Current Status of Group A Streptococcal Vaccine Development

  • James B. Dale
Part of the Advances in Experimental Medicine and Biology book series (AEMB, volume 609)

Group A streptococci (GAS) are ubiquitous human pathogens that cause a wide spectrum of clinical syndromes. The acute infections range from uncomplicated pharyngitis, cellulitis, and pyoderma to necrotizing fasciitis, sepsis, pneumonia, and streptococcal toxic shock syndrome. The non-suppurative sequelae that may follow GAS infections are acute rheumatic fever (ARF) and post-streptococcal glomerulonephritis (PSGN). The burden of disease caused by GAS in economically developed and developing countries is significant. The search for a safe and effective vaccine to prevent GAS infections and their complications has been ongoing for more than 80 years. This chapter details the worldwide burden of disease, the obstacles encountered in vaccine development, current vaccine strategies and an update on the clinical development of M protein-based vaccines.


Rheumatic Fever Necrotizing Fasciitis Rheumatic Heart Disease Acute Rheumatic Fever Streptococcal Toxic Shock Syndrome 
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.


Unable to display preview. Download preview PDF.

Unable to display preview. Download preview PDF.


  1. Beachey EH and Seyer JM. (1986). Protective and nonprotective epitopes of chemically synthesized peptides of the NH2-terminal region of type 6 streptococcal M protein. J Immunol, 136:2287–2292.PubMedGoogle Scholar
  2. Bessen D and Fischetti VA. (1988). Influence of intranasal immunization with synthetic peptides corresponding to conserved epitopes of M protein on mucosal colonization by group A streptococci. Infect Immun, 56:2666–2672.PubMedGoogle Scholar
  3. Bisno AL. (2001). Acute pharyngitis. N Engl J Med, 344:205–211.PubMedCrossRefGoogle Scholar
  4. Bisno AL, Rubin FA, Cleary PP, and Dale JB. (2005). Prospects for a group A streptococcal vaccine: rationale, feasibility, and obstacles–report of a National Institute of Allergy and Infectious Diseases workshop. Clin Infect Dis, 41:1150–1156.PubMedCrossRefGoogle Scholar
  5. Bolken TC, Franke CA, Jones KF, Bell RH, Swanson RM, King DS, Fischetti VA, and Hruby DE. (2002). Analysis of factors affecting surface expression and immunogenicity of recombinant proteins expressed by gram-positive commensal vectors. Infect Immun, 70:2487–2491.PubMedCrossRefGoogle Scholar
  6. Brandt ER, Hayman WA, Currie B, Pruksakorn S, and Good MF. (1997). Human antibodies to the conserved region of the M protein: opsonization of heterologous strains of group A streptococci. Vaccine, 15:1805–1812.PubMedCrossRefGoogle Scholar
  7. Brandt ER, Sriprakash KS, Hobb RI, Hayman WA, Zeng W, Batzloff MR, Jackson DC, and Good MF. (2000). New multi-determinant strategy for a group A streptococcal vaccine designed for the Australian Aboriginal population. Nat Med, 6:455–459.PubMedCrossRefGoogle Scholar
  8. Bronze MS, Courtney HS, and Dale JB. (1992). Epitopes of group A streptococcal M protein that evoke cross-protective local immune responses. J Immunol, 148:888–893.PubMedGoogle Scholar
  9. Carapetis JR, Steer AC, Mulholland EK, and Weber M. (2005). The global burden of group A streptococcal diseases. Lancet Infect Dis, 5:685–694.PubMedCrossRefGoogle Scholar
  10. Courtney HS, Li Y, Dale JB, and Hasty DL. (1994). Cloning, sequencing, and expression of a fibronectin/fibrinogen-binding protein from group A streptococci. Infect Immun, 62:3937.PubMedGoogle Scholar
  11. Courtney HS, Hasty DL, and Dale JB. (2003). Serum opacity factor (SOF) of Streptococcus pyogenes evokes antibodies that opsonize homologous and heterologous SOF-positive serotypes of group A streptococci. Infect Immun, 71:5097–5103.PubMedCrossRefGoogle Scholar
  12. Cunningham MW. (2000). Pathogenesis of group A streptococcal infections. Clin Microbiol Rev, 13:470–511.PubMedCrossRefGoogle Scholar
  13. Dale JB and Beachey EH. (1986). Localization of protective epitopes of the amino terminus of type 5 streptococcal M protein. J Exp Med, 163:1191–1202.PubMedCrossRefGoogle Scholar
  14. Dale JB, Seyer JM, and Beachey EH. (1983). Type-specific immunogenicity of a chemically synthesized peptide fragment of type 5 streptococcal M protein. J Exp Med, 158:1727–1732.PubMedCrossRefGoogle Scholar
  15. Dale JB, Chiang EY, and Lederer JW. (1993). Recombinant tetravalent group A streptococcal M protein vaccine. J Immunol, 151:2188–2194.PubMedGoogle Scholar
  16. Dale JB, Washburn RG, Marques MB, and Wessels MR. (1996). Hyaluronate capsule and surface M protein in resistance to phagocytosis of group A streptococci. Infect Immun, 64:1495–1501.PubMedGoogle Scholar
  17. Dale JB, Chiang EY, Liu SY, Courtney HS, and Hasty DL. (1999). New protective antigen of group A streptococci. J Clin Invest, 103:1261–1268.PubMedCrossRefGoogle Scholar
  18. Dale JB, Chiang EY, Hasty DL, and Courtney HC. (2002). Antibodies against a synthetic peptide of SagA neutralize the cytolytic activity of streptolysin S from group A streptococci. Infect Immun, 70:2166–2170.PubMedCrossRefGoogle Scholar
  19. Dey N, McMillan DJ, Yarwood PJ, Joshi RM, Kumar R, Good MF, Sriprakash KS, and Vohra H. (2005). High diversity of group A Streptococcal emm types in an Indian community: the need to tailor multivalent vaccines. Clin Infect Dis, 40:46–51.PubMedCrossRefGoogle Scholar
  20. Fischetti VA. (1989). Streptococcal M protein: molecular design and biological behavior. Clin Microbiol Rev, 2:285.PubMedGoogle Scholar
  21. Fischetti VA, Horstman RD, and Pancholi V. (1995). Location of the complement factor H binding site on streptococcal M protein. Infect Immun, 63:149.PubMedGoogle Scholar
  22. Hasty DL, Ofek I, Courtney HS, and Doyle RJ. (1992). Multiple adhesins of streptococci. Infect Immun, 60:2147–2152.PubMedGoogle Scholar
  23. Ho PL, Johnson DR, Yue AW, Tsang DN, Que TL, Beall B, and Kaplan EL. (2003). Epidemiologic analysis of invasive and noninvasive group a streptococcal isolates in Hong Kong. J Clin Microbiol, 41:937–942.PubMedCrossRefGoogle Scholar
  24. Hu M, Walls M, Stroop S, Reddish M, Beall B, and Dale J. (2002). Immunogenicity of a 26-valent group A streptococcal vaccine. Infect Immun, 70:2171–2177.PubMedCrossRefGoogle Scholar
  25. Ji Y, McLandsborough L, Kondagunta A, and Cleary PP. (1996). C5a peptidase alters clearance and trafficking of group A streptococci by infected mice. Infect Immun, 64:503.PubMedGoogle Scholar
  26. Jones KF and Fischetti VA. (1988). The importance of the location of antibody binding on the M6 protein for opsonization and phagocytosis of group A M6 streptococci. J Exp Med, 167:1114–1123.PubMedCrossRefGoogle Scholar
  27. Jones KF, Manjula BN, Johnston KH, Hollingshead SK, Scott JR, and Fischetti VA. (1985). Location of variable and conserved epitopes among the multiple serotypes of streptococcal M protein. J Exp Med, 161:623–628.PubMedCrossRefGoogle Scholar
  28. Jones KF, Khan SA, Erickson BW, Hollingshead DK, Scott JR, and Fischetti VA. (1986). Immunochemical localization and amino acid sequence of cross-reactive epitopes within the group A streptococcal M6 protein. J Exp Med, 164:1226–1238.PubMedCrossRefGoogle Scholar
  29. Kapur V, Maffei JT, Greer RS, Li LL, Adams GJ, and Musser JM. (1994). Vaccination with streptococcal extracellular cysteine protease (interleukin 1B convertase) protects mice against challenge with heterologous group A streptococci. Microb Pathog, 16:443.PubMedCrossRefGoogle Scholar
  30. Kawabata S, Kunitomo E, Terao Y, Nakagawa I, Kikuchi K, Totsuka K, and Hamada S. (2001). Systemic and mucosal immunizations with fibronectin-binding protein FBP54 induce protective immune responses against Streptococcus pyogenes challenge in mice. Infect Immun, 69:924–930.PubMedCrossRefGoogle Scholar
  31. Kotb M. (1995). Bacterial pyrogenic exotoxins as superantigens. Clin Microbiol Rev, 8:411.PubMedGoogle Scholar
  32. Lancefield RC. (1962). Current knowledge of the type specific M antigens of group A streptococci. J Immunol, 89:307–313.PubMedGoogle Scholar
  33. Land MA and Bisno AL. (1983). Acute rheumatic fever: a vanishing disease in suburbia. JAMA, 249:895.PubMedCrossRefGoogle Scholar
  34. Lindahl G and Stenberg L. (1990). Binding of IgA and/or IgG is a common property among clinical isolates of group A streptococci. Epidemiol Infect, 105:87.PubMedCrossRefGoogle Scholar
  35. McNeil SA, Halperin SA, Langley JM, Smith B, Warren A, Sharratt GP, Baxendale DM, Reddish MA, Hu MC, Stroop SD, Linden J, Fries LF, Vink PE, and Dale JB. (2005). Safety and immunogenicity of 26-valent group a streptococcus vaccine in healthy adult volunteers. Clin Infect Dis, 41:1114–1122.PubMedCrossRefGoogle Scholar
  36. Moses AE, Wessels MR, Zalcman K, Alberti S, Natanson-Yaron S, Menes T, and Hanski E. (1997). Relative contributions of hyaluronic acid capsule and M protein to virulence in a mucoid strain of the group A streptococcus. Infect Immun, 65:64.PubMedGoogle Scholar
  37. Olive C, Sun HK, Ho MF, Dyer J, Horvath A, Toth I, and Good MF. (2006). Intranasal administration is an effective mucosal vaccine delivery route for self-adjuvanting lipid core peptides targeting the group a streptococcal m protein. J Infect Dis, 194:316–324.PubMedCrossRefGoogle Scholar
  38. Phillips GN, Flicker PF, Cohen C, Manjula BN, and Fischetti VA. (1981). Streptococcal M protein: alpha-helical coiled-coil structure and arrangement on the cell surface. Proc Natl Acad Sci U S A, 78:4689–4693.PubMedCrossRefGoogle Scholar
  39. Pruksakorn S, Currie B, Brandt E, Martin D, Galbraith A, Phornphutkul C, Hunsakunachai S, Manmontri A, and Good MF. (1994). Towards a vaccine for rheumatic fever: identification of a conserved target epitope on M protein of group A streptococci. Lancet, 334:639.CrossRefGoogle Scholar
  40. Pruksakorn S, Sittisombut N, Phornphutkul C, Pruksachatkunakorn C, Good MF, and Brandt E. (2000). Epidemiological analysis of non-M-typeable group A Streptococcus isolates from a Thai population in northern Thailand. J Clin Microbiol, 38:1250–1254.PubMedGoogle Scholar
  41. Roggiani M, Stoehr JA, Olmsted SB, Matsuka YV, Pillai S, Ohlendorf DH, and Schlievert PM. (2000). Toxoids of streptococcal pyrogenic exotoxin A are protective in rabbit models of streptococcal toxic shock syndrome. Infect Immun, 68:5011–5017.PubMedCrossRefGoogle Scholar
  42. Sabharwal H, Michon F, Nelson D, Dong W, Fuchs K, Manjarrez RC, Sarkar A, Uitz C, Viteri-Jackson A, Suarez RS, Blake M, and Zabriskie JB. (2006). Group A streptococcus (GAS) carbohydrate as an immunogen for protection against GAS infection. J Infect Dis, 193:129–135.PubMedCrossRefGoogle Scholar
  43. Schuchat A, Hilger T, Zell E, Farley MM, Reingold A, Harrison L, Lefkowitz L, Danila R, Stefonek K, Barrett N, Morse D, and Pinner R. (2001). Active bacterial core surveillance of the emerging infections program network. Emerg Infect Dis, 7:92–99.PubMedCrossRefGoogle Scholar
  44. Shulman ST, Tanz RR, Kabat W, Kabat K, Cederlund E, Patel D, Li Z, Sakota V, Dale JB, and Beall B. (2004). Group A streptococcal pharyngitis serotype surveillance in North America, 2000–2002. Clin Infect Dis, 39:325–332.PubMedCrossRefGoogle Scholar
  45. Steer AC, Carapetis JR, Nolan TM, and Shann F. (2002). Systematic review of rheumatic heart disease prevalence in children in developing countries: the role of environmental factors. J Paediatr Child Health, 38:229–234.PubMedCrossRefGoogle Scholar
  46. Stollerman GH. (1975). Rheumatic Fever and Streptococcal Infection. Grune and Stratton, New York, NY.Google Scholar
  47. Stollerman GH. (1997). Rheumatic fever. Lancet, 349:935–942.PubMedCrossRefGoogle Scholar
  48. Stollerman GH. (2001). Rheumatic fever in the 21st century. Clin Infect Dis, 33:806–14.PubMedCrossRefGoogle Scholar
  49. Veasey LG, Wiedneier SW, Osmond GS, Ruttenburt HD, Boucek MM, Roth SW, Tait VF, Thompson JA, Salz JA, Kaplan EL, and Hill HR. (1987). Resurgence of acute rheumatic fever in the intermountain region of the United States. N Engl J Med, 316:421.CrossRefGoogle Scholar
  50. Whitnack E and Beachey EH. (1982). Antiopsonic activity of fibrinogen bound to M protein on the surface of group A streptococci. J Clin Invest, 69:1042–1048.PubMedCrossRefGoogle Scholar
  51. WHO. (1992). WHO programme for the prevention of rheumatic fever/rheumatic heart disease in 16 developing countries: report from Phase I (1986–90). WHO Cardiovascular Diseases Unit and principal investigators. In Bull World Health Organ, Vol. 70, pp. 213–218.Google Scholar
  52. Zabriskie JB, Poon-King T, Blake MS, Michon F, and Yoshinaga M. (1997). Phagocytic, serological, and protective properties of streptococcal group A carbohydrate antibodies. Adv Exp Med Biol, 418:917–919.PubMedGoogle Scholar

Copyright information

© Springer 2008

Authors and Affiliations

  • James B. Dale
    • 1
  1. 1.University of Tennessee Health Science Center and VA Medical CenterMemphis

Personalised recommendations