Anna Lundgren1, Louis Bourgeois2, Nils Carlin3, John Clements4, Björn Gustafsson5, Marianne Hartford6, Jan Holmgren7, Max Petzold8, Richard Walker9, Ann-Mari Svennerholm10. 1. University of Gothenburg Vaccine Research Institute (GUVAX), Dept. of Microbiology and Immunology, University of Gothenburg, Box 435, 405 30 Gothenburg, Sweden. Electronic address: anna.lundgren@microbio.gu.se. 2. PATH, 455 Massachusetts Ave, NW, WA, DC 20001, USA. Electronic address: lbourgeois@path.org. 3. Scandinavian Biopharma, Gunnar Asplunds allé 16, 171 63 Solna, Sweden. Electronic address: nils.carlin@etvax.se. 4. Department of Microbiology and Immunology, Tulane University School of Medicine, New Orleans, LA 70112, USA. Electronic address: jclemen@tulane.edu. 5. Scandinavian Biopharma, Gunnar Asplunds allé 16, 171 63 Solna, Sweden. Electronic address: bjorn.gustafsson@etvax.se. 6. Clinical Trial Center, Sahlgrenska University Hospital, Gröna stråket 12, 413 45 Gothenburg, Sweden. Electronic address: amhgbg@gmail.com. 7. University of Gothenburg Vaccine Research Institute (GUVAX), Dept. of Microbiology and Immunology, University of Gothenburg, Box 435, 405 30 Gothenburg, Sweden. Electronic address: jan.holmgren@microbio.gu.se. 8. Centre for Applied Biostatistics, Sahlgrenska Academy, University of Gothenburg, Box 414, 405 30 Gothenburg, Sweden. Electronic address: max.petzold@gu.se. 9. PATH, 455 Massachusetts Ave, NW, WA, DC 20001, USA. Electronic address: rwalker@path.org. 10. University of Gothenburg Vaccine Research Institute (GUVAX), Dept. of Microbiology and Immunology, University of Gothenburg, Box 435, 405 30 Gothenburg, Sweden. Electronic address: ann-mari.svennerholm@microbio.gu.se.
Abstract
BACKGROUND: 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. METHODS: 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 10 μg or 25 μg 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. RESULTS: 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 10 μg 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 10 μg dmLT responded with significantly increased intestine-derived anti-CS6 responses compared to subjects receiving vaccine alone. CONCLUSIONS: 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.
BACKGROUND: 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. METHODS: 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 10 μg or 25 μg 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. RESULTS: 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 10 μg 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 10 μg dmLT responded with significantly increased intestine-derived anti-CS6 responses compared to subjects receiving vaccine alone. CONCLUSIONS: 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.
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