GMMA as an Alternative Carrier for a Glycoconjugate Vaccine against Group A Streptococcus
Abstract
:1. Introduction
2. Materials and Methods
2.1. Materials
2.2. GAC Glycoconjugates Synthesis and Characterization
2.2.1. GAC-CRM197 Conjugate
2.2.2. GAC-GMMA Conjugate
2.3. Formulation of Conjugates
2.4. Immunogenicity Studies in Mice and Rabbits
2.5. ELISA for Anti-GAC IgG Response in Mice
2.6. Luminex for Anti-GAC IgG Response in Rabbits
2.7. Flow Cytometry (FACS)
2.8. Antibody Affinity Measurements
2.9. Techno-Economic Analysis
2.10. Statistical Analysis
3. Results
3.1. Synthesis and Characterization of GAC-CRM197 and GAC-GMMA Conjugates
3.2. Immunogenicity in Mice and Rabbits of GAC-GMMA vs. GAC-CRM197 in the Presence of Alhydrogel
3.3. Immunogenicity Study in Mice of GAC-GMMA vs. GAC-CRM197 in Absence of Alhydrogel
3.4. Techno-Economic Analysis: GMMA vs. CRM197 as Carrier
4. Discussion
Supplementary Materials
Author Contributions
Funding
Institutional Review Board Statement
Data Availability Statement
Conflicts of Interest
References
- Ralph, A.P.; Carapetis, J.R. Group A Streptococcal Diseases and Their Global Burden. In Host-Pathogen Interactions in Streptococcal Diseases; Chhatwal, G.S., Ed.; Springer: Berlin/Heidelberg, Germany, 2013; pp. 1–27. [Google Scholar]
- Mitchell, T.J. The pathogenesis of streptococcal infections: From Tooth decay to meningitis. Nat. Rev. Microbiol. 2003, 1, 219–230. [Google Scholar] [CrossRef] [PubMed]
- Carapetis, J.R.; Steer, A.C.; Mulholland, E.K.; Weber, M. The global burden of group A streptococcal diseases. Lancet Infect. Dis. 2005, 5, 685–694. [Google Scholar] [CrossRef]
- Marijon, E.; Mirabel, M.; Celermajer, D.S.; Jouven, X. Rheumatic heart disease. Lancet 2012, 379, 953–964. [Google Scholar] [CrossRef]
- Watkins, D.A.; Johnson, C.O.; Colquhoun, S.M.; Karthikeyan, G.; Beaton, A.; Bukhman, G.; Forouzanfar, M.H.; Longenecker, C.T.; Mayosi, B.M.; Mensah, G.A.; et al. Global, Regional, and National Burden of Rheumatic Heart Disease, 1990–2015. N. Engl. J. Med. 2017, 377, 713–722. [Google Scholar] [CrossRef]
- Dooling, K.L.; Shapiro, D.J.; Van Beneden, C.; Hersh, A.L.; Hicks, L.A. Overprescribing and Inappropriate Antibiotic Selection for Children With Pharyngitis in the United States, 1997–2010. JAMA Pediatr. 2014, 168, 1073–1074. [Google Scholar] [CrossRef] [Green Version]
- Micoli, F.; Bagnoli, F.; Rappuoli, R.; Serruto, D. The role of vaccines in combatting antimicrobial resistance. Nat. Rev. Microbiol. 2021, 19, 287–302. [Google Scholar] [CrossRef]
- Sanderson-Smith, M.; De Oliveira, D.M.P.; Guglielmini, J.; McMillan, D.J.; Vu, T.; Holien, J.K.; Henningham, A.; Steer, A.C.; Bessen, D.E.; Dale, J.B.; et al. A Systematic and Functional Classification of Streptococcus pyogenes That Serves as a New Tool for Molecular Typing and Vaccine Development. J. Infect. Dis. 2014, 210, 1325–1338. [Google Scholar] [CrossRef]
- Steer, A.C.; Law, I.; Matatolu, L.; Beall, B.W.; Carapetis, J.R. Global emm type distribution of group A streptococci: Systematic review and implications for vaccine development. Lancet Infect. Dis. 2009, 9, 611–616. [Google Scholar] [CrossRef]
- McCarty, M. The lysis of group A hemolytic streptococci by extracellular enzymes of Streptomyces albus. II. Nature of the cellular substrate attacked by the lytic enzymes. J. Exp. Med. 1952, 96, 569–580. [Google Scholar] [CrossRef]
- Cunningham, M.W. Pathogenesis of Group A Streptococcal Infections. Clin. Microbiol. Rev. 2000, 13, 470–511. [Google Scholar] [CrossRef]
- Van Sorge, N.M.; Cole, J.N.; Kuipers, K.; Henningham, A.; Aziz, R.K.; Kasirer-Friede, A.; Lin, L.; Berends, E.T.M.; Davies, M.R.; Dougan, G.; et al. The Classical Lancefield Antigen of Group A Streptococcus Is a Virulence Determinant with Implications for Vaccine Design. Cell Host Microbe 2014, 15, 729–740. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Sabharwal, H.; Michon, F.; Nelson, D.; Dong, W.; Fuchs, K.; Manjarrez, R.C.; Sarkar, A.; Uitz, C.; Viteri-Jackson, A.; Suarez, R.S.R.; et al. Group A Streptococcus (GAS) Carbohydrate as an Immunogen for Protection against GAS Infection. J. Infect. Dis. 2006, 193, 129–135. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Salvadori, L.G.; Blake, M.S.; McCarty, M.; Tai, J.Y.; Zabriskie, J.B. Group A Streptococcus-Liposome Elisa Antibody Titers To Group A Polysaccharide And Opsonophagocytic Capabilities Of The Antibodies. J. Infect. Dis. 1995, 171, 593–600. [Google Scholar] [CrossRef] [PubMed]
- Rappuoli, R. Glycoconjugate vaccines: Principles and mechanisms. Sci. Transl. Med. 2018, 10, eaat4615. [Google Scholar] [CrossRef] [PubMed]
- Di Benedetto, R.; Mancini, F.; Carducci, M.; Gasperini, G.; Moriel, D.G.; Saul, A.; Necchi, F.; Rappuoli, R.; Micoli, F. Rational Design of a Glycoconjugate Vaccine against Group A Streptococcus. Int. J. Mol. Sci. 2020, 21, 8558. [Google Scholar] [CrossRef]
- Kabanova, A.; Margarit, I.; Berti, F.; Romano, M.R.; Grandi, G.; Bensi, G.; Chiarot, E.; Proietti, D.; Swennen, E.; Cappelletti, E.; et al. Evaluation of a Group A Streptococcus synthetic oligosaccharide as vaccine candidate. Vaccine 2010, 29, 104–114. [Google Scholar] [CrossRef]
- McCluskie, M.J.; Evans, D.M.; Zhang, N.; Benoit, M.; McElhiney, S.P.; Unnithan, M.; DeMarco, S.C.; Clay, B.; Huber, C.; Deora, A.; et al. The effect of preexisting anti-carrier immunity on subsequent responses to CRM197 or Qb-VLP conjugate vaccines. Immunopharmacol. Immunotoxicol. 2016, 38, 184–196. [Google Scholar] [CrossRef]
- Micoli, F.; Costantino, P.; Adamo, R. Potential targets for next generation antimicrobial glycoconjugate vaccines. FEMS Microbiol. Rev. 2018, 42, 388–423. [Google Scholar] [CrossRef] [Green Version]
- Bensi, G.; Mora, M.; Tuscano, G.; Biagini, M.; Chiarot, E.; Bombaci, M.; Capo, S.; Falugi, F.; Manetti, A.G.O.; Donato, P.; et al. Multi High-Throughput Approach for Highly Selective Identification of Vaccine Candidates: The Group A Streptococcus Case. Mol. Cell. Proteom. 2012, 11, M111.015693. [Google Scholar] [CrossRef] [Green Version]
- Wang, G.; Zhao, J.; Zhao, Y.; Wang, S.; Feng, S.; Gu, G. Immunogenicity Assessment of Different Segments and Domains of Group A Streptococcal C5a Peptidase and Their Application Potential as Carrier Protein for Glycoconjugate Vaccine Development. Vaccines 2021, 9, 139. [Google Scholar] [CrossRef]
- Furuyama, N.; Sircili, M.P. Outer Membrane Vesicles (OMVs) Produced by Gram-Negative Bacteria: Structure, Functions, Biogenesis, and Vaccine Application. BioMed. Res. Int. 2021, 2021, 1490732. [Google Scholar] [CrossRef] [PubMed]
- Tan, K.; Li, R.; Huang, X.; Liu, Q. Outer Membrane Vesicles: Current Status and Future Direction of These Novel Vaccine Adjuvants. Front. Microbiol. 2018, 9, 783. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- van der Pol, L.; Stork, M.; van der Ley, P. Outer membrane vesicles as platform vaccine technology. Biotechnol. J. 2015, 10, 1689–1706. [Google Scholar] [CrossRef] [PubMed]
- Mancini, F.; Micoli, F.; Necchi, F.; Pizza, M.; Berlanda Scorza, F.; Rossi, O. GMMA-Based Vaccines: The Known and The Unknown. Front. Immunol. 2021, 12, 715393. [Google Scholar] [CrossRef]
- Kis, Z.; Shattock, R.; Shah, N.; Kontoravdi, C. Emerging Technologies for Low-Cost, Rapid Vaccine Manufacture. Biotechnol. J. 2019, 14, 1970055. [Google Scholar] [CrossRef] [Green Version]
- Micoli, F.; Rondini, S.; Alfini, R.; Lanzilao, L.; Necchi, F.; Negrea, A.; Rossi, O.; Brandt, C.; Clare, S.; Mastroeni, P.; et al. Comparative immunogenicity and efficacy of equivalent outer membrane vesicle and glycoconjugate vaccines against nontyphoidal Salmonella. Proc. Natl. Acad. Sci. USA 2018, 115, 10428–10433. [Google Scholar] [CrossRef] [Green Version]
- Micoli, F.; Alfini, R.; Di Benedetto, R.; Necchi, F.; Schiavo, F.; Mancini, F.; Carducci, M.; Palmieri, E.; Balocchi, C.; Gasperini, G.; et al. GMMA Is a Versatile Platform to Design Effective Multivalent Combination Vaccines. Vaccines 2020, 8, 540. [Google Scholar] [CrossRef]
- Micoli, F.; Adamo, R.; Costantino, P. Protein Carriers for Glycoconjugate Vaccines: History, Selection Criteria, Characterization and New Trends. Molecules 2018, 23, 1451. [Google Scholar] [CrossRef] [Green Version]
- Wang, S.; Zhao, Y.; Wang, G.; Feng, S.; Guo, Z.; Gu, G. Group A Streptococcus Cell Wall Oligosaccharide-Streptococcal C5a Peptidase Conjugates as Effective Antibacterial Vaccines. ACS Infect. Dis. 2020, 6, 281–290. [Google Scholar] [CrossRef]
- Pancholi, V.; Fischetti, V.A. Isolation and characterization of the cell-associated region of group A streptococcal M6 protein. J. Bacteriol. 1988, 170, 2618–2624. [Google Scholar] [CrossRef] [Green Version]
- Datsenko, K.A.; Wanner, B.L. One-step inactivation of chromosomal genes in Escherichia coli K-12 using PCR products. Proc. Natl. Acad. Sci. USA 2000, 97, 6640–6645. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Micoli, F.; Alfini, R.; Giannelli, C. Methods for Assessment of OMV/GMMA Quality and Stability. In Bacterial Vaccines: Methods and Protocols; Bidmos, F., Bossé, J., Langford, P., Eds.; Springer: New York, NY, USA, 2022; pp. 227–279. [Google Scholar]
- Pitirollo, O.; Micoli, F.; Necchi, F.; Mancini, F.; Carducci, M.; Adamo, R.; Evangelisti, C.; Morelli, L.; Polito, L.; Lay, L. Gold nanoparticles morphology does not affect the multivalent presentation and antibody recognition of Group A Streptococcus synthetic oligorhamnans. Bioorganic Chem. 2020, 99, 103815. [Google Scholar] [CrossRef] [PubMed]
- Lei, Q.P.; Lamb, D.H.; Heller, R.; Pietrobon, P. Quantitation of low level unconjugated polysaccharide in tetanus toxoid-conjugate vaccine by HPAEC/PAD following rapid separation by deoxycholate/HCl. J. Pharm. Biomed. Anal. 2000, 21, 1087–1091. [Google Scholar] [CrossRef]
- Micoli, F.; Giannelli, C.; Di Benedetto, R. O-Antigen Extraction, Purification, and Chemical Conjugation to a Carrier Protein. In Vaccine Delivery Technology: Methods and Protocols; Pfeifer, B.A., Hill, A., Eds.; Springer: New York, NY, USA, 2021; pp. 267–304. [Google Scholar]
- De Benedetto, G.; Alfini, R.; Cescutti, P.; Caboni, M.; Lanzilao, L.; Necchi, F.; Saul, A.; MacLennan, C.A.; Rondini, S.; Micoli, F. Characterization of O-antigen delivered by Generalized Modules for Membrane Antigens (GMMA) vaccine candidates against nontyphoidal Salmonella. Vaccine 2017, 35, 419–426. [Google Scholar] [CrossRef]
- Micoli, F.; Ravenscroft, N.; Cescutti, P.; Stefanetti, G.; Londero, S.; Rondini, S.; MacLennan, C.A. Structural analysis of O-polysaccharide chains extracted from different Salmonella Typhimurium strains. Carbohydr. Res. 2014, 385, 1–8. [Google Scholar] [CrossRef]
- De Benedetto, G.; Cescutti, P.; Giannelli, C.; Rizzo, R.; Micoli, F. Multiple Techniques for Size Determination of Generalized Modules for Membrane Antigens from Salmonella typhimurium and Salmonella enteritidis. ACS Omega 2017, 2, 8282–8289. [Google Scholar] [CrossRef]
- Myzithras, M.; Bigwarfe, T.; Waltz, E.; Li, H.; Ahlberg, J.; Rybina, I.; Low, S.; Kenny, C.H.; Miglietta, J.; Kroe-Barrett, R. Optimizing NBE PK/PD assays using the Gyrolab Affinity Software; conveniently within the bioanalyst’s existing workflow. Bioanalysis 2018, 10, 397–406. [Google Scholar] [CrossRef] [PubMed]
- Goffin, P.; Dewerchin, M.; De Rop, P.; Blais, N.; Dehottay, P. High-yield production of recombinant CRM197, a non-toxic mutant of diphtheria toxin, in the periplasm of Escherichia coli. Biotechnol. J. 2017, 12, 1700168. [Google Scholar] [CrossRef]
- Carapetis, J.R. Rheumatic Heart Disease in Asia. Circulation 2008, 118, 2748–2753. [Google Scholar] [CrossRef] [Green Version]
- Zühlke, L.; Engel, M.E.; Karthikeyan, G.; Rangarajan, S.; Mackie, P.; Cupido, B.; Mauff, K.; Islam, S.; Joachim, A.; Daniels, R.; et al. Characteristics, complications, and gaps in evidence-based interventions in rheumatic heart disease: The Global Rheumatic Heart Disease Registry (the REMEDY study). Eur. Heart J. 2015, 36, 1115–1122. [Google Scholar] [CrossRef] [Green Version]
- Sims Sanyahumbi, A.; Colquhoun, S.; Wyber, R.; Carapetis, J.R. Global Disease Burden of Group A Streptococcus. In Streptococcus pyogenes: Basic Biology to Clinical Manifestations; Ferretti, J.J., Stevens, D.L., Fischetti, V.A., Eds.; University of Oklahoma Health Sciences Center: Oklahoma City, OK, USA, 2016. [Google Scholar]
- Vekemans, J.; Gouvea-Reis, F.; Kim, J.H.; Excler, J.-L.; Smeesters, P.R.; O’Brien, K.L.; Van Beneden, C.A.; Steer, A.C.; Carapetis, J.R.; Kaslow, D.C. The Path to Group A Streptococcus Vaccines: World Health Organization Research and Development Technology Roadmap and Preferred Product Characteristics. Clin. Infect. Dis. 2019, 69, 877–883. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Dale, J.B.; Penfound, T.A.; Chiang, E.Y.; Walton, W.J. New 30-valent M protein-based vaccine evokes cross-opsonic antibodies against non-vaccine serotypes of group A streptococci. Vaccine 2011, 29, 8175–8178. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Postol, E.; Alencar, R.; Higa, F.T.; Freschi de Barros, S.; Demarchi, L.M.F.; Kalil, J.; Guilherme, L. StreptInCor: A Candidate Vaccine Epitope against S. pyogenes Infections Induces Protection in Outbred Mice. PLoS ONE 2013, 8, e60969. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Sekuloski, S.; Batzloff, M.R.; Griffin, P.; Parsonage, W.; Elliott, S.; Hartas, J.; O’Rourke, P.; Marquart, L.; Pandey, M.; Rubin, F.A.; et al. Evaluation of safety and immunogenicity of a group A Streptococcus vaccine candidate (MJ8VAX) in a randomized clinical trial. PLoS ONE 2018, 13, e0198658. [Google Scholar] [CrossRef]
- Steer, A.C.; Carapetis, J.R.; Dale, J.B.; Fraser, J.D.; Good, M.F.; Guilherme, L.; Moreland, N.J.; Mulholland, E.K.; Schodel, F.; Smeesters, P.R. Status of research and development of vaccines for Streptococcus pyogenes. Vaccine 2016, 34, 2953–2958. [Google Scholar] [CrossRef]
- Avci, F.; Berti, F.; Dull, P.; Hennessey, J.; Pavliak, V.; Prasad, A.K.; Vann, W.; Wacker, M.; Marcq, O.; Papasianm, C.J. Glycoconjugates: What It Would Take To Master These Well-Known yet Little-Understood Immunogens for Vaccine Development. mSphere 2019, 4, e00520-19. [Google Scholar] [CrossRef] [Green Version]
- Dagan, R.; Poolman, J.; Siegrist, C.-A. Glycoconjugate vaccines and immune interference: A review. Vaccine 2010, 28, 5513–5523. [Google Scholar] [CrossRef]
- Micoli, F.; Alfini, R.; Di Benedetto, R.; Necchi, F.; Schiavo, F.; Mancini, F.; Carducci, M.; Oldrini, D.; Pitirollo, O.; Gasperini, G.; et al. Generalized Modules for Membrane Antigens as Carrier for Polysaccharides: Impact of Sugar Length, Density, and Attachment Site on the Immune Response Elicited in Animal Models. Front. Immunol. 2021, 12, 719315. [Google Scholar] [CrossRef]
- Mancini, F.; Rossi, O.; Necchi, F.; Micoli, F. OMV Vaccines and the Role of TLR Agonists in Immune Response. Int. J. Mol. Sci. 2020, 21, 4416. [Google Scholar] [CrossRef]
- McKee, A.S.; Munks, M.W.; Marrack, P. How Do Adjuvants Work? Important Considerations for New Generation Adjuvants. Immunity 2007, 27, 687–690. [Google Scholar] [CrossRef] [Green Version]
- Marrack, P.; McKee, A.S.; Munks, M.W. Towards an understanding of the adjuvant action of aluminium. Nat. Rev. Immunol. 2009, 9, 287–293. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- HogenEsch, H. Mechanism of Immunopotentiation and Safety of Aluminum Adjuvants. Front. Immunol. 2013, 3, 406. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Xu, L.; Li, Z.; Su, Z.; Yang, Y.; Ma, G.; Yu, R.; Zhang, S. Development of meningococcal polysaccharide conjugate vaccine that can elicit long-lasting and strong cellular immune response with hepatitis B core antigen virus-like particles as a novel carrier protein. Vaccine 2019, 37, 956–964. [Google Scholar] [CrossRef]
- Roose, K.; Baets, S.D.; Schepens, B.; Saelens, X. Hepatitis B core–based virus–like particles to present heterologous epitopes. Expert Rev. Vaccines 2013, 12, 183–198. [Google Scholar] [CrossRef] [PubMed]
- Suan, D.; Sundling, C.; Brink, R. Plasma cell and memory B cell differentiation from the germinal center. Curr. Opin. Immunol. 2017, 45, 97–102. [Google Scholar] [CrossRef]
- Yuseff, M.-I.; Pierobon, P.; Reversat, A.; Lennon-Duménil, A.-M. How B cells capture, process and present antigens: A crucial role for cell polarity. Nat. Rev. Immunol. 2013, 13, 475–486. [Google Scholar] [CrossRef]
- Micoli, F.; MacLennan, C.A. Outer membrane vesicle vaccines. Semin. Immunol. 2020, 50, 101433. [Google Scholar] [CrossRef]
- van der Ley, P.A.; Zariri, A.; van Riet, E.; Oosterhoff, D.; Kruiswijk, C.P. An Intranasal OMV-Based Vaccine Induces High Mucosal and Systemic Protecting Immunity Against a SARS-CoV-2 Infection. Front. Immunol. 2021, 12, 781280. [Google Scholar] [CrossRef]
Group | Average Relative Concentration in ng/mL + SD | IgG2a:IgG1 Ratio | |
---|---|---|---|
IgG1 | IgG2a | ||
GAC-CRM197 Alhydrogel | 3017 ± 2670 | 20 ± 36 | 0.0083 |
GAC-GMMA | 3049 ± 4941 | 1101 ± 1352 | 1.3886 |
Significance between groups | p > 0.05 | p < 0.01 | p < 0.01 |
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Palmieri, E.; Kis, Z.; Ozanne, J.; Di Benedetto, R.; Ricchetti, B.; Massai, L.; Carducci, M.; Oldrini, D.; Gasperini, G.; Aruta, M.G.; et al. GMMA as an Alternative Carrier for a Glycoconjugate Vaccine against Group A Streptococcus. Vaccines 2022, 10, 1034. https://doi.org/10.3390/vaccines10071034
Palmieri E, Kis Z, Ozanne J, Di Benedetto R, Ricchetti B, Massai L, Carducci M, Oldrini D, Gasperini G, Aruta MG, et al. GMMA as an Alternative Carrier for a Glycoconjugate Vaccine against Group A Streptococcus. Vaccines. 2022; 10(7):1034. https://doi.org/10.3390/vaccines10071034
Chicago/Turabian StylePalmieri, Elena, Zoltán Kis, James Ozanne, Roberta Di Benedetto, Beatrice Ricchetti, Luisa Massai, Martina Carducci, Davide Oldrini, Gianmarco Gasperini, Maria Grazia Aruta, and et al. 2022. "GMMA as an Alternative Carrier for a Glycoconjugate Vaccine against Group A Streptococcus" Vaccines 10, no. 7: 1034. https://doi.org/10.3390/vaccines10071034
APA StylePalmieri, E., Kis, Z., Ozanne, J., Di Benedetto, R., Ricchetti, B., Massai, L., Carducci, M., Oldrini, D., Gasperini, G., Aruta, M. G., Rossi, O., Kontoravdi, C., Shah, N., Mawas, F., & Micoli, F. (2022). GMMA as an Alternative Carrier for a Glycoconjugate Vaccine against Group A Streptococcus. Vaccines, 10(7), 1034. https://doi.org/10.3390/vaccines10071034