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

Anna Lundgren, Louis Bourgeois, Nils Carlin, John Clements, Björn Gustafsson, Marianne Hartford, Jan Holmgren, Max Petzold, Richard Walker, Ann Mari Svennerholm

Research output: Contribution to journalArticle

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, LCTB. A. 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.

Original languageEnglish (US)
Pages (from-to)7077-7084
Number of pages8
JournalVaccine
Volume32
Issue number52
DOIs
StatePublished - Dec 12 2014
Externally publishedYes

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Escherichia coli Vaccines
Enterotoxigenic Escherichia coli
enterotoxigenic Escherichia coli
adjuvants
placebos
mouth
toxins
Vaccines
Hot Temperature
Placebos
immune response
vaccines
heat
Safety
mutants
antigens
Immunoglobulin A
Intestines
intestines
Toxoids

Keywords

  • DmLT
  • ETEC
  • Human
  • IgA
  • Intestinal immunity
  • Vaccine

ASJC Scopus subject areas

  • Immunology and Microbiology(all)
  • Infectious Diseases
  • Public Health, Environmental and Occupational Health
  • veterinary(all)
  • Molecular Medicine
  • Medicine(all)

Cite this

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. / Lundgren, Anna; Bourgeois, Louis; Carlin, Nils; Clements, John; Gustafsson, Björn; Hartford, Marianne; Holmgren, Jan; Petzold, Max; Walker, Richard; Svennerholm, Ann Mari.

In: Vaccine, Vol. 32, No. 52, 12.12.2014, p. 7077-7084.

Research output: Contribution to journalArticle

Lundgren, Anna ; Bourgeois, Louis ; Carlin, Nils ; Clements, John ; Gustafsson, Björn ; Hartford, Marianne ; Holmgren, Jan ; Petzold, Max ; Walker, Richard ; Svennerholm, Ann Mari. / 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. In: Vaccine. 2014 ; Vol. 32, No. 52. pp. 7077-7084.
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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, LCTB. A. 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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T1 - 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

AU - Lundgren, Anna

AU - Bourgeois, Louis

AU - Carlin, Nils

AU - Clements, John

AU - Gustafsson, Björn

AU - Hartford, Marianne

AU - Holmgren, Jan

AU - Petzold, Max

AU - Walker, Richard

AU - Svennerholm, Ann Mari

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KW - Human

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KW - Intestinal immunity

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