Immunogenicity Assessment of Different Segments and Domains of Group A Streptococcal C5a Peptidase and Their Application Potential as Carrier Protein for Glycoconjugate Vaccine Development

Wang, Guirong; Zhao, Jielin; Zhao, Yawen; Wang, Subo; Feng, Shaojie; Gu, Guofeng

doi:10.3390/vaccines9020139

Cited by 5 publications

(3 citation statements)

References 53 publications

(78 reference statements)

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“…From this, either a monovalent or bivalent (combining two target antigens) approach is used to target specific pathogens ( Table 3 ). Wang et al targeted S. pyogenes (Group A Streptococcus , GAS) cell wall oligosaccharides (GAC) conjugated to the streptococcal C5a peptidase carrier as a bivalent conjugate vaccine [ 82 , 83 ]. Furthermore, Kapoor et al also target the GAC oligosaccharides from GAS.…”

Section: Conjugate Vaccine Carriersmentioning

confidence: 99%

Carriers and Antigens: New Developments in Glycoconjugate Vaccines

2023

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Glycoconjugate vaccines have proven their worth in the protection and prevention of infectious diseases. The introduction of the Haemophilus influenzae type b vaccine is the prime example, followed by other glycoconjugate vaccines. Glycoconjugate vaccines consist of two components: the carrier protein and the carbohydrate antigen. Current carrier proteins are tetanus toxoid, diphtheria toxoid, CRM197, Haemophilus protein D and the outer membrane protein complex of serogroup B meningococcus. Carbohydrate antigens have been produced mainly by extraction and purification from the original host. However, current efforts show great advances in the development of synthetically produced oligosaccharides and bioconjugation. This review evaluates the advances of glycoconjugate vaccines in the last five years. We focus on developments regarding both new carriers and antigens. Innovative developments regarding carriers are outer membrane vesicles, glycoengineered proteins, new carrier proteins, virus-like particles, protein nanocages and peptides. With regard to conjugated antigens, we describe recent developments in the field of antimicrobial resistance (AMR) and ESKAPE pathogens.

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Section: Conjugate Vaccine Carriersmentioning

confidence: 99%

Carriers and Antigens: New Developments in Glycoconjugate Vaccines

2023

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“…In addition to its virulence characteristic, research on ScpA also focused on its ability to target C5a as an immune modulatory enzyme and as a potential target for vaccine development. − Other recombinant enzymes expressed in bacteria, similar to ScpA, are being explored as potential treatments for many pathologies and conditions. Improvements around monitoring activation of patients’ immune systems as well as the use of encapsulated delivery mechanisms are being developed to mitigate adverse anti-enzyme immune responses. , Functionally, ScpA was characterized to be a highly specific protease and cleaves C5a between H67 and K68. , The crystal structure of ScpA and its interactions with C5a highlighted key structural features on the activity and ability to cleave C5a. , Overall, ScpA is classified as a multi-domain protein with an N-terminal signal peptide, a propeptide, a catalytic domain, three Fn domains, and C-terminal membrane-associated domains .…”

Section: Introductionmentioning

confidence: 99%

Impact of Propeptide Cleavage on the Stability and Activity of a Streptococcal Immunomodulatory C5a Peptidase for Biopharmaceutical Development

et al. 2023

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Posttranslational modifications of proteins can impact their therapeutic efficacy, stability, and potential for pharmaceutical development. The Group AStreptococcus pyogenesC5a peptidase (ScpA) is a multi-domain protein composed of an N-terminal signal peptide, a catalytic domain (including propeptide), three fibronectin domains, and cell membrane-associated domains. It is one of several proteins produced by Group AS. pyogenesknown to cleave components of the human complement system. After signal peptide removal, ScpA undergoes autoproteolysis and cleaves its propeptide for full maturation. The exact location and mechanism of the propeptide cleavage, and the impact of this cleavage on stability and activity, are not clearly understood, and the exact primary sequence of the final enzyme is not known. A form of ScpA with no autoproteolysis fragments of propeptide present may be more desirable for pharmaceutical development from a regulatory and a biocompatibility in the body perspective. The current study describes an in-depth structural and functional characterization of propeptide truncated variants of ScpA expressed inEscherichia colicells. All three purified ScpA variants, ScpA, 79ΔPro, and 92ΔPro, starting with N32, D79, and A92 positions, respectively, showed similar activity against C5a, which suggests a propeptide-independent activity profile of ScpA. CE-SDS and MALDI top-down sequencing analyses highlight a time-dependent propeptide autoproteolysis of ScpA at 37 °C with a distinct end point at A92 and/or D93. In comparison, all three variants of ScpA exhibit similar stability, melting temperatures, and secondary structure orientation. In summary, this work not only highlights propeptide localization but also provides a strategy to recombinantly produce a final mature and active form of ScpA without any propeptide-related fragments.

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“…However, conjugation of GAC negatively impacted the anti-protein responses. In addition, fragments of Group A streptococcal C5a peptidase, another highly conserved surface virulence factor, have been proposed as carrier proteins for a glycoconjugate vaccine against GAS [ 21 ].…”

Section: Introductionmentioning

confidence: 99%

GMMA as an Alternative Carrier for a Glycoconjugate Vaccine against Group A Streptococcus

et al. 2022

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Group A Streptococcus (GAS) causes about 500,000 annual deaths globally, and no vaccines are currently available. The Group A Carbohydrate (GAC), conserved across all GAS serotypes, conjugated to an appropriate carrier protein, represents a promising vaccine candidate. Here, we explored the possibility to use Generalized Modules for Membrane Antigens (GMMA) as an alternative carrier system for GAC, exploiting their intrinsic adjuvant properties. Immunogenicity of GAC-GMMA conjugate was evaluated in different animal species in comparison to GAC-CRM197; and the two conjugates were also compared from a techno-economic point of view. GMMA proved to be a good alternative carrier for GAC, resulting in a higher immune response compared to CRM197 in different mice strains, as verified by ELISA and FACS analyses. Differently from CRM197, GMMA induced significant levels of anti-GAC IgG titers in mice also in the absence of Alhydrogel. In rabbits, a difference in the immune response could not be appreciated; however, antibodies from GAC-GMMA-immunized animals showed higher affinity toward purified GAC antigen compared to those elicited by GAC-CRM197. In addition, the GAC-GMMA production process proved to be more cost-effective, making this conjugate particularly attractive for low- and middle-income countries, where this pathogen has a huge burden.

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Immunogenicity Assessment of Different Segments and Domains of Group A Streptococcal C5a Peptidase and Their Application Potential as Carrier Protein for Glycoconjugate Vaccine Development

Cited by 5 publications

References 53 publications

Carriers and Antigens: New Developments in Glycoconjugate Vaccines

Carriers and Antigens: New Developments in Glycoconjugate Vaccines

Impact of Propeptide Cleavage on the Stability and Activity of a Streptococcal Immunomodulatory C5a Peptidase for Biopharmaceutical Development

GMMA as an Alternative Carrier for a Glycoconjugate Vaccine against Group A Streptococcus

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