title: Development and preclinical evaluation of safety and immunogenicity of an oral ETEC vaccine containing inactivated E. coli bacteria overexpressing colonization factors CFA/I, CS3, CS5 and CS6 combined with a hybrid LT/CT B subunit antigen, administered alone and together with dmLT adjuvant.
abstract: A first-generation oral inactivated whole-cell enterotoxigenic Escherichia coli (ETEC) vaccine, comprising formalin-killed ETEC bacteria expressing different colonization factor (CF) antigens combined with cholera toxin B subunit (CTB), when tested in phase III studies did not significantly reduce overall (generally mild) ETEC diarrhea in travelers or children although it reduced more severe ETEC diarrhea in travelers by almost 80%. We have now developed a novel more immunogenic ETEC vaccine based on recombinant non-toxigenic E. coli strains engineered to express increased amounts of CF antigens, including CS6 as well as an ETEC-based B subunit protein (LCTBA), and the optional combination with a nontoxic double-mutant heat-labile toxin (LT) molecule (dmLT) as an adjuvant. Two test vaccines were prepared under GMP: (1) A prototype E. coli CFA/I-only formalin-killed whole-cell+LCTBA vaccine, and (2) A "complete" inactivated multivalent ETEC-CF (CFA/I, CS3, CS5 and CS6 antigens) whole-cell+LCTBA vaccine. These vaccines, when given intragastrically alone or together with dmLT in mice, were well tolerated and induced strong intestinal-mucosal IgA antibody responses as well as serum IgG and IgA responses to each of the vaccine CF antigens as well as to LT B subunit (LTB). Both mucosal and serum responses were further enhanced (adjuvanted) when the vaccines were co-administered with dmLT. We conclude that the new multivalent oral ETEC vaccine, both alone and especially in combination with the dmLT adjuvant, shows great promise for further testing in humans.
authors.affiliation: University of Gothenburg Vaccine Research Institute (GUVAX), Department of Microbiology and Immunology, University of Gothenburg, Box 435, 405 30 Gothenburg, Sweden. jan.holmgren@microbio.gu.se
authors.forename: J
authors.initials: J
authors.lastname: Holmgren
authors.forename: L
authors.initials: L
authors.lastname: Bourgeois
authors.forename: N
authors.initials: N
authors.lastname: Carlin
authors.forename: J
authors.initials: J
authors.lastname: Clements
authors.forename: B
authors.initials: B
authors.lastname: Gustafsson
authors.forename: A
authors.initials: A
authors.lastname: Lundgren
authors.forename: E
authors.initials: E
authors.lastname: Nygren
authors.forename: J
authors.initials: J
authors.lastname: Tobias
authors.forename: R
authors.initials: R
authors.lastname: Walker
authors.forename: A-M
authors.initials: AM
authors.lastname: Svennerholm
mesh_terms: D000276:Adjuvants, Immunologic / Q000008:administration & dosage; D000284:Administration, Oral; D000818:Animals; D000917:Antibody Formation / Q000276:immunology; D000942:Antigens, Bacterial / Q000235:genetics / Q000276:immunology; D001427:Bacterial Toxins / Q000008:administration & dosage / Q000235:genetics / Q000276:immunology*; D002772:Cholera Toxin / Q000008:administration & dosage / Q000235:genetics / Q000276:immunology*; D054307:Enterotoxigenic Escherichia coli / Q000276:immunology*; D004768:Enterotoxins / Q000008:administration & dosage / Q000235:genetics / Q000276:immunology*; D004927:Escherichia coli Infections / Q000276:immunology / Q000382:microbiology / Q000517:prevention & control; D029968:Escherichia coli Proteins / Q000008:administration & dosage / Q000235:genetics / Q000276:immunology*; D022361:Escherichia coli Vaccines / Q000008:administration & dosage / Q000009:adverse effects / Q000235:genetics / Q000276:immunology*; D005260:Female; D036781:Fimbriae Proteins / Q000235:genetics / Q000276:immunology*; D018928:Immunity, Mucosal / Q000276:immunology; D007070:Immunoglobulin A / Q000032:analysis / Q000097:blood / Q000276:immunology; D007074:Immunoglobulin G / Q000032:analysis / Q000097:blood / Q000276:immunology; D007422:Intestines / Q000276:immunology; D051379:Mice; D008807:Mice, Inbred BALB C; D050505:Mutant Proteins / Q000008:administration & dosage / Q000276:immunology; D015164:Vaccines, Inactivated / Q000008:administration & dosage / Q000009:adverse effects / Q000235:genetics* / Q000276:immunology*
chemical_list: D000276:Adjuvants, Immunologic; D000942:Antigens, Bacterial; D001427:Bacterial Toxins; D004768:Enterotoxins; D029968:Escherichia coli Proteins; D022361:Escherichia coli Vaccines; D007070:Immunoglobulin A; D007074:Immunoglobulin G; D050505:Mutant Proteins; D015164:Vaccines, Inactivated; C022924:colonization factor antigens; D036781:Fimbriae Proteins; D002772:Cholera Toxin; C027538:heat-labile enterotoxin, E coli