterase Sse Protect Mice against Subcutaneous Infection with Group A Streptococci , 2007, Infection and Immunity.

[40]  J. Carapetis,et al.  Clinical and epidemiological features of group A streptococcal bacteraemia in a region with hyperendemic superficial streptococcal infection , 1999, Epidemiology and Infection.

[41]  M. Good,et al.  Human antibodies to the conserved region of the M protein: opsonization of heterologous strains of group A streptococci. , 1997, Vaccine.

[42]  A. Podbielski,et al.  The SpeB virulence factor of Streptococcus pyogenes, a multifunctional secreted and cell surface molecule with strepadhesin, laminin‐binding and cysteine protease activity , 2001, Molecular microbiology.

[43]  G. Mccracken,et al.  The Pediatric Infectious Disease Journal newsletter. , 2012, The Pediatric infectious disease journal.

[44]  R. Lancefield Current knowledge of type-specific M antigens of group A streptococci. , 1962, Journal of immunology.

[45]  Dwight R. Johnson,et al.  Immune response to group A streptococcal C5a peptidase in children: implications for vaccine development. , 2003, The Journal of infectious diseases.

[46]  H. Swift,et al.  INTRAVENOUS VACCINATION WITH HEMOLYTIC STREPTOCOCCI: ITS INFLUENCE ON THE INCIDENCE OF RECURRENCE OF RHEUMATIC FEVER IN CHILDREN , 1931 .

[47]  D. Goldmann,et al.  Burden and Economic Cost of Group A Streptococcal Pharyngitis , 2008, Pediatrics.

[48]  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.

[49]  R. Lancefield THE ANTIGENIC COMPLEX OF STREPTOCOCCUS HAEMOLYTICUS : I. DEMONSTRATION OF A TYPE-SPECIFIC SUBSTANCE IN EXTRACTS OF STREPTOCOCCUS HAEMOLYTICUS. , 1927, The Journal of experimental medicine.

[50]  J. Zabriskie,et al.  Group A streptococcus-liposome ELISA antibody titers to group A polysaccharide and opsonophagocytic capabilities of the antibodies. , 1995, The Journal of infectious diseases.

[51]  J. Musser,et al.  Identification and Characterization of HtsA, a Second Heme-Binding Protein Made by Streptococcus pyogenes , 2003, Infection and Immunity.

[52]  R. Tanz,et al.  Seven-year surveillance of north american pediatric group a streptococcal pharyngitis isolates. , 2009, Clinical infectious diseases : an official publication of the Infectious Diseases Society of America.

[53]  L. Guilherme,et al.  Molecular mimicry in the autoimmune pathogenesis of rheumatic heart disease , 2006, Autoimmunity.

[54]  I. Margarit,et al.  Preventing bacterial infections with pilus-based vaccines: the group B streptococcus paradigm. , 2009, The Journal of infectious diseases.

[55]  J. Musser,et al.  Identification of new candidate vaccine antigens made by Streptococcus pyogenes: purification and characterization of 16 putative extracellular lipoproteins. , 2004, The Journal of infectious diseases.

[56]  M. Davies,et al.  Prospecting for new group A streptococcal vaccine candidates. , 2004, The Indian journal of medical research.

[57]  R. Zagursky,et al.  Application of genomics in bacterial vaccine discovery: a decade in review. , 2008, Current opinion in pharmacology.

[58]  J. Dale,et al.  Intranasal immunization with recombinant group A streptococcal M protein fragment fused to the B subunit of Escherichia coli labile toxin protects mice against systemic challenge infections. , 1995, The Journal of infectious diseases.

[59]  C. Gillen,et al.  Human pathogenic streptococcal proteomics and vaccine development , 2008, Proteomics. Clinical applications.

[60]  S. Hamada,et al.  Systemic and Mucosal Immunizations with Fibronectin-Binding Protein FBP54 Induce Protective Immune Responses against Streptococcus pyogenes Challenge in Mice , 2001, Infection and Immunity.

[61]  M. McDonald,et al.  Low rates of streptococcal pharyngitis and high rates of pyoderma in Australian aboriginal communities where acute rheumatic fever is hyperendemic. , 2006, Clinical infectious diseases : an official publication of the Infectious Diseases Society of America.

[62]  Jon Cohen,et al.  Superantigens: microbial agents that corrupt immunity. , 2002, The Lancet. Infectious diseases.

[63]  J. Zabriskie,et al.  Group A streptococcus (GAS) carbohydrate as an immunogen for protection against GAS infection. , 2006, The Journal of infectious diseases.

[64]  P. Cleary,et al.  Mechanism of action of the group A streptococcal C5a inactivator. , 1985, Proceedings of the National Academy of Sciences of the United States of America.

[65]  Kevin F. Jones,et al.  Clinical and Microbiological Responses of Volunteers to Combined Intranasal and Oral Inoculation with a Streptococcus gordonii Carrier Strain Intended for Future Use as a Group A Streptococcus Vaccine , 2005, Infection and Immunity.

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

[67]  M. McDonald,et al.  Acute rheumatic fever: a chink in the chain that links the heart to the throat? , 2004, The Lancet. Infectious diseases.

[68]  R. Ulrich Vaccine based on a ubiquitous cysteinyl protease and streptococcal pyrogenic exotoxin A protects against Streptococcus pyogenes sepsis and toxic shock , 2008, Journal of immune based therapies and vaccines.

[69]  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.

[70]  C. Duran,et al.  Pathogenic mechanisms in rheumatic carditis: focus on valvular endothelium. , 2001, The Journal of infectious diseases.

[71]  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.

[72]  P. Cleary,et al.  Intranasal immunization with C5a peptidase prevents nasopharyngeal colonization of mice by the group A Streptococcus , 1997, Infection and immunity.

[73]  A. Sette,et al.  T-Cell Reactivity against Streptococcal Antigens in the Periphery Mirrors Reactivity of Heart-Infiltrating T Lymphocytes in Rheumatic Heart Disease Patients , 2001, Infection and Immunity.

[74]  G. S. Chhatwal,et al.  Protective immune response against Streptococcus pyogenes in mice after intranasal vaccination with the fibronectin-binding protein SfbI. , 1999, The Journal of infectious diseases.

[75]  R. Lynfield,et al.  The epidemiology of invasive group A streptococcal infection and potential vaccine implications: United States, 2000-2004. , 2007, Clinical infectious diseases : an official publication of the Infectious Diseases Society of America.

[76]  E. Ingulli,et al.  Acute poststreptococcal glomerulonephritis: an update , 2008, Current opinion in pediatrics.

[77]  E. C. Peck,et al.  The Dick Reaction and Scarlet Fever Morbidity Following Injec-tions of a Purified and Tannie Acid Precipi-tated Erythrogenie Toxin. , 1941 .

[78]  W. Schmidt,et al.  Type-specific antibody formation in man following injection of streptococcal M protein. , 1960, The Journal of infectious diseases.

[79]  J. Gilsdorf Haemophilus influenzae type B conjugate vaccines , 1990 .

[80]  M. Davies,et al.  Toward the development of an antidisease, transmission-blocking intranasal vaccine for group a streptococcus. , 2005, The Journal of infectious diseases.

[81]  M. Davies,et al.  Identification and assessment of new vaccine candidates for group A streptococcal infections. , 2004, Vaccine.

[82]  S. Romero-Steiner,et al.  Prevention of Haemophilus influenzae type b colonization by vaccination: correlation with serum anti-capsular IgG concentration. , 2000, The Journal of infectious diseases.

[83]  R. Lancefield PERSISTENCE OF TYPE-SPECIFIC ANTIBODIES IN MAN FOLLOWING INFECTION WITH GROUP A STREPTOCOCCI , 1959, The Journal of experimental medicine.

[84]  J. McArthur,et al.  Domains of group A streptococcal M protein that confer resistance to phagocytosis, opsonization and protection: implications for vaccine development , 2006, Molecular microbiology.

[85]  M. Boyle,et al.  Streptococcal pyrogenic exotoxin B enhances tissue damage initiated by other Streptococcus pyogenes products. , 2001, The Journal of infectious diseases.

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

[87]  I. Toth,et al.  Synthesis and in vivo studies of carbohydrate-based vaccines against group A streptococcus. , 2008, Biopolymers.

[88]  P. Ferrieri,et al.  Conservation of the C5a peptidase genes in group A and B streptococci , 1996, Infection and immunity.

[89]  R. Edwards,et al.  Impact of immunization against SpyCEP during invasive disease with two streptococcal species: Streptococcus pyogenes and Streptococcus equi , 2009, Vaccine.

[90]  Daniela Schweiger,et al.  Chemokine degradation by the Group A streptococcal serine proteinase ScpC can be reconstituted in vitro and requires two separate domains. , 2009, The Biochemical journal.

[91]  Manisha Pandey,et al.  Mechanism of Protection Induced by Group A Streptococcus Vaccine Candidate J8-DT: Contribution of B and T-Cells Towards Protection , 2009, PloS one.

[92]  E. Kaplan,et al.  The human antibody response to streptococcal C5a peptidase. , 1991, The Journal of infectious diseases.

[93]  J. Carapetis,et al.  Opsonic human antibodies from an endemic population specific for a conserved epitope on the M protein of group A streptococci , 1996, Immunology.

[94]  R. Bhatnagar,et al.  Oral vaccines: new needs, new possibilities. , 2007, BioEssays : news and reviews in molecular, cellular and developmental biology.

[95]  M. V. Veldee A further study of the purification and tannic acid precipitation of scarlet fever toxin , 1938 .

[96]  I. Toth,et al.  Development of a liposaccharide-based delivery system and its application to the design of group A streptococcal vaccines. , 2008, Journal of medicinal chemistry.

[97]  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.

[98]  G. Bensi,et al.  Characterization and identification of vaccine candidate proteins through analysis of the group A Streptococcus surface proteome , 2006, Nature Biotechnology.

[99]  A. Bisno,et al.  Antecedent streptococcal infection in acute rheumatic fever. , 2006, Clinical infectious diseases : an official publication of the Infectious Diseases Society of America.

[100]  V. Fischetti,et al.  The importance of the location of antibody binding on the M6 protein for opsonization and phagocytosis of group A M6 streptococci , 1988, The Journal of experimental medicine.

[101]  D. Jackson,et al.  Intranasal vaccination with a lipopeptide containing a conformationally constrained conserved minimal peptide, a universal T cell epitope, and a self-adjuvanting lipid protects mice from group A streptococcus challenge and reduces throat colonization. , 2006, The Journal of infectious diseases.

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

[103]  V. P. Wasson,et al.  Immunization against rheumatic fever , 1943 .

[104]  J. McArthur,et al.  Intranasal Vaccination with Streptococcal Fibronectin Binding Protein Sfb1 Fails To Prevent Growth and Dissemination of Streptococcus pyogenes in a Murine Skin Infection Model , 2004, Infection and Immunity.

[105]  G. Walsh,et al.  Type-specific antibody response in man to injections of cell walls and M protein from group A, type 14 streptococci. , 1963, The Journal of laboratory and clinical medicine.

[106]  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.

[107]  E. N. Fox,et al.  Protective studies with group A streptococcal M protein vaccine. III. Challenge of volunteers after systemic or intranasal immunization with Type 3 or Type 12 group A Streptococcus. , 1978, The Journal of infectious diseases.

[108]  J. G. Michael,et al.  Secondary and apparent primary antibody responses after group A streptococcal vaccination of 21 children. , 1968, Applied microbiology.

[109]  J. Carapetis,et al.  emm and C-Repeat Region Molecular Typing of Beta-Hemolytic Streptococci in a Tropical Country: Implications for Vaccine Development , 2009, Journal of Clinical Microbiology.