Development of a Monocyte Activation Test as an Alternative to the Rabbit Pyrogen Test for Mono- and Multi-Component Shigella GMMA-Based Vaccines
Abstract
:1. Introduction
2. Materials and Methods
2.1. Preparation of GMMA Drug Substance
2.2. Formulation of the GMMA Drug Product
2.3. Preparation of Peripheral Blood Mononuclear Cells
2.4. Monocyte Activation Test
2.5. Data Analysis
3. Results
3.1. MAT Method A and B Cannot Be Used to Test the Shigella GMMA Vaccine
3.2. The GMMA Drug Product Demonstrates a Decrease in IL-6 Release over Time
3.3. IL-6 Response to Shigella Drug Substance Is Comparable to Drug Product and Can Be Proposed as a Reference for MAT Using Method C of Ph. Eur. Chapter 2.6.30
3.4. Shigella GMMA Drug Substance Is More Stable Than the GMMA Drug Product
4. Discussion
Supplementary Materials
Author Contributions
Funding
Institutional Review Board Statement
Informed Consent Statement
Data Availability Statement
Acknowledgments
Conflicts of Interest
Disclaimer
References
- Kotloff, K.L.; Riddle, M.S.; Platts-Mills, J.A.; Pavlinac, P.; Zaidi, A.K.M. Shigellosis. Lancet 2018, 391, 801–812. [Google Scholar] [CrossRef]
- Khalil, I.; Troeger, C.; Blacker, B.F.; Rao, P.C.; Brown, A.; Atherly, D.; Brewer, T.G.; Engmann, C.M.; Houpt, E.R.; Kang, G.; et al. Morbidity and mortality due to shigella and enterotoxigenic Escherichia coli diarrhoea: The Global Burden of Disease Study 1990–2016. Lancet Infect. Dis. 2018, 18, 1229–1240. [Google Scholar] [CrossRef] [Green Version]
- WHO. Global priority list of antibiotic-resistant bacteria to guide research, discovery, and development of new antibiotics. Fecha de Consult. 2017, 21, 7. [Google Scholar]
- Giersing, B.K.; Vekemans, J.; Nava, S.; Kaslow, D.C.; Moorthy, V.; the WHO Product Development for Vaccines Advisory Committee. Report from the World Health Organization’s third Product Development for Vaccines Advisory Committee (PDVAC) meeting, Geneva, 8–10th June 2016. Vaccine 2019, 37, 7315–7327. [Google Scholar] [CrossRef]
- Maggiore, L.; Yu, L.; Omasits, U.; Rossi, O.; Dougan, G.; Thomson, N.R.; Saul, A.; Choudhary, J.; Gerke, C. Quantitative proteomic analysis of Shigella flexneri and Shigella sonnei Generalized Modules for Membrane Antigens (GMMA) reveals highly pure preparations. Int. J. Med Microbiol. 2016, 306, 99–108. [Google Scholar] [CrossRef] [PubMed] [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] [PubMed]
- Scorza, F.B.; Colucci, A.M.; Maggiore, L.; Sanzone, S.; Rossi, O.; Ferlenghi, I.; Pesce, I.; Caboni, M.; Norais, N.; Di Cioccio, V.; et al. High Yield Production Process for Shigella Outer Membrane Particles. PLoS ONE 2012, 7, e35616. [Google Scholar]
- Gerke, C.; Colucci, A.M.; Giannelli, C.; Sanzone, S.; Vitali, C.G.; Sollai, L.; Rossi, O.; Martin, L.B.; Auerbach, J.; Di Cioccio, V.; et al. Production of a Shigella sonnei Vaccine Based on Generalized Modules for Membrane Antigens (GMMA), 1790GAHB. PLoS ONE 2015, 10, e0134478. [Google Scholar] [CrossRef]
- Rossi, O.; Pesce, I.; Giannelli, C.; Aprea, S.; Caboni, M.; Citiulo, F.; Valentini, S.; Ferlenghi, I.; MacLennan, C.A.; D’Oro, U.; et al. Modulation of endotoxicity of Shigella generalized modules for membrane antigens (GMMA) by genetic lipid A modifications: Relative activation of TLR4 and TLR2 pathways in different mutants. J. Biol. Chem. 2014, 289, 24922–24935. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Obiero, C.W.; Ndiaye, A.G.W.; Sciré, A.S.; Kaunyangi, B.M.; Marchetti, E.; Gone, A.M.; Schütte, L.D.; Riccucci, D.; Auerbach, J.; Saul, A.; et al. A Phase 2a Randomized Study to Evaluate the Safety and Immunogenicity of the 1790GAHB Generalized Modules for Membrane Antigen Vaccine against Shigella sonnei Administered Intramuscularly to Adults from a Shigellosis-Endemic Country. Front. Immunol. 2017, 8, 1884. [Google Scholar] [CrossRef] [Green Version]
- Launay, O.; Lewis, D.J.; Anemona, A.; Loulergue, P.; Leahy, J.; Sciré, A.S.; Maugard, A.; Marchetti, E.; Zancan, S.; Huo, Z.; et al. Safety Profile and Immunologic Responses of a Novel Vaccine Against Shigella sonnei Administered Intramuscularly, Intradermally and Intranasally: Results From Two Parallel Randomized Phase 1 Clinical Studies in Healthy Adult Volunteers in Europe. EBioMedicine 2017, 22, 164–172. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- LLaunay, O.; Ndiaye, A.G.W.; Conti, V.; Loulergue, P.; Sciré, A.S.; Landre, A.M.; Ferruzzi, P.; Nedjaai, N.; Schütte, L.D.; Auerbach, J.; et al. Booster Vaccination With GVGH Shigella sonnei 1790GAHB GMMA Vaccine Compared to Single Vaccination in Unvaccinated Healthy European Adults: Results From a Phase 1 Clinical Trial. Front. Immunol. 2019, 10, 335. [Google Scholar] [CrossRef] [Green Version]
- 10.0, E.P. Chapter 2.6.8 Rabbit Pyrogen Test; 2019; Volume 10, Available online: https://www.edqm.eu/en/european-pharmacopoeia-ph-eur-10th-edition (accessed on 30 April 2021).
- 10.0, E.P. Chapter 2.6.14 Bacterial Endotoxins; 2019; Volume 10, Available online: https://www.edqm.eu/en/european-pharmacopoeia-ph-eur-10th-edition (accessed on 30 April 2021).
- 10.0, E.P. Chapter 2.6.30 Monocyte-Activation Test; 2019; Volume 10, Available online: https://www.edqm.eu/en/european-pharmacopoeia-ph-eur-10th-edition (accessed on 30 April 2021).
- Hartung, T. The human whole blood pyrogen test—Lessons learned in twenty years. ALTEX 2015, 32, 79–100. [Google Scholar] [CrossRef] [Green Version]
- Studholme, L.; Sutherland, J.; Desai, T.; Hockley, J.; Care, R.; Nordgren, I.K.; Vipond, C. Evaluation of the monocyte activation test for the safety testing of meningococcal B vaccine Bexsero: A collaborative study. Vaccine 2019, 37, 3761–3769. [Google Scholar] [CrossRef]
- Valentini, S.; Santoro, G.; Baffetta, F.; Franceschi, S.; Paludi, M.; Brandini, E.; Gherardini, L.; Serruto, D.; Capecchi, B. Monocyte-activation test to reliably measure the pyrogenic content of a vaccine: An in vitro pyrogen test to overcome in vivo limitations. Vaccine 2019, 37, 3754–3760. [Google Scholar] [CrossRef]
- Rossi, O.; Citiulo, F.; Mancini, F. Outer membrane vesicles: Moving within the intricate labyrinth of assays that can predict risks of reactogenicity in humans. Hum. Vaccines Immunother. 2021, 17, 601–613. [Google Scholar] [CrossRef]
- Vaure, C.; Liu, Y. A Comparative Review of Toll-Like Receptor 4 Expression and Functionality in Different Animal Species. Front. Immunol. 2014, 5, 316. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Piehler, M.; Roeder, R.; Blessing, S.; Reich, J. Comparison of LAL and rFC Assays—Participation in a Proficiency Test Program between 2014 and 2019. Microorganisms 2020, 8, 41. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- 10.3, E.P. Chapter 2.6.32 Test for Bacterial Endotoxins Using Recombinant Factor C; Supplement 10.3; 2020; Volume 10, p. 3. Available online: https://www.edqm.eu/en/news/european-pharmacopoeia-supplement-103-now-available (accessed on 30 April 2021).
- PPoole, S. Detection of pyrogen by cytokine release. Lancet 1988, 331, 130. [Google Scholar] [CrossRef]
- Duff, G.W.; Atkins, E. The detection of endotoxin by in vitro production of endogenous pyrogen: Comparison with limulus amebocyte lysate gelation. J. Immunol. Methods 1982, 52, 323–331. [Google Scholar] [CrossRef]
- Flecknell, P. Replacement, reduction and refinement. ALTEX 2002, 19, 73–78. [Google Scholar] [PubMed]
- Palmieri, E.; Arato, V.; Oldrini, D.; Ricchetti, B.; Aruta, M.; Pansegrau, W.; Marchi, S.; Giusti, F.; Ferlenghi, I.; Rossi, O.; et al. Stability of Outer Membrane Vesicles-Based Vaccines, Identifying the Most Appropriate Methods to Detect Changes in Vaccine Potency. Vaccines 2021, 9, 229. [Google Scholar] [CrossRef]
- Mancini, F.; Gasperini, G.; Rossi, O.; Aruta, M.G.; Raso, M.M.; Alfini, R.; Biagini, M.; Necchi, F.; Micoli, F. Dissecting the contribution of O-Antigen and proteins to the immunogenicity of Shigella sonnei generalized modules for membrane antigens (GMMA). Sci. Rep. 2021, 11, 1–10. [Google Scholar] [CrossRef]
- Hoffmann, S.; Peterbauer, A.; Schindler, S.; Fennrich, S.; Poole, S.; Mistry, Y.; Montag-Lessing, T.; Spreitzer, I.; Löschner, B.; van Aalderen, M.; et al. International validation of novel pyrogen tests based on human monocytoid cells. J. Immunol. Methods 2005, 298, 161–173. [Google Scholar] [CrossRef]
- Nordgren, I.K. Leukoreduction system chambers provide a valuable source of functional monocytes for the monocyte activation test by comparison with internationally validated methods. J. Immunol. Methods 2016, 428, 42–49. [Google Scholar] [CrossRef]
- Findlay, L.; Eastwood, D.; Stebbings, R.; Sharp, G.; Mistry, Y.; Ball, C.; Hood, J.; Thorpe, R.; Poole, S. Improved in vitro methods to predict the in vivo toxicity in man of therapeutic monoclonal antibodies including TGN1412. J. Immunol. Methods 2010, 352, 1–12. [Google Scholar] [CrossRef] [PubMed]
- Micoli, F.; MacLennan, C.A. Outer membrane vesicle vaccines. Semin. Immunol. 2020, 50, 101433. [Google Scholar] [CrossRef] [PubMed]
- Vipond, C.; Sutherland, J.; Nordgren, K.; Kemp, G.; Heath, A.; Care, R.; Studholme, L. Development and validation of a monocyte activation test for the control/safety testing of an OMV-based meningococcal B vaccine. Vaccine 2019, 37, 3747–3753. [Google Scholar] [CrossRef]
- Backer, M.W.A.M.-D. Performance of monocyte activation test supplemented with human serum compared to fetal bovine serum. ALTEX 2020. [Google Scholar] [CrossRef]
- Solati, S.; Aarden, L.; Zeerleder, S.; Wouters, D. An improved monocyte activation test using cryopreserved pooled human mononuclear cells. Innate Immun. 2015, 21, 677–684. [Google Scholar] [CrossRef] [PubMed]
- Norimatsu, M.; Ogikubo, Y.; Aoki, A.; Takahashi, T.; Watanabe, G.; Taya, K.; Sasamoto, S.; Tsuchiya, M.; Tamura, Y. Effects of aluminum adjuvant on systemic reactions of lipopolysaccharides in swine. Vaccine 1995, 13, 1325–1329. [Google Scholar] [CrossRef]
- Shi, Y.; HogenEsch, H.; Regnier, F.E.; Hem, S.L. Detoxification of endotoxin by aluminum hydroxide adjuvant. Vaccine 2001, 19, 1747–1752. [Google Scholar] [CrossRef]
Donor | EE (IU/μg) | NP 1 (p-Value) | NL 2 (p-Value) | Equivalence Ratio with Standard | Correlation (r, Weighted) |
---|---|---|---|---|---|
C162 | 1419.4 | 0.000 | 0.000 | 1.291 | 0.949 |
C163 | 3137.6 | 0.263 | 0.050 | 0.914 | 0.956 |
C164 | 384.47 | 0.075 | 0.174 | 0.779 | 0.904 |
C165 | 235.57 | 0.000 | 0.000 | −0.163 | 0.879 |
GMMA Vaccine DP | Donor Average RPU 1 | Fold Change | Inter-Donor GCV (%) |
---|---|---|---|
1790GAHB SH15-001 | 0.17 | 5.71 | 14.04 |
Batch A | 0.65 | 1.54 | 31.94 |
Batch B | 0.53 | 1.91 | 18.17 |
Batch C | 1.02 | 0.98 | 35.07 |
Publisher’s Note: MDPI stays neutral with regard to jurisdictional claims in published maps and institutional affiliations. |
© 2021 by the authors. Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (https://creativecommons.org/licenses/by/4.0/).
Share and Cite
Carson, D.; Myhill, S.; Palmieri, E.; Necchi, F.; Rijpkema, S.; Micoli, F.; Nordgren, I.K.; Rossi, O.; Vipond, C. Development of a Monocyte Activation Test as an Alternative to the Rabbit Pyrogen Test for Mono- and Multi-Component Shigella GMMA-Based Vaccines. Microorganisms 2021, 9, 1375. https://doi.org/10.3390/microorganisms9071375
Carson D, Myhill S, Palmieri E, Necchi F, Rijpkema S, Micoli F, Nordgren IK, Rossi O, Vipond C. Development of a Monocyte Activation Test as an Alternative to the Rabbit Pyrogen Test for Mono- and Multi-Component Shigella GMMA-Based Vaccines. Microorganisms. 2021; 9(7):1375. https://doi.org/10.3390/microorganisms9071375
Chicago/Turabian StyleCarson, Danielle, Sophie Myhill, Elena Palmieri, Francesca Necchi, Sjoerd Rijpkema, Francesca Micoli, Ida Karin Nordgren, Omar Rossi, and Caroline Vipond. 2021. "Development of a Monocyte Activation Test as an Alternative to the Rabbit Pyrogen Test for Mono- and Multi-Component Shigella GMMA-Based Vaccines" Microorganisms 9, no. 7: 1375. https://doi.org/10.3390/microorganisms9071375