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Induction of long term mucosal immunological memory in humans by an oral inactivated multivalent enterotoxigenic Escherichia coli vaccine

Journal article
Authors Anna Lundgren
Marianne Jertborn
Ann-Mari Svennerholm
Published in Vaccine
Volume 34
Issue 27
Pages 3132-3140
ISSN 0264-410X
Publication year 2016
Published at Institute of Biomedicine, Department of Microbiology and Immunology
Pages 3132-3140
Language en
Keywords ETEC, Oral vaccine, Immunological memory, Mucosal immunity, IgA, b-subunit vaccine, intestinal immune-responses, antibody-secreting cell, cholerae o1 infection, colonization factors, bangladeshi adults, dmlt, adjuvant, etec vaccine, double-blind, phase-i, Immunology, Research & Experimental Medicine
Subject categories Clinical Medicine


We have evaluated the capacity of an oral multivalent enterotoxigenic Escherichia call (ETEC) vaccine (MEV) to induce mucosal immunological memory. MEV consists of four inactivated E. coli strains over expressing the major colonization factors (CFs) CFA/I, CS3, CS5 and CS6 and the LTB-related toxoid LCTBA. Memory responses were analyzed by comparing the magnitudes and kinetics of intestine-derived antibody-secreting cell responses to a single dose of MEV in three groups of adult Swedish volunteers (n = 16-19 subjects per group) in a Phase I trial: non-immunized controls (I) and subjects who in a previous Phase I trial 13-23 months earlier had received two biweekly doses of MEV (II) or MEV + double mutant LT (dmLT) adjuvant (III). Responses against CFs and LTB were analyzed in antibodies in lymphocyte secretions (ALS) of blood mononuclear cells collected before (day 0) and 4/5 and 7 days after immunization. Specific circulating memory B cells present at the time of the single dose vaccination were also studied to determine if such cells may reflect mucosal memory. Considerably higher and significantly more frequent IgA ALS responses against all CFs and LTB were induced by the single vaccine dose in the previously immunized than in non-immunized volunteers. Furthermore, peak IgA ALS responses against all antigens were observed on days 4/5 in most of the previously immunized subjects whereas only a few previously non-vaccinated individuals responded before day 7. Priming with adjuvant did not influence memory responses. Circulating vaccine specific IgA memory B cells were not detected, whereas anti-toxin IgG memory B cells were identified 13-23 months after priming vaccination. We conclude that MEV induces functional mucosal immunological memory which remains at least 1-2 years. Furthermore, our results support that analysis of antibody-secreting cell responses after booster vaccination may be a useful approach to evaluate longstanding mucosal immunological memory in humans. Clinical trials registration: ISRCTN27096290.

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