Towards a vaccine for rheumatic fever: identification of a conserved target epitope on M protein of group A streptococci

Pruksakorn, Sumalee; Brandt, Evelyn R.; Good, Michael F.; Currie, Bart J.; Martin, Diana; Galbraith, Andrew; Phornphutkul, Charlie; Hunsakunachai, Somchai; Manmontri, Anon

doi:10.1016/s0140-6736(94)92083-4

Cited by 89 publications

(51 citation statements)

References 24 publications

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“…We previously described a vaccine candidate peptide, J8, based on a minimal epitope from the conserved C3 repeat of the GAS surface M protein (8,9). When linked to the carrier protein, diphtheria toxoid (DT), and administered with Alhydrogel, J8 induces opsonic Abs that protect mice from a systemic i.p.…”

Section: S Treptococcus Pyogenes (Group a Streptococcus [Gas]mentioning

confidence: 99%

A Synthetic M Protein Peptide Synergizes with a CXC Chemokine Protease To Induce Vaccine-Mediated Protection against Virulent Streptococcal Pyoderma and Bacteremia

Pandey

Langshaw

Hartas

et al. 2015

The Journal of Immunology

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Infections caused by Streptococcus pyogenes (group A Streptococcus [GAS]) are highly prevalent in the tropics, in developing countries, and in the Indigenous populations of developed countries. These infections and their sequelae are responsible for almost 500,000 lives lost prematurely each year. A synthetic peptide vaccine (J8-DT) from the conserved region of the M protein has shown efficacy against disease that follows i.p. inoculation of bacteria. By developing a murine model for infection that closely mimics human skin infection, we show that the vaccine can protect against pyoderma and subsequent bacteremia caused by multiple GAS strains, including strains endemic in Aboriginal communities in the Northern Territory of Australia. However, the vaccine was ineffective against a hypervirulent cluster of virulence responder/sensor mutant GAS strain; this correlated with the strain’s ability to degrade CXC chemokines, thereby preventing neutrophil chemotaxis. By combining J8-DT with an inactive form of the streptococcal CXC protease, S. pyogenes cell envelope proteinase, we developed a combination vaccine that is highly effective in blocking CXC chemokine degradation and permits opsonic Abs to kill the bacteria. Mice receiving the combination vaccine were strongly protected against pyoderma and bacteremia, as evidenced by a 100–1000-fold reduction in bacterial burden following challenge. To our knowledge, a vaccine requiring Abs to target two independent virulence factors of an organism is unique.

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Section: S Treptococcus Pyogenes (Group a Streptococcus [Gas]mentioning

confidence: 99%

A Synthetic M Protein Peptide Synergizes with a CXC Chemokine Protease To Induce Vaccine-Mediated Protection against Virulent Streptococcal Pyoderma and Bacteremia

Pandey

Langshaw

Hartas

et al. 2015

The Journal of Immunology

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“…The M protein is a major virulence factor in GAS infection and consists of a variable amino-terminal region which defines the GAS serotype (over 100 serotypes are known) and a highly conserved carboxy-terminal C-repeat region (10). Protective immunity to GAS infection has been associated with typespecific opsonic antibodies against M protein (10,21), although the presence of opsonic antibodies specific to the Cregion has been demonstrated in humans (17) and in mice immunized with C-region peptides (18) and is also important in the elicitation of protective immunity to GAS (4). The variability in M proteins and the potential for the induction of autoimmunity due to antigenic molecular mimicry between the GAS M protein and heart antigens (6,11,13,19) represent significant hurdles in the development of a vaccine covering a wide range of strains.…”

mentioning

confidence: 99%

A Lipid Core Peptide Construct Containing a Conserved Region Determinant of the Group A Streptococcal M Protein Elicits Heterologous Opsonic Antibodies

et al. 2002

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The study reported here investigated the immunogenicity and protective potential of a lipid core peptide (LCP) construct containing a conserved region determinant of M protein, defined as peptide J8. Parenteral immunization of mice with LCP-J8 led to the induction of high-titer serum immunoglobulin G J8-specific antibodies when the construct was coadministered with complete Freund's adjuvant (CFA) or administered alone. LCP-J8 in CFA had significantly enhanced immunogenicity compared with the monomeric peptide J8 given in CFA. Moreover, LCP-J8/CFA and LCP-J8 antisera opsonized four different group A streptococcal (GAS) strains, and the antisera did not cross-react with human heart tissue proteins. These data indicate the potential of an LCP-based M protein conserved region GAS vaccine in the induction of broadly protective immune responses in the absence of a conventional adjuvant.

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“…[5][6][7][8] A second approach is based on the more highly conserved C-terminal region of the M protein. [9][10][11] This approach is expected to be advantageous since sequence conservation would imply broader strain coverage with fewer vaccine components; although, safety concerns exist since this region of the protein has been shown to induce T cell responses that are cross reactive with human cardiac myosin. 12 Good et al defined a peptide sequence (p145) located in this region, which was recognized by antibodies in the sera of most adults living in areas of endemic streptococcal disease.…”

Section: Immunogenicity In Mice and Non-human Primates Of The Group Amentioning

confidence: 99%

“…12 Good et al defined a peptide sequence (p145) located in this region, which was recognized by antibodies in the sera of most adults living in areas of endemic streptococcal disease. 11,13 A minimal B cell epitope and non-host reactive peptide derived from p145, termed J8, has been shown to be immunogenic and protective in mice, either administered as a peptide alone formulated with Freund's adjuvant in B10.BR (H2 k ) mice 14 or conjugated to Diphtheria Toxoid (DT) and formulated on an aluminum phosphate adjuvant. 15,16 Here we describe conjugation of J8 to an alternate protein carrier, CRM197, a non-toxic analog of DT which has been used as the basis for multiple bacterial polysaccharide conjugate vaccines.…”

Section: Immunogenicity In Mice and Non-human Primates Of The Group Amentioning

confidence: 99%

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

Caro-Aguilar

Ottinger

Hepler

et al. 2013

Human Vaccines & Immunotherapeutics

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Towards a vaccine for rheumatic fever: identification of a conserved target epitope on M protein of group A streptococci

Cited by 89 publications

References 24 publications

A Synthetic M Protein Peptide Synergizes with a CXC Chemokine Protease To Induce Vaccine-Mediated Protection against Virulent Streptococcal Pyoderma and Bacteremia

A Synthetic M Protein Peptide Synergizes with a CXC Chemokine Protease To Induce Vaccine-Mediated Protection against Virulent Streptococcal Pyoderma and Bacteremia

A Lipid Core Peptide Construct Containing a Conserved Region Determinant of the Group A Streptococcal M Protein Elicits Heterologous Opsonic Antibodies

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

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