title: Clinical trial to evaluate safety and immunogenicity of an oral inactivated enterotoxigenic Escherichia coli prototype vaccine containing CFA/I overexpressing bacteria and recombinantly produced LTB/CTB hybrid protein.
abstract: We have developed a new oral vaccine against enterotoxigenic Escherichia coli (ETEC) diarrhea containing killed recombinant E. coli bacteria expressing increased levels of ETEC colonization factors (CFs) and a recombinant protein (LCTBA), i.e. a hybrid between the binding subunits of E. coli heat labile toxin (LTB) and cholera toxin (CTB). We describe a randomized, comparator controlled, double-blind phase I trial in 60 adult Swedish volunteers of a prototype of this vaccine. The safety and immunogenicity of the prototype vaccine, containing LCTBA and an E. coli strain overexpressing the colonization factor CFA/I, was compared to a previously developed oral ETEC vaccine, consisting of CTB and inactivated wild type ETEC bacteria expressing CFA/I (reference vaccine). Groups of volunteers were given two oral doses of either the prototype or the reference vaccine; the prototype vaccine was administered at the same or a fourfold higher dosage than the reference vaccine. The prototype vaccine was found to be safe and equally well-tolerated as the reference vaccine at either dosage tested. The prototype vaccine induced mucosal IgA (fecal secretory IgA and intestine-derived IgA antibody secreting cell) responses to both LTB and CFA/I, as well as serum IgA and IgG antibody responses to LTB. Immunization with LCTBA resulted in about twofold higher mucosal and systemic IgA responses against LTB than a comparable dose of CTB. The higher dose of the prototype vaccine induced significantly higher fecal and systemic IgA responses to LTB and fecal IgA responses to CFA/I than the reference vaccine. These results demonstrate that CF over-expression and inclusion of the LCTBA hybrid protein in an oral inactivated ETEC vaccine does not change the safety profile when compared to a previous generation of such a vaccine and that the prototype vaccine induces significant dose dependent mucosal immune responses against CFA/I and LTB.
authors.affiliation: Gothenburg University Vaccine Research Institute, Department of Microbiology and Immunology, University of Gothenburg, 405 30 Gothenburg, Sweden. anna.lundgren@microbio.gu.se
authors.forename: A
authors.initials: A
authors.lastname: Lundgren
authors.forename: S
authors.initials: S
authors.lastname: Leach
authors.forename: J
authors.initials: J
authors.lastname: Tobias
authors.forename: N
authors.initials: N
authors.lastname: Carlin
authors.forename: B
authors.initials: B
authors.lastname: Gustafsson
authors.forename: M
authors.initials: M
authors.lastname: Jertborn
authors.forename: L
authors.initials: L
authors.lastname: Bourgeois
authors.forename: R
authors.initials: R
authors.lastname: Walker
authors.forename: J
authors.initials: J
authors.lastname: Holmgren
authors.forename: A-M
authors.initials: AM
authors.lastname: Svennerholm
mesh_terms: D000276:Adjuvants, Immunologic / Q000235:genetics / Q000378:metabolism; D000284:Administration, Oral; D000328:Adult; D000907:Antibodies, Bacterial / Q000032:analysis / Q000097:blood; D001427:Bacterial Toxins / Q000235:genetics / Q000378:metabolism*; D002772:Cholera Toxin / Q000235:genetics / Q000378:metabolism*; D003087:Colicins; D004311:Double-Blind Method; D054307:Enterotoxigenic Escherichia coli / Q000276:immunology*; D004768:Enterotoxins / Q000235:genetics / Q000378:metabolism*; D029968:Escherichia coli Proteins / Q000235:genetics / Q000276:immunology* / Q000378:metabolism*; D022361:Escherichia coli Vaccines / Q000008:administration & dosage / Q000009:adverse effects* / Q000276:immunology*; D005260:Female; D036781:Fimbriae Proteins / Q000235:genetics / Q000276:immunology*; D006805:Human Experimentation; D006801:Humans; D018928:Immunity, Mucosal; D007070:Immunoglobulin A / Q000032:analysis / Q000097:blood; D007074:Immunoglobulin G / Q000097:blood; D008297:Male; D008875:Middle Aged; D015164:Vaccines, Inactivated / Q000008:administration & dosage / Q000009:adverse effects / Q000276:immunology; D014614:Vaccines, Synthetic / Q000008:administration & dosage / Q000009:adverse effects / Q000276:immunology; D055815:Young Adult
chemical_list: D000276:Adjuvants, Immunologic; D000907:Antibodies, Bacterial; D001427:Bacterial Toxins; D003087:Colicins; D004768:Enterotoxins; D029968:Escherichia coli Proteins; D022361:Escherichia coli Vaccines; D007070:Immunoglobulin A; D007074:Immunoglobulin G; D015164:Vaccines, Inactivated; D014614:Vaccines, Synthetic; C096880:colicin 5 protein, E coli; C022924:colonization factor antigens; C071886:i protein, E coli; D036781:Fimbriae Proteins; D002772:Cholera Toxin; C027538:heat-labile enterotoxin, E coli