Abstract
Rheumatic fever (RF) and rheumatic heart disease (RHD) are post-infectious complications of an infection (or repeated infection) with the Gram-positive bacterium Streptococcus pyogenes (also known as group A streptococcus, GAS). RF and RHD are global problems and affect many indigenous populations of developed countries and many developing countries. However, RF and RHD are only part of a larger spectrum of diseases caused by this organism. The development of a vaccine against GAS has primarily targeted the abundant cell-surface protein called the M-protein. This review focuses on different M-protein-based-subunit vaccine approaches and the different delivery technologies used to administer these vaccine candidates in preclinical studies.
Article PDF
Similar content being viewed by others
References
WHO: Global Polio Eradication Initiative: Strategic Plan 2004–2008. World Health Organization. Geneva, 2003.
Merrifield RB: Solid phase peptide synthesis I: The synthesis of a tetrapeptide. J Am Chem Soc 1963;85: 2149–2153.
Carpino LA, Han GY: The 9-fluorenylmethoxycarbonyl amino-protecting group. J Org Chem 1972;37:3404–3409.
Fields GB, Nobel RL: Solid phase peptide synthesis utilizing 9-fluorenylmethoxycarbonyl amino acids. Intern J Pep Prot Res 1990;35:161–214.
Cherry DK, Woodwell DA: National Ambulatory Medical Care Survey: 2000 summary. Adv Data 2002;1–32.
Bisno AL: Acute pharyngitis. N Engl J Med 2001; 344:205–211.
Bisno AL, Rubin FA, Cleary PP, Dale JB: 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 2005;41:1150–1156.
Komaroff AL, Pass TM, Aronson MD, et al: The prediction of streptococcal pharyngitis in adults. J Gen Intern Med 1986;1:1–7.
Massell BF: Rheumatic fever and streptococal infection. Harvard University Press, Boston, 1997.
Cunningham MW: Pathogenesis of group A streptococcal infections. Clin Microbiol Rev 2000;13:470–511.
Steer AC, Carapetis JR, Nolan TM, Shann F: Systematic review of rheumatic heart disease prevalence in children in developing countries: the role of environmental factors. J Paediatr Child Health 2002;38:229–234.
Carapetis JR, Wolff DR, Currie BJ: Acute rheumatic fever and rheumatic heart disease in the top end of Australia's Northern Territory. Med J Aust 1996;164: 146–149.
World Health Organization World Health Report. Office of Publications, World Health Organization, Geneva, 2000, pp. 164–169.
Carapetis J: A review of WHO activities in, the burden of, and the evidence for strategies to control group A streptococcal diseases: part 3—the current evidence for the burden of group A streptococcal diseases. University of Melbourne. Melbourne, 2004, pp. 1–49.
Carapetis JR, Steer, AC, Mulholland EK, Weber M: The global burden of group A streptococcal diseases. Lancet Infect Dis 2005;5:685–694.
Thomson D, Thomson R: The role of the Streptococci in scarlet fever. Annals of the Pickett-Thomson Research Laboratory 1930;4:244–252.
Beachey EH, Stollerman GH, Johnson RH, Ofek I, Bisno AL. Human immune response to immunization with a structurally defined polypeptide fragment of streptococcal M protein. J Exp Med 1979;150: 862–877.
Fox EN, Wittner MK, Dorfman A: Antigenicity of the M proteins of group A hemolytic streptococci. 3. Antibody responses and cutaneous hypersensitivity in humans. J Exp Med 1966;124:1135–1151.
Massell BF, Michael JG, Amezcua J, Siner M: Secondary and apparent primary antibody responses after group A streptococcal vaccination of 21 children. Appl Microbiol 1968;16:509–518.
Fox EN, Pachman LM, Wittner MK, Dorfman A: Primary immunization of infants and children with group A streptococcal M protein. J Infect Dis 1969;120: 598–604.
Lyampert IM, Danilova TA, Borodyuk NA, Beletskaya LV: Mechanism of formation of antibodies to heart tissue in immunization with group A streptococci. Folia Biol (Praha) 1966;12:108–115.
Beachey EH, Stollerman GH: The common antigen(s) of streptococcal M protein vaccines causing hyperimmune reactions in man. Trans Assoc Am Physicians 1972; 85:212–221.
Massell BF, Honikman LH, Amezcua J: Rheumatic fever following streptococcal vaccination. Report of three cases. JAMA 1969;207:1115–1119.
Fox EN: M proteins of group A streptococci. Bacteriol Rev 1974;38:57–86.
Park HS, Cleary PP: 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. Infect Immun 2005;73:7878–7886.
McMillan DJ, Batzloff MR, Browning CL, et al Identification and assessment of new vaccine candidates for group A streptococcal infections. Vaccine 2004;22: 2783–2790.
Zabriskie JB, Poon-King T, Blake MS, Michon F, Yoshinaga M: Phagocytic, serological, and protective properties of streptococcal group A carbohydrate antibodies. Adv Exp Med Biol 1997;418:917–919.
Fischetti VA, Jones KF, Hollingshead SK, Scott JR: Structure, function, and genetics of streptococcal M protein. Rev Infect Dis 1988;10(Suppl 2):S356–359.
Hu MC, Walls MA, Stroop SD, Reddish MA, Beall B, Dale JB: Immunogenicity of a 26-valent group A streptococcal vaccine. Infect Immun 2002;70:2171–2177.
Kotloff KL, Corretti M, Palmer K, et al Safety and immunogenicity of a recombinant multivalent group a streptococcal vaccine in healthy adults: phase 1 trial. JAMA 2004;292:709–715.
Bessen D, Fischetti VA: Influence of intranasal immunization with synthetic peptides corresponding to conserved epitopes of M protein on mucosal colonization by group A streptococci. Infect Immun 1988;56:2666–2672.
Dale JB, Penfound T, Chiang EY, Long V, Shulman ST, Beall B: Multivalent group A streptococcal vaccine elicits bactericidal antibodies against variant M subtypes. Clin Diagn Lab Immunol 2005;12:833–836.
McNeil SA, Halperin SA, Langley JM, et al: Safety and immunogenicity of 26-valent group a streptococcus vaccine in healthy adult volunteers. Clin Infect Dis 2005;41:1114–1122.
Bessen D, Fischetti VA: Passive acquired mucosal immunity to group A streptococci by secretory immunoglobulin A. J Exp Med 1988;167:1945–1950.
Brandtzaeg P: Role of secretory antibodies in the defence against infections. Int J Med Microbiol 2003;293:3–15.
Bronze MS, Courtney HS, Dale JB: Epitopes of group-a streptococcal M-protein that evoke cross-protective local immune-responses. J Immunol 1992;148:888–893.
Pruksakorn S, Currie B, Brandt E, et al: Towards a vaccine for rheumatic fever: identification of a conserved target epitope on M protein of group A streptococci. Lancet 1994;344:639–642.
Pruksakorn S, Galbraith A, Houghten RA, Good MF: Conserved T and B cell epitopes on the M protein of group A streptococci. Induction of bactericidal antibodies. J Immunol 1992;149:2729–2735.
Hayman WA, Brandt ER, Relf WA, Cooper J, Saul A, Good MF: 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. Int Immunol 1997;9:1723–1733.
Brandt ER, Hayman WA, Currie B, et al: Opsonic human antibodies from an endemic population specific for a conserved epitope on the M protein of group A streptococci. Immunology 1996;89:331–337.
Batzloff M, Yan H, Davies M, Hartas J, Good M: Preclinical evaluation of a vaccine based on conserved region of M protein that prevents group A streptococcal infection. Indian J Med Res 2004;119(Suppl):104–107.
Batzloff MR, Hayman WA, Davies MR, et al: Protection against group A streptococcus by immunization with J8-diphtheria toxoid: contribution of J8- and diphtheria toxoid-specific antibodies to protection. J Infect Dis 2003;187:1598–1608.
Batzloff MR, Yan H, Davies MR, et al: Toward the development of an antidisease, transmission-blocking intranasal vaccine for group a streptococcus. J Infect Dis 2005;192:1450–1455.
Brandt ER, Hayman WA, Currie B, et al: Functional analysis of IgA antibodies specific for a conserved epitope within the M protein of group A streptococci from Australian Aboriginal endemic communities. Int Immunol 1999;11:569–576.
D'Alessandri R, Plotkin G, Kluge RM, 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. J Infect Dis 1978;138:712–718.
Brandt ER, Teh T, Relf WA, Hobb RI, Good MF: Protective and nonprotective epitopes from amino termini of M proteins from Australian aboriginal isolates and reference strains of group A streptococci. Infect Immun 2000;68:6587–6594.
Olive C, Clair T, Yarwood P, Good MF: Protection of mice from group A streptococcal infection by intranasal immunization with a peptide vaccine that contains a conserved M protein B cell epitope and lacks a T cell autoepitope. Vaccine 2002;20:2816–2825.
Bran5dt ER, Sriprakash KS, Hobb RI, et al: New multideterminant strategy for a group A streptococcal vacciae designed for the Australian Aboriginal population. Nat Med 2000;6:455–459.
Jackson DC, O'Brien-Simpson N, Ede NJ, Brown LE: Free radical induced polymerization of synthetic peptides into polymeric immunogens. Vaccine 1997; 15:1697–1705.
Hantke K, Braun V: Covalent binding of lipid to protein. Diglyceride and amide-linked fatty acid at the N-terminal end of the murein-lipoprotein of the Escherichia coli outer membrane. Eur J Biochem 1973;34:284–296.
Luke CJ, Huebner RC, Kasmiersky V, Barbour AG: Oral delivery of purified lipoprotein OspA protects mice from systemic infection with Borrelia burgdorferi. Vaccine 1997;15:739–746.
Keller D, Koster FT, Marks DH, Hosbach P, Erdile LF, Mays JP: Safety and immunogenicity of a recombinant outer surface protein A Lyme vaccine. JAMA 1994; 271:1764–1768.
Melchers F, Braun V, Galanos C: The lipoprotein of the outer membrane of Escherichia coli: a B-lymphocyte mitogen. Exp Med 1975;142:473–482.
Norgard MV, Arndt LL, Akins DR, Curetty LL, Harrich DA, Radolf JD: Activation of human monocytic cells by Treponema pallidum and Borrelia burgdorferi lipoproteins and synthetic lipopeptides proceeds via a path way distinct from that of lipopolysaccharide but involves the transcriptional activator NF-[kappa]B. Infect Immun 1996;64:3845–3852.
Kreutz M, Ackermann U, Hauschildt S, et al: A comparative analysis of cytokine production and tolerance induction by bacterial lipopeptides, lipopolysaccharides and staphyloccocus aureus in human monocytes. Immunology 1997;92:396–401.
Wiesmuller KH, Bessler W, Jung G: Synthesis of the mitogenic S-[2,3-bis(palmitoyloxy)propyl]-N-palmitoylpentapeptide from Escherichia coli lipoprotein. Hoppe Seyler Physiol Chem 1983;364:593–606.
Hoffmann P, Heinle S, Schade UF, et al: Stimulation of human and murine adherent cells by bacterial lipoprotein and synthetic lipopeptide analogues. Immunobiology 1988;177:158–170.
Seifert R, Schultz G, Richter-Freund M, et al: Activation of superoxide formation and lysozyme release in human neutrophils by the synthetic lipopeptide Pam3Cys-Ser-(Lys)4. Involvement of guanine-nucleotide-binding proteins and synergism with chemotactic peptides. Biochem J 1990;267:795–802.
Berg M, Offermanns S, Seifert R, Schultz G: Synthetic lipopeptide Pam3CysSer(Lys)4 is an effective activator of human platelets. Am J Physiol 1994;266:C1684-C1691.
Wiesmuller K-H, Jung G, Hess G: Novel low-molecular-weight synthetic vaccine against foot-and-mouth disease containing a potent B-cell and macrophage activator. Vaccine 1989;7:29–33.
Re F, Strominger J-L: Toll-like receptor 2 (TLR2) and TLR4 differentially activate human dendritic cells. J Biol Chem 2001;276:37692–37699.
Takeda K, Kaisho T, Akira S: Toll-like receptors. Annu Rev Immunol 2003;21:335–376.
Jackson DC, Lau YF, Le T, et al: A totally synthetic vaccine of generic structure that targets Toll-like receptor 2 on dendritic cells and promotes antibody or cytotoxic T cell responses. Proc Natl Acad Sci USA 2004; 101:15440–15445.
Zeng W, Ghosh S, Lau YF, Brown LE, Jackson DC: Highly immunogenic and totally synthetic lipopeptides as self-adjuvanting immunocontraceptive vaccines. J Immunol 2002;169:4905–4912.
Tam JP Synthetic peptide vaccine design: synthesis and properties of a high-density multiple antigenic peptide system. Proc Natl Acad Sci USA 1988;85:5409–5413.
Olive C, Batzloff MR, Toth I: Lipid core peptide technology and group A streptococcal vaccine delivery. Expert Rev Vaccines 2004;3:43–58.
McGeary RP, Olive C, Toth I: Lipid and carbohydrate based adjuvant/carriers in immunology. J Pept Sci 2003;9:405–418.
Olive C, Toth I, Jackson D: Technological advances in antigen delivery and synthetic peptide vaccine developmental strategies. Mini Rev Med Chem 2001;1:429–438.
Wong A, Toth I: Lipid, sugar and liposaccharide based delivery systems. Curr Med Chem 2001;8:1123–1136.
Hayman WA, Toth I, Flinn N, Scanlon M, Good MF: Enhancing the immunogenicity and modulating the fine epitope recognition of antisera to a helical group A streptococcal peptide vaccine candidate from the M protein using lipid-core peptide technology. Immunol Cell Biol 2002;80:178–187.
Olive C, Batzloff MR, Horvath A, et al: A lipid core peptide construct containing a conserved region determinant of the group A streptococcal M protein elicits heterologous opsonic antibodies. Infect Immun 2002;70: 2734–2738.
Olive C, Batzloff M, Horvath A, et al: Potential of lipid core peptide technology as a novel self-adjuvanting vaccine delivery system for multiple different synthetic peptide immunogens. Infect Immun 2003;71:2373–2383.
Olive C, Hsien K, Horvath A, et al: Protection against group A streptococcal infection by vaccination with self-adjuvanting lipid core M protein peptides. Vaccine 2005;23:2298–2303.
Lowell G, Burt DS, White GL, Fries LF: Proteosome™ technology for vaccines and adjuvants; in: Levine MM, Kaper JB, Rappuoli R, Liu MA, Good MF (eds). New Generation Vaccines, 3rd ed. Marcel Dekker, New York, 2004; pp. 271–282.
Massari P, Henneke P, Ho Y, Latz E, Golenbock DT, Wetzler LM: Cutting edge: immune stimulation by neisserial porins is toll-like receptor 2 and MyD88 dependent. J Immunol 2002;168:1533–1537.
Mannam P, Jones KF, Geller BL: Mucosal vaccine made from live, recombinant Lactococcus lactis protects mice against pharyngeal infection with Streptococcus pyogenes. Infect Immun 2004;72:3444–3450.
Ferretti JJ, McShan WM, Ajdic D, et al Complete genome sequence of an M1 strain of Streptococcus pyogenes. Proc Natl Acad Sci USA 2001;98:4658–4663.
Author information
Authors and Affiliations
Rights and permissions
About this article
Cite this article
Batzloff, M.R., Pandey, M., Olive, C. et al. Advances in potential M-protein peptide-based vaccines for preventing rheumatic fever and rheumatic heart disease. Immunol Res 35, 233–248 (2006). https://doi.org/10.1385/IR:35:3:233
Issue Date:
DOI: https://doi.org/10.1385/IR:35:3:233