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

Caro-Aguilar, Ivette; Ottinger, Elizabeth A.; Hepler, Robert; Nahas, Deborah D.; Wu, Chengwei; Good, Michael F.; Batzloff, Michael R.; Joyce, Joseph G.; Heinrichs, Jon H.; Skinner, Julie M.

doi:10.4161/hv.23224

Cited by 17 publications

(13 citation statements)

References 33 publications

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“…The most studied antigen is the surface M protein where both the variable N-terminal and its conserved C-terminal region have been proposed as vaccine candidates 3 4 5 6 . However, the presence of more than 220 different emm types 7 and the extensive amount of evidence that immune responses against the M protein are associated with development of post-strep sequelae 8 9 have made the investigation of conserved non-M protein antigens attractive.…”

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confidence: 99%

Identifying protective Streptococcus pyogenes vaccine antigens recognized by both B and T cells in human adults and children

Mortensen

Nissen

Fredslund

et al. 2016

Sci Rep

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No commercial vaccine exists against Group A streptococci (GAS; Streptococcus pyogenes) and only little is known about anti-GAS protective immunity. In our effort to discover new protective vaccine candidates, we selected 21 antigens based on an in silico evaluation. These were all well-conserved among different GAS strains, upregulated in host-pathogen interaction studies, and predicted to be extracellular or associated with the surface of the bacteria. The antigens were tested for both antibody recognition and T cell responses in human adults and children. The antigenicity of a selected group of antigens was further validated using a high-density peptide array technology that also identified the linear epitopes. Based on immunological recognition, four targets were selected and tested for protective capabilities in an experimental GAS infection model in mice. Shown for the first time, three of these targets (spy0469, spy1228 and spy1801) conferred significant protection whereas one (spy1643) did not.

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confidence: 99%

Identifying protective Streptococcus pyogenes vaccine antigens recognized by both B and T cells in human adults and children

Mortensen

Nissen

Fredslund

et al. 2016

Sci Rep

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“…Each year millions of people are infected, and it is estimated that GAS account for .500,000 deaths worldwide, mostly from invasive infections and complications following GAS infections such as rheumatic fever and rheumatic heart disease (2). Despite decades of research, there are no licensed vaccines against GAS, but vaccine candidates are currently under clinical (3)(4)(5) and preclinical investigation [reviewed in (6)]. …”

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confidence: 99%

Adaptive Immunity against Streptococcus pyogenes in Adults Involves Increased IFN-γ and IgG3 Responses Compared with Children

Mortensen

Nissen

Blauenfeldt

et al. 2015

The Journal of Immunology

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Each year, millions of people are infected with Streptococcus pyogenes, leading to an estimated 500,000 annual deaths worldwide. For unknown reasons, school-aged children have substantially higher infection rates than adults. The goal for this study was to provide, to our knowledge, the first detailed characterization of the human adaptive immune response against S. pyogenes in both children and adults. We report that all adults in our study, as well as most children, showed immunity against the two conserved group A streptococci (GAS) Ags, streptococcal C5a peptidase and immunogenic secreted protein. The response primarily consisted of three subsets of Th1 T cells, in which the TNF-α+ and IL-2+TNF-α+ subsets were most frequent. Humoral immunity was dominated by IgG1 and IgG3, whereas the Th2-associated IgG4 isotype was only detected at very low amounts. IgG3 levels correlated significantly with IFN-γ, but not with IL-5, IL-13, IL-17, or TNF-α. Interestingly, children showed a similar pattern of Ag-specific cytokine release, but displayed significantly lower levels of IgG3 and IFN-γ compared with adults. Thus, human immune responses against S. pyogenes consist of a robust Th1 cellular memory response in combination with IgG1/IgG3-dominated humoral immunity that increase with age. The significance of these data regarding both the increased GAS infection rate in children and the development of protective GAS vaccines is discussed.

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“…The peptides were conjugated to a recombinant CRM197 carrier, 32 via a linker of aminohexanoic acid at the C-terminus, and glutamic acids (E or EEE) to balance pI as described previously. 33,34 Conjugation of peptides was confirmed by the shift of the molecular weight of CRM197 protein on SDS-PAGE (data not shown). In addition, vaccines were characterized by amino acid analysis for purity, peptide loading efficiency and peptide-conjugate concentration (Supplemental Table 1).…”

Section: Antigens and Vaccinesmentioning

confidence: 89%

Preclinical evaluations of peptide-conjugate vaccines targeting the antigenic domain-2 of glycoprotein B of human cytomegalovirus

Finnefrock

Freed

Tang

et al. 2016

Human Vaccines & Immunotherapeutics

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The Antigenic Domain 2 (AD-2) is a short region near the N-terminus of glycoprotein B of human cytomegalovirus (HCMV). AD-2 has been shown to contain linear epitopes that are targets for neutralizing monoclonal antibodies from human subjects with natural HCMV infection. However, AD-2 appears to be masked by the adjacent immunodominant AD-1 region. We assessed a serum panel from HCMV-seropositive individuals and found a wide range of antibody titers to AD-2; these did not correlate to serum neutralization. To expose potential epitopes in AD-2, we constructed a series of AD-2 peptide-conjugate vaccines. Mice were immunized 3 times and produced high and sustained antibody titers to AD-2 peptides, but neutralization was weak even after a single boost with whole HCMV virions. Rabbits were likewise immunized with AD-2 peptide vaccines, and produced a robust antibody response, but neutralization was inferior to a recombinant gB vaccine with an oil-in-water adjuvant. These results highlight the challenges of developing a peptide-based vaccine specific to the HCMV gB AD-2 region.

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

Cited by 17 publications

References 33 publications

Identifying protective Streptococcus pyogenes vaccine antigens recognized by both B and T cells in human adults and children

Identifying protective Streptococcus pyogenes vaccine antigens recognized by both B and T cells in human adults and children

Adaptive Immunity against Streptococcus pyogenes in Adults Involves Increased IFN-γ and IgG3 Responses Compared with Children

Preclinical evaluations of peptide-conjugate vaccines targeting the antigenic domain-2 of glycoprotein B of human cytomegalovirus

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