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Preparation and preclinical evaluation of a freeze-dried formulation of a novel combined multivalent whole-cell/B-subunit oral vaccine against enterotoxigenic Escherichia coli diarrhea.
Eur J Pharm Biopharm 2016; 108:18-24EJ

Abstract

A promising liquid killed multivalent whole-cell plus enterotoxin B-subunit oral vaccine against enterotoxigenic Escherichia coli (ETEC), the primary cause of diarrhea among children in low-income countries and travelers to these areas, has recently been developed and tested in preclinical and phase-I and phase-II clinical studies. The vaccine contains killed E. coli bacteria over-expressing the main ETEC colonization factors (CFs) CFA/I, CS3, C5 and C6, and a recombinant enterotoxin B subunit protein (LCTBA) given together with a recently developed enterotoxin-derived adjuvant, dmLT. A dry-powder vaccine formulation should be advantageous especially for use in low-income countries. Here we describe a method to produce a dry-powder formulation by freeze-drying of the vaccine using inulin as stabilizer. Although not completely preventing aggregation of bacteria during freeze-drying, the stabilizer provided both improved overall bacterial morphology and almost complete recovery of the CF and B subunit antigens. Most importantly, oral-intragastric immunization of mice with the freeze-dried vaccine together with dmLT adjuvant elicited strong intestinal mucosal and serum antibody responses against all vaccine antigens, which were comparable to those achieved with the liquid vaccine. Our results indicate the feasibility to use freeze-drying with inulin as stabilizer for preparing a dry-powder formulation of the novel ETEC vaccine with retained oral-mucosal immunogenicity compared to the liquid formulation.

Authors+Show Affiliations

University of Gothenburg Vaccine Research Institute (GUVAX), Department of Microbiology and Immunology, The Sahlgrenska Academy of University of Gothenburg, SE-40530 Gothenburg, Sweden. Electronic address: annika.borde@astrazeneca.com.University of Gothenburg Vaccine Research Institute (GUVAX), Department of Microbiology and Immunology, The Sahlgrenska Academy of University of Gothenburg, SE-40530 Gothenburg, Sweden. Electronic address: annelie.ekman@microbio.gu.se.Pharmaceutical Technology, Chemical and Biological Engineering, Chalmers University of Technology, SE-41296 Gothenburg, Sweden. Electronic address: anette.larsson@chalmers.se.Scandinavian Biopharma, Gunnar Asplunds allé 16, 171 63 Solna, Sweden. Electronic address: nils.carlin@etvax.se.University of Gothenburg Vaccine Research Institute (GUVAX), Department of Microbiology and Immunology, The Sahlgrenska Academy of University of Gothenburg, SE-40530 Gothenburg, Sweden. Electronic address: jan.holmgren@microbio.gu.se.University of Gothenburg Vaccine Research Institute (GUVAX), Department of Microbiology and Immunology, The Sahlgrenska Academy of University of Gothenburg, SE-40530 Gothenburg, Sweden. Electronic address: joshua.tobias@microbio.gu.se.

Pub Type(s)

Journal Article

Language

eng

PubMed ID

27485398

Citation

Borde, Annika, et al. "Preparation and Preclinical Evaluation of a Freeze-dried Formulation of a Novel Combined Multivalent whole-cell/B-subunit Oral Vaccine Against Enterotoxigenic Escherichia Coli Diarrhea." European Journal of Pharmaceutics and Biopharmaceutics : Official Journal of Arbeitsgemeinschaft Fur Pharmazeutische Verfahrenstechnik E.V, vol. 108, 2016, pp. 18-24.
Borde A, Ekman A, Larsson A, et al. Preparation and preclinical evaluation of a freeze-dried formulation of a novel combined multivalent whole-cell/B-subunit oral vaccine against enterotoxigenic Escherichia coli diarrhea. Eur J Pharm Biopharm. 2016;108:18-24.
Borde, A., Ekman, A., Larsson, A., Carlin, N., Holmgren, J., & Tobias, J. (2016). Preparation and preclinical evaluation of a freeze-dried formulation of a novel combined multivalent whole-cell/B-subunit oral vaccine against enterotoxigenic Escherichia coli diarrhea. European Journal of Pharmaceutics and Biopharmaceutics : Official Journal of Arbeitsgemeinschaft Fur Pharmazeutische Verfahrenstechnik E.V, 108, pp. 18-24. doi:10.1016/j.ejpb.2016.07.011.
Borde A, et al. Preparation and Preclinical Evaluation of a Freeze-dried Formulation of a Novel Combined Multivalent whole-cell/B-subunit Oral Vaccine Against Enterotoxigenic Escherichia Coli Diarrhea. Eur J Pharm Biopharm. 2016;108:18-24. PubMed PMID: 27485398.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Preparation and preclinical evaluation of a freeze-dried formulation of a novel combined multivalent whole-cell/B-subunit oral vaccine against enterotoxigenic Escherichia coli diarrhea. AU - Borde,Annika, AU - Ekman,Annelie, AU - Larsson,Anette, AU - Carlin,Nils, AU - Holmgren,Jan, AU - Tobias,Joshua, Y1 - 2016/07/30/ PY - 2015/07/05/received PY - 2016/05/04/revised PY - 2016/07/10/accepted PY - 2016/8/4/pubmed PY - 2017/3/24/medline PY - 2016/8/4/entrez KW - ETEC KW - Freeze-dried KW - Immunogenicity KW - Inulin KW - Stabilizer KW - Vaccine SP - 18 EP - 24 JF - European journal of pharmaceutics and biopharmaceutics : official journal of Arbeitsgemeinschaft fur Pharmazeutische Verfahrenstechnik e.V JO - Eur J Pharm Biopharm VL - 108 N2 - A promising liquid killed multivalent whole-cell plus enterotoxin B-subunit oral vaccine against enterotoxigenic Escherichia coli (ETEC), the primary cause of diarrhea among children in low-income countries and travelers to these areas, has recently been developed and tested in preclinical and phase-I and phase-II clinical studies. The vaccine contains killed E. coli bacteria over-expressing the main ETEC colonization factors (CFs) CFA/I, CS3, C5 and C6, and a recombinant enterotoxin B subunit protein (LCTBA) given together with a recently developed enterotoxin-derived adjuvant, dmLT. A dry-powder vaccine formulation should be advantageous especially for use in low-income countries. Here we describe a method to produce a dry-powder formulation by freeze-drying of the vaccine using inulin as stabilizer. Although not completely preventing aggregation of bacteria during freeze-drying, the stabilizer provided both improved overall bacterial morphology and almost complete recovery of the CF and B subunit antigens. Most importantly, oral-intragastric immunization of mice with the freeze-dried vaccine together with dmLT adjuvant elicited strong intestinal mucosal and serum antibody responses against all vaccine antigens, which were comparable to those achieved with the liquid vaccine. Our results indicate the feasibility to use freeze-drying with inulin as stabilizer for preparing a dry-powder formulation of the novel ETEC vaccine with retained oral-mucosal immunogenicity compared to the liquid formulation. SN - 1873-3441 UR - https://www.unboundmedicine.com/medline/citation/27485398/Preparation_and_preclinical_evaluation_of_a_freeze_dried_formulation_of_a_novel_combined_multivalent_whole_cell/B_subunit_oral_vaccine_against_enterotoxigenic_Escherichia_coli_diarrhea_ DB - PRIME DP - Unbound Medicine ER -