Safety, tolerability, and immunogenicity of an oral inactivated ETEC vaccine (ETVAX®) with dmLT adjuvant in healthy adults and children in Zambia: An age descending randomised, placebo-controlled trial

Enterotoxigenic Escherichia coli (ETEC) is an important cause of moderate to severe diarrhoea in children for which there is no licensed vaccine. We evaluated ETVAX®, an oral, inactivated ETEC vaccine containing four E. coli strains over-expressing the major colonization factors CFA/I, CS3, CS5, and...

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Published in:	Vaccine Vol. 41; no. 46; pp. 6884 - 6894
Main Authors:	Sukwa, Nsofwa, Mubanga, Cynthia, Hatyoka, Luiza M., Chilyabanyama, Obvious N., Chibuye, Mwelwa, Mundia, Samson, Munyinda, Masiliso, Kamuti, Ethel, Siyambango, Muyunda, Badiozzaman, Sharif, Bosomprah, Samuel, Carlin, Nils, Kaim, Joanna, Sjöstrand, Björn, Simuyandi, Michelo, Chilengi, Roma, Svennerholm, Ann-Mari
Format:	Journal Article
Language:	English
Published:	Netherlands Elsevier Ltd 02-11-2023 Elsevier Limited
Subjects:	Adjuvants Adjuvants, Immunologic - administration & dosage Adjuvants, Immunologic - adverse effects Administration, Oral Adolescent Adult Adults Adverse events Age Antibodies Antibodies, Bacterial - blood Antigens Bacterial Toxins - immunology burden Children Cholera Clinical trials colonization Deactivation developing-countries Diarrhea Diarrhoea disease Double-Blind Method E coli Enterotoxigenic Escherichia coli - immunology enterotoxigenic-escherichia-coli Enterotoxins - administration & dosage Enterotoxins - immunology Escherichia coli Escherichia coli Infections - immunology Escherichia coli Infections - prevention & control Escherichia coli Proteins - immunology Escherichia coli Vaccines - administration & dosage Escherichia coli Vaccines - adverse effects Escherichia coli Vaccines - immunology ETEC ETVAX ETVAX (R) factors Female Fever Heat-labile enterotoxin Humans immune-responses Immunization Immunogenicity Immunogenicity, Vaccine Immunoglobulin A Immunoglobulin A - blood Immunoglobulin G Immunoglobulin G - blood Immunologi inom det medicinska området Immunology Immunology in the medical area Infant infants Male Middle Aged Pharmacists Placebos Product development Research & Experimental Medicine Safety Vaccine Vaccines Vaccines, Inactivated - administration & dosage Vaccines, Inactivated - adverse effects Vaccines, Inactivated - immunology Young Adult Zambia Sweden Zambia Immunogenicity Vaccine Diarrhoea Zambia Safety ETEC ETVAX
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Summary:	Enterotoxigenic Escherichia coli (ETEC) is an important cause of moderate to severe diarrhoea in children for which there is no licensed vaccine. We evaluated ETVAX®, an oral, inactivated ETEC vaccine containing four E. coli strains over-expressing the major colonization factors CFA/I, CS3, CS5, and CS6, a toxoid (LCTBA) and double mutant heat-labile enterotoxin (dmLT) adjuvant for safety, tolerability, and immunogenicity. A double-blind, placebo-controlled, age-descending, dose-finding trial was undertaken in 40 adults, 60 children aged 10–23 months, and 146 aged 6–9 months. Adults received one full dose of ETVAX® and children received 3 doses of either 1/4 or 1/8 dose. Safety was evaluated as solicited and unsolicited events for 7 days following vaccination. Immunogenicity was assessed by evaluation of plasma IgA antibody responses to CFA/I, CS3, CS5, CS6, and LTB, and IgG responses to LTB. Solicited adverse events were mostly mild or moderate with only 2 severe fever reports which were unrelated to the vaccine. The most common events were abdominal pain in adults (26.7 % in vaccinees vs 20 % in placebos), and fever in children aged 6–9 months (44 % vs 54 %). Dosage, number of vaccinations and decreasing age had no influence on severity or frequency of adverse events. The vaccine induced plasma IgA and IgG responses against LTB in 100 % of the adults and 80–90 % of the children. In the 6–23 months cohort, IgA responses to more than 3 vaccine antigens after 3 doses determined as ≥2-fold rise was significantly higher for 1/4 dose compared to placebo (56.7 % vs 27.2 %, p = 0.01). In the 6–9 months cohort, responses to the 1/4 dose were significantly higher than 1/8 dose after 3 rather than 2 doses. ETVAX® was safe, tolerable, and immunogenic in Zambian adults and children. The 1/4 dose induced significantly stronger IgA responses and is recommended for evaluation of protection in children. Clinical trials registration: The trial is registered with the Pan African Clinical Trials Registry (PACTR Ref. 201905764389804) and a description of this clinical trial is available on: https://pactr.samrc.ac.za/Trial Design.
Bibliography:	ObjectType-Article-1 SourceType-Scholarly Journals-1 ObjectType-Feature-2 content type line 23 ObjectType-Undefined-3
ISSN:	0264-410X 1873-2518 1873-2518
DOI:	10.1016/j.vaccine.2023.09.052