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Article ; Online: CHO cells for virus-like particle and subunit vaccine manufacturing.

Sanchez-Martinez, Zalma V / Alpuche-Lazcano, Sergio P / Stuible, Matthew / Durocher, Yves

2024 Volume 42, Issue 10, Page(s) 2530–2542

Abstract: Chinese Hamster Ovary (CHO) cells, employed primarily for manufacturing monoclonal antibodies and other recombinant protein (r-protein) therapeutics, are emerging as a promising host for vaccine antigen production. This is exemplified by the recently ... ...

Abstract	Chinese Hamster Ovary (CHO) cells, employed primarily for manufacturing monoclonal antibodies and other recombinant protein (r-protein) therapeutics, are emerging as a promising host for vaccine antigen production. This is exemplified by the recently approved CHO cell-derived subunit vaccines (SUV) against respiratory syncytial virus (RSV) and varicella-zoster virus (VZV), as well as the enveloped virus-like particle (eVLP) vaccine against hepatitis B virus (HBV). Here, we summarize the design, production, and immunogenicity features of these vaccine and review the most recent progress of other CHO-derived vaccines in pre-clinical and clinical development. We also discuss the challenges associated with vaccine production in CHO cells, with a focus on ensuring viral clearance for eVLP products.
MeSH term(s)	Cricetinae ; Animals ; Humans ; CHO Cells ; Cricetulus ; Respiratory Syncytial Virus Infections/prevention & control ; Antibodies, Neutralizing ; Antibodies, Viral ; Respiratory Syncytial Virus, Human ; Vaccines, Virus-Like Particle ; Herpesvirus 3, Human ; Vaccines, Subunit ; Respiratory Syncytial Virus Vaccines
Chemical Substances	Antibodies, Neutralizing ; Antibodies, Viral ; Vaccines, Virus-Like Particle ; Vaccines, Subunit ; Respiratory Syncytial Virus Vaccines
Language	English
Publishing date	2024-03-19
Publishing country	Netherlands
Document type	Journal Article ; Review
ZDB-ID	605674-x
ISSN	1873-2518 ; 0264-410X
ISSN (online)	1873-2518
ISSN	0264-410X
DOI	10.1016/j.vaccine.2024.03.034
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Article ; Online: Outer membrane vesicles derived from

Pschunder, Bernarda / Locati, Lucia / López, Oriana / Martin Aispuro, Pablo / Zurita, Eugenia / Stuible, Matthew / Durocher, Yves / Hozbor, Daniela

Frontiers in immunology

2024 Volume 15, Page(s) 1387534

Abstract: For several years, we have been committed to exploring the potential ... ...

Abstract	For several years, we have been committed to exploring the potential of
MeSH term(s)	Bordetella pertussis/immunology ; Animals ; Adjuvants, Immunologic/administration & dosage ; Mice ; Th1 Cells/immunology ; Whooping Cough/immunology ; Whooping Cough/prevention & control ; Female ; Immunoglobulin G/blood ; Immunoglobulin G/immunology ; Pertussis Vaccine/immunology ; Pertussis Vaccine/administration & dosage ; Antibodies, Bacterial/immunology ; Antibodies, Bacterial/blood ; Spike Glycoprotein, Coronavirus/immunology ; Mice, Inbred BALB C ; SARS-CoV-2/immunology ; Bacterial Outer Membrane Proteins/immunology ; Humans ; COVID-19/immunology ; COVID-19/prevention & control ; Tetanus Toxoid/immunology
Chemical Substances	Adjuvants, Immunologic ; Immunoglobulin G ; Pertussis Vaccine ; Antibodies, Bacterial ; Spike Glycoprotein, Coronavirus ; spike protein, SARS-CoV-2 ; Bacterial Outer Membrane Proteins ; Tetanus Toxoid
Language	English
Publishing date	2024-04-08
Publishing country	Switzerland
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	2606827-8
ISSN	1664-3224 ; 1664-3224
ISSN (online)	1664-3224
ISSN	1664-3224
DOI	10.3389/fimmu.2024.1387534
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Article ; Online: Repressing expression of difficult-to-express recombinant proteins during the selection process increases productivity of CHO stable pools.

Maltais, Jean-Sébastien / Lord-Dufour, Simon / Morasse, Audrey / Stuible, Matthew / Loignon, Martin / Durocher, Yves

Biotechnology and bioengineering

2023 Volume 120, Issue 10, Page(s) 2840–2852

Abstract: More than half of licensed therapeutic recombinant proteins (r-proteins) are manufactured using constitutively-expressing, stably-transfected Chinese hamster ovary (CHO) clones. While constitutive CHO expression systems have proven their efficacy for the ...

Abstract	More than half of licensed therapeutic recombinant proteins (r-proteins) are manufactured using constitutively-expressing, stably-transfected Chinese hamster ovary (CHO) clones. While constitutive CHO expression systems have proven their efficacy for the manufacturing of monoclonal antibodies, many next-generation therapeutics such as cytokines and bispecific antibodies as well as biological targets such as ectodomains of transmembrane receptors remain intrinsically challenging to produce. Herein, we exploited a cumate-inducible CHO platform allowing reduced expression of various classes of r-proteins during selection of stable pools. Following stable pool generation, fed-batch productions showed that pools generated without cumate (OFF-pools) were significantly more productive than pools selected in the presence of cumate (ON-pools) for 8 out of the 10 r-proteins tested, including cytokines, G-protein coupled receptors (GPCRs), the HVEM membrane receptor ectodomain, the multifunctional protein High Mobility Group protein B1 (HMGB1), as well as monoclonal and bispecific T-cell engager antibodies. We showed that OFF-pools contain a significantly larger proportion of cells producing high levels of r-proteins and that these cells tend to proliferate faster when expression is turned off, suggesting that r-protein overexpression imposes a metabolic burden on the cells. Cell viability was lower and pool recovery was delayed during selection of ON-pools (mimicking constitutive expression), suggesting that high producers were likely lost or overgrown by faster-growing, low-producing cells. We also observed a correlation between the expression levels of the GPCRs with Binding immunoglobulin Protein, an endoplasmic reticulum (ER) stress marker. Taken together, these data suggest that using an inducible system to minimize r-protein expression during stable CHO pool selection reduces cellular stresses, including ER stress and metabolic burden, leading to pools with greater frequency of high-expressing cells, resulting in improved volumetric productivity.
MeSH term(s)	Cricetinae ; Animals ; Cricetulus ; CHO Cells ; Recombinant Proteins/metabolism ; Antibodies, Monoclonal ; Cytokines
Chemical Substances	Recombinant Proteins ; Antibodies, Monoclonal ; Cytokines
Language	English
Publishing date	2023-05-26
Publishing country	United States
Document type	Journal Article
ZDB-ID	280318-5
ISSN	1097-0290 ; 0006-3592
ISSN (online)	1097-0290
ISSN	0006-3592
DOI	10.1002/bit.28435
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Article ; Online: Intranasal administration of unadjuvanted SARS-CoV-2 spike antigen boosts antigen-specific immune responses induced by parenteral protein subunit vaccine prime in mice and hamsters.

Agbayani, Gerard / Akache, Bassel / Renner, Tyler M / Tran, Anh / Stuible, Matthew / Dudani, Renu / Harrison, Blair A / Duque, Diana / Bavananthasivam, Jegarubee / Deschatelets, Lise / Hemraz, Usha D / Régnier, Sophie / Durocher, Yves / McCluskie, Michael J

European journal of immunology

2024 , Page(s) e2350620

Abstract: With the continued transmission of SARS-CoV-2 across widely vaccinated populations, it remains important to develop new vaccines and vaccination strategies capable of providing protective immunity and limiting the spread of disease. Heterologous prime- ... ...

Abstract	With the continued transmission of SARS-CoV-2 across widely vaccinated populations, it remains important to develop new vaccines and vaccination strategies capable of providing protective immunity and limiting the spread of disease. Heterologous prime-boost vaccination based on the selection of different vaccine formulations and administration routes for priming and booster doses presents a promising strategy for inducing broader immune responses in key systemic and respiratory mucosal compartments. Intranasal vaccination can induce mucosal immune responses at the site of SARS-CoV-2 infection; however, the lack of clinically approved mucosal adjuvants makes it difficult to induce robust immune responses with protein subunit vaccines. Herein, we evaluated the immunogenicity of heterologous prime-boost regimens in mice and hamsters based on a parenteral vaccination of the antigen in combination with sulfated lactosylarchaeol (SLA) archaeosomes, a liposome adjuvant comprised of a single semisynthetic archaeal lipid, followed by an intranasally administered unadjuvanted SARS-CoV-2 spike antigen. Intranasal administration of unadjuvanted spike to mice and hamsters increased serum spike-specific IgG titers and spike-neutralizing activity compared with nonboosted animals. Spike-specific IgA responses were also detected in the bronchoalveolar lavage fluid in the lungs of mice that received an intranasal boost. In hamsters, the intranasal boost showed high efficacy against SARS-CoV-2 infection by protecting from body weight loss and reducing viral titers in the lungs and nasal turbinate. Overall, our heterologous intramuscular prime-intranasal boost with SLA-adjuvanted and unadjuvanted spike, respectively, demonstrated the potential of protein subunit formulations to promote antigen-specific systemic and mucosal immune responses.
Language	English
Publishing date	2024-04-01
Publishing country	Germany
Document type	Journal Article
ZDB-ID	120108-6
ISSN	1521-4141 ; 0014-2980
ISSN (online)	1521-4141
ISSN	0014-2980
DOI	10.1002/eji.202350620
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Article ; Online: A Biosensor Assay Based on Coiled-Coil-Mediated Human ACE2 Receptor Capture for the Analysis of Its Interactions with the SARS-CoV-2 Receptor Binding Domain.

Forest-Nault, Catherine / Koyuturk, Izel / Gaudreault, Jimmy / Pelletier, Alex / L'Abbé, Denis / Cass, Brian / Bisson, Louis / Burlacu, Alina / Delafosse, Laurence / Stuible, Matthew / Henry, Olivier / De Crescenzo, Gregory / Durocher, Yves

Methods in molecular biology (Clifton, N.J.)

2024 Volume 2762, Page(s) 89–105

Abstract: Surface plasmon resonance (SPR)-based biosensing enables the characterization of protein-protein interactions. Several SPR-based approaches have been designed to evaluate the binding mechanism between the angiotensin-converting enzyme 2 (ACE2) receptor ... ...

Abstract	Surface plasmon resonance (SPR)-based biosensing enables the characterization of protein-protein interactions. Several SPR-based approaches have been designed to evaluate the binding mechanism between the angiotensin-converting enzyme 2 (ACE2) receptor and the receptor-binding domain (RBD) of the SARS-CoV-2 spike protein leading to a large range of kinetic and thermodynamic constants. This chapter describes a robust SPR assay based on the K5/E5 coiled-coil capture strategy that reduces artifacts. In this method, ACE2 receptors were produced with an E5-tag and immobilized as ligands in the SPR assay. This chapter details methods for high-yield production and purification of the studied proteins, functionalization of the sensor chip, conduction of the SPR assay, and data analysis.
MeSH term(s)	Humans ; SARS-CoV-2/metabolism ; Angiotensin-Converting Enzyme 2/metabolism ; COVID-19 ; Spike Glycoprotein, Coronavirus/metabolism ; Biosensing Techniques/methods ; Protein Binding
Chemical Substances	spike protein, SARS-CoV-2 ; Angiotensin-Converting Enzyme 2 (EC 3.4.17.23) ; Spike Glycoprotein, Coronavirus
Language	English
Publishing date	2024-02-05
Publishing country	United States
Document type	Journal Article
ISSN	1940-6029
ISSN (online)	1940-6029
DOI	10.1007/978-1-0716-3666-4_6
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Article ; Online: Production and Characterization of a SARS-CoV-2 Nucleocapsid Protein Reference Material.

Stocks, Bradley B / Thibeault, Marie-Pier / L'Abbé, Denis / Stuible, Matthew / Durocher, Yves / Melanson, Jeremy E

ACS measurement science au

2022 Volume 2, Issue 6, Page(s) 620–628

Abstract: Rapid antigen tests have become a widely used COVID-19 diagnostic tool with demand accelerating in response to the highly contagious SARS-CoV-2 Omicron variant. Hundreds of such test kits are approved for use worldwide, predominantly reporting on the ... ...

Abstract	Rapid antigen tests have become a widely used COVID-19 diagnostic tool with demand accelerating in response to the highly contagious SARS-CoV-2 Omicron variant. Hundreds of such test kits are approved for use worldwide, predominantly reporting on the presence of the viral nucleocapsid (N) protein, yet the comparability among manufacturers remains unclear and the need for reference standards is recognized. To address this lack of standardization, the National Research Council Canada has developed a SARS-CoV-2 nucleocapsid protein reference material solution, NCAP-1. Reference value determination for N protein content was realized by amino acid analysis (AAA) via double isotope dilution liquid chromatography-tandem mass spectrometry (LC-ID-MS/MS) following acid hydrolysis of the protein, in conjunction with UV spectrophotometry based on tryptophan and tyrosine absorbance at 280 nm. The homogeneity of the material was established through spectrophotometric absorbance readings at 280 nm. The molar concentration of the N protein in NCAP-1 was 10.0 ± 1.9 μmol L
Language	English
Publishing date	2022-09-02
Publishing country	United States
Document type	Journal Article
ISSN	2694-250X
ISSN (online)	2694-250X
DOI	10.1021/acsmeasuresciau.2c00050
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Article ; Online: Assessment of the longitudinal humoral response in non-hospitalized SARS-CoV-2-positive individuals at decentralized sites: Outcomes and concordance.

Djaïleb, Abdelhadi / Lavallée, Étienne / Parker, Megan-Faye / Cayer, Marie-Pierre / Desautels, Florence / de Grandmont, Marie Joëlle / Stuible, Matthew / Gervais, Christian / Durocher, Yves / Trottier, Sylvie / Boudreau, Denis / Masson, Jean-Francois / Brouard, Danny / Pelletier, Joelle N

Frontiers in immunology

2023 Volume 13, Page(s) 1052424

Abstract: Introduction: Early in the COVID-19 pandemic, reagent availability was not uniform, and infrastructure had to be urgently adapted to undertake COVID-19 surveillance.: Methods: Before the validation of centralized testing, two enzyme-linked ... ...

Abstract	Introduction: Early in the COVID-19 pandemic, reagent availability was not uniform, and infrastructure had to be urgently adapted to undertake COVID-19 surveillance. Methods: Before the validation of centralized testing, two enzyme-linked immunosorbent assays (ELISA) were established independently at two decentralized sites using different reagents and instrumentation. We compared the results of these assays to assess the longitudinal humoral response of SARS-CoV-2-positive (i.e., PCR-confirmed), non-hospitalized individuals with mild to moderate symptoms, who had contracted SARSCoV-2 prior to the appearance of variants of concern in Québec, Canada. Results: The two assays exhibited a high degree of concordance to identify seropositive individuals, thus validating the robustness of the methods. The results also confirmed that serum immunoglobulins persist ≥ 6 months post-infection among non-hospitalized adults and that the antibodies elicited by infection cross-reacted with the antigens from P.1 (Gamma) and B.1.617.2 (Delta) variants of concern. Discussion: Together, these results demonstrate that immune surveillance assays can be rapidly and reliably established when centralized testing is not available or not yet validated, allowing for robust immune surveillance.
MeSH term(s)	Adult ; Humans ; COVID-19 ; SARS-CoV-2 ; Pandemics ; Antibodies, Viral
Chemical Substances	Antibodies, Viral
Language	English
Publishing date	2023-01-20
Publishing country	Switzerland
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	2606827-8
ISSN	1664-3224 ; 1664-3224
ISSN (online)	1664-3224
ISSN	1664-3224
DOI	10.3389/fimmu.2022.1052424
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Article ; Online: Heterologous booster with a novel formulation containing glycosylated trimeric S protein is effective against Omicron.

Bottero, Daniela / Rudi, Erika / Martin Aispuro, Pablo / Zurita, Eugenia / Gaillard, Emilia / Gonzalez Lopez Ledesma, Maria M / Malito, Juan / Stuible, Matthew / Ambrosis, Nicolas / Durocher, Yves / Gamarnik, Andrea V / Wigdorovitz, Andrés / Hozbor, Daniela

Frontiers in immunology

2023 Volume 14, Page(s) 1271209

Abstract: In this study, we evaluated the efficacy of a heterologous three-dose vaccination schedule against the Omicron BA.1 SARS-CoV-2 variant infection using a mouse intranasal challenge model. The vaccination schedules tested in this study consisted of a ... ...

Abstract	In this study, we evaluated the efficacy of a heterologous three-dose vaccination schedule against the Omicron BA.1 SARS-CoV-2 variant infection using a mouse intranasal challenge model. The vaccination schedules tested in this study consisted of a primary series of 2 doses covered by two commercial vaccines: an mRNA-based vaccine (mRNA1273) or a non-replicative vector-based vaccine (AZD1222/ChAdOx1, hereafter referred to as AZD1222). These were followed by a heterologous booster dose using one of the two vaccine candidates previously designed by us: one containing the glycosylated and trimeric spike protein (S) from the ancestral virus (SW-Vac 2µg), and the other from the Delta variant of SARS-CoV-2 (SD-Vac 2µg), both formulated with Alhydrogel as an adjuvant. For comparison purposes, homologous three-dose schedules of the commercial vaccines were used. The mRNA-based vaccine, whether used in heterologous or homologous schedules, demonstrated the best performance, significantly increasing both humoral and cellular immune responses. In contrast, for the schedules that included the AZD1222 vaccine as the primary series, the heterologous schemes showed superior immunological outcomes compared to the homologous 3-dose AZD1222 regimen. For these schemes no differences were observed in the immune response obtained when SW-Vac 2µg or SD-Vac 2µg were used as a booster dose. Neutralizing antibody levels against Omicron BA.1 were low, especially for the schedules using AZD1222. However, a robust Th1 profile, known to be crucial for protection, was observed, particularly for the heterologous schemes that included AZD1222. All the tested schedules were capable of inducing populations of CD4 T effector, memory, and follicular helper T lymphocytes. It is important to highlight that all the evaluated schedules demonstrated a satisfactory safety profile and induced multiple immunological markers of protection. Although the levels of these markers were different among the tested schedules, they appear to complement each other in conferring protection against intranasal challenge with Omicron BA.1 in K18-hACE2 mice. In summary, the results highlight the potential of using the S protein (either ancestral Wuhan or Delta variant)-based vaccine formulation as heterologous boosters in the management of COVID-19, particularly for certain commercial vaccines currently in use.
MeSH term(s)	Humans ; Animals ; ChAdOx1 nCoV-19 ; 2019-nCoV Vaccine mRNA-1273 ; Adjuvants, Immunologic ; Disease Models, Animal ; RNA, Messenger
Chemical Substances	ChAdOx1 nCoV-19 (B5S3K2V0G8) ; 2019-nCoV Vaccine mRNA-1273 (EPK39PL4R4) ; Adjuvants, Immunologic ; RNA, Messenger
Language	English
Publishing date	2023-11-10
Publishing country	Switzerland
Document type	Journal Article ; Research Support, Non-U.S. Gov't ; Comment
ZDB-ID	2606827-8
ISSN	1664-3224 ; 1664-3224
ISSN (online)	1664-3224
ISSN	1664-3224
DOI	10.3389/fimmu.2023.1271209
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Article ; Online: Longitudinal Study on Seroprevalence and Immune Response to SARS-CoV-2 in a Population of Food and Retail Workers Through Transformation of ELISA Datasets

Djaïleb, Abdelhadi / Parker, Megan-Faye / Lavallée, Étienne / Stuible, Matthew / Durocher, Yves / Thériault, Mathieu / Santerre, Kim / Gilbert, Caroline / Boudreau, Denis / Baz, Mariana / Masson, Jean-Francois / Langlois, Marc-André / Trottier, Sylvie / Quaglia, Daniela / Pelletier, Joelle N.

medRxiv

Abstract: Since the onset of the global pandemic caused by the emergence and spread of SARS-CoV-2 in early 2020, numerous studies have been conducted worldwide to understand our immune response to the virus. This study investigates the humoral response elicited by ...

Abstract	Since the onset of the global pandemic caused by the emergence and spread of SARS-CoV-2 in early 2020, numerous studies have been conducted worldwide to understand our immune response to the virus. This study investigates the humoral response elicited by vaccination and by SARS-CoV-2 infection in the poorly studied food and retail workers in the Quebec City area. The 1.5-year study period spans from early 2021, when vaccination became available in this region, to mid-2022, following waves of virulence due to the emergence of the first Omicron variants. Cross-correlated with data on workplace protective measures, pre-existing conditions, activities and other potentially relevant factors, this longitudinal study applies recently developed ELISA data transformation to our dataset to obtain normal distribution. This unlocked the possibility to use the ANOVA-Welsh method for statistical analysis to obtain a statistical perspective of the serological response. Our work allows the identification of factors contributing to statistically relevant differences in the humoral response of the cohort and strengthens the utility of the use of decentralized approaches to serological analysis.
Keywords	covid19
Language	English
Publishing date	2024-01-29
Publisher	Cold Spring Harbor Laboratory Press
Document type	Article ; Online
DOI	10.1101/2024.01.27.24301877
Database	COVID19

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Article ; Online: Influence of variant-specific mutations, temperature and pH on conformations of a large set of SARS-CoV-2 spike trimer vaccine antigen candidates.

Stuible, Matthew / Schrag, Joseph D / Sheff, Joey / Zoubchenok, Daria / Lord-Dufour, Simon / Cass, Brian / L'Abbé, Denis / Pelletier, Alex / Rossotti, Martin A / Tanha, Jamshid / Gervais, Christian / Maurice, Roger / El Bakkouri, Majida / Acchione, Mauro / Durocher, Yves

Scientific reports

2023 Volume 13, Issue 1, Page(s) 16498

Abstract: SARS-CoV-2 subunit vaccines continue to be the focus of intense clinical development worldwide. Protein antigens in these vaccines most commonly consist of the spike ectodomain fused to a heterologous trimerization sequence, designed to mimic the compact, ...

Abstract	SARS-CoV-2 subunit vaccines continue to be the focus of intense clinical development worldwide. Protein antigens in these vaccines most commonly consist of the spike ectodomain fused to a heterologous trimerization sequence, designed to mimic the compact, prefusion conformation of the spike on the virus surface. Since 2020, we have produced dozens of such constructs in CHO cells, consisting of spike variants with different mutations fused to different trimerization sequences. This set of constructs displayed notable conformational heterogeneity, with two distinct trimer species consistently detected by analytical size exclusion chromatography. A recent report showed that spike ectodomain fusion constructs can adopt an alternative trimer conformation consisting of loosely associated ectodomain protomers. Here, we applied multiple biophysical and immunological techniques to demonstrate that this alternative conformation is formed to a significant extent by several SARS-CoV-2 variant spike proteins. We have also examined the influence of temperature and pH, which can induce inter-conversion of the two forms. The substantial structural differences between these trimer types may impact their performance as vaccine antigens.
MeSH term(s)	Animals ; Cricetinae ; Humans ; SARS-CoV-2 ; COVID-19 Vaccines/genetics ; COVID-19 ; Temperature ; Cricetulus ; Antigens ; Mutation ; Hydrogen-Ion Concentration ; Antibodies, Neutralizing
Chemical Substances	COVID-19 Vaccines ; Antigens ; Antibodies, Neutralizing
Language	English
Publishing date	2023-10-01
Publishing country	England
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	2615211-3
ISSN	2045-2322 ; 2045-2322
ISSN (online)	2045-2322
ISSN	2045-2322
DOI	10.1038/s41598-023-43661-2
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