Safety and immunogenicity of an improved oral inactivated multivalent enterotoxigenic Escherichia coli (ETEC) vaccine administered alone and together with dmLT adjuvant in a double-blind, randomized, placebo-controlled Phase I study

• Published in: Vaccine Vol. 32; no. 52; pp. 7077 - 7084
• Main Authors: Lundgren, Anna, Bourgeois, Louis, Carlin, Nils, Clements, John, Gustafsson, Björn, Hartford, Marianne, Holmgren, Jan, Petzold, Max, Walker, Richard, Svennerholm, Ann-Mari
• Format: Journal Article
• Language: English
• Published: Kidlington Elsevier Ltd 12.12.2014; Elsevier
• Subjects: adjuvants; Adjuvants, Immunologic - administration & dosage; Adjuvants, Immunologic - genetics; Administration, Oral; Adolescent; Adult; adults; Allergy and Immunology; antibodies; Antibodies, Bacterial - analysis; Antibody-Producing Cells - immunology; ANTIBODY-RESPONSES; antigens; Applied microbiology; BACTERIA; Bacterial Toxins - administration & dosage; Bacterial Toxins - genetics; Bacteriology; Bangladesh; Biological and medical sciences; CELL; children; COLONIZATION FACTORS; DEVELOPING-COUNTRIES; DIARRHEA; dmLT; Double-Blind Method; edible vaccines; enterotoxigenic Escherichia coli; Enterotoxigenic Escherichia coli - immunology; Enterotoxins - administration & dosage; Enterotoxins - genetics; EPIDEMIOLOGY; Escherichia coli; Escherichia coli Infections - prevention & control; Escherichia coli Proteins - administration & dosage; Escherichia coli Proteins - genetics; Escherichia coli Vaccines - administration & dosage; Escherichia coli Vaccines - adverse effects; Escherichia coli Vaccines - immunology; ETEC; feces; Feces - chemistry; Female; Fundamental and applied biological sciences. Psychology; Human; Humans; IgA; immune response; Immunity, Mucosal; immunoglobulin A; Immunoglobulin A - analysis; Immunologi inom det medicinska området; Immunology; Immunology in the Medical Area; infants; INFECTION; Intestinal immunity; Male; Medicine; Microbiology; Miscellaneous; mucosal immunity; Mutant Proteins - administration & dosage; Mutant Proteins - genetics; Placebos - administration & dosage; Research & Experimental; Sweden; TRIAL; Vaccine; Vaccines, antisera, therapeutical immunoglobulins and monoclonal antibodies (general aspects); VOLUNTEERS; Young Adult; Sweden; Bangladesh; Intestinal immunity; Human; ST; IgA; CF; AE; SAS; GM; ALS; LT; Vaccine; ETEC; PBMCs; CTB; ASC; CT; LCTBA; PPS; mLT; SIgA; LTB; dmLT; MEV; LCTB A; cholera toxin; antibodies in lymphocyte supernatants assay; cholera toxin binding subunit; safety analysis set; antibody secreting cell; multivalent ETEC vaccine; secretory IgA; CTB/LTB hybrid protein; peripheral blood mononuclear cells; heat labile toxin; adverse event; geometric mean; heat labile toxin binding subunit; heat-stable toxin; single-mutant LT; enterotoxigenic Escherichia coli; double mutant LT; colonization factor; per protocol analysis set; Digestive system; Escherichia coli; Gut; Immunogenicity; Immunological adjuvant; Bacteria; Enterobacteriaceae
• ISSN: 0264-410X; 1873-2518; 1873-2518
• DOI: 10.1016/j.vaccine.2014.10.069

•We have tested a new oral killed ETEC vaccine±dmLT adjuvant in Swedish adults.•The vaccine contained E. coli bacteria overexpressing common colonization factors.•The vaccine also contained a recombinant hybrid LTB/CTB protein; LCTBA.•The vaccine was safe and induced immune responses to all major vaccine antigens.•dmLT enhanced mucosal responses to antigens present in low amounts in the vaccine. We have developed a new oral vaccine against enterotoxigenic Escherichia coli (ETEC), which is the most common cause of bacterial diarrhea in children in developing countries and in travelers. The vaccine was tested for safety and immunogenicity alone and together with double-mutant heat-labile toxin (dmLT) adjuvant in a double-blind, placebo-controlled Phase I study in 129 Swedish adults. The vaccine consists of four inactivated recombinant E. coli strains overexpressing the major ETEC colonization factors (CFs) CFA/I, CS3, CS5, and CS6 mixed with an LT B-subunit related toxoid, LCTBA. Volunteers received two oral doses of vaccine alone, vaccine plus 10μg or 25μg dmLT or placebo. Secretory IgA antibody responses in fecal samples and IgA responses in secretions from circulating intestine-derived antibody secreting cells were assessed as primary measures of vaccine immunogenicity. The vaccine was safe and well tolerated; adverse events were few and generally mild with no significant differences between subjects receiving placebo or vaccine with or without adjuvant. As many as 74% of subjects receiving vaccine alone and 83% receiving vaccine plus 10μg dmLT showed significant mucosal IgA responses to all five primary vaccine antigens and about 90% of all vaccinees responded to at least four of the antigens. Subjects receiving vaccine plus 10μg dmLT responded with significantly increased intestine-derived anti-CS6 responses compared to subjects receiving vaccine alone. The vaccine was safe and broadly immunogenic. dmLT further enhanced mucosal immune responses to CF antigens present in low amounts in the vaccine. Based on these encouraging results, the vaccine will be tested for safety and immunogenicity in different age groups including infants in Bangladesh and for protective efficacy in travelers.