Abstract
The safety and immunogenicity of the second generation oral enterotoxigenic Escherichia coli (ETEC) vaccine ETVAX, consisting of inactivated recombinant E. coli strains over-expressing the colonization factors (CFs) CFA/I, CS3, CS5 and CS6 and the heat labile toxoid LCTBA, were evaluated in Bangladeshi volunteers. To enable analysis of antibody responses against multiple vaccine antigens for subsequent use in small sample volumes from children, a sensitive electrochemiluminescence (ECL) assay for analysis of intestine-derived antibody-secreting cell responses using the antibodies in lymphocyte secretions (ALS) assay was established using Meso Scale Discovery technology.Three groups of Bangladeshi adults (n = 15 per group) received two oral doses of ETVAX with or without double mutant LT (dmLT) adjuvant or placebo in the initial part of a randomized, double-blind, placebo-controlled, age-descending, dose-escalation trial. CF- and LTB-specific ALS and plasma IgA responses were analyzed by ECL and/or ELISA.ETVAX was safe and well tolerated in the adults. Magnitudes of IgA ALS responses determined by ECL and ELISA correlated well (r = 0.85 to 0.98 for the five primary antigens, P < 0.001) and ECL was selected as the ALS readout method. ALS IgA responses against each of the primary antigens were detected in 87–100% of vaccinees after the first and in 100% after the second vaccine dose. Plasma IgA responses against different CFs and LTB were observed in 62–93% and 100% of vaccinees, respectively. No statistically significant adjuvant effect of dmLT on antibody responses to any antigen was detected, but the overall antigenic breadth of the plasma IgA response tended to favor the adjuvanted vaccine when responses to 4 or more or 5 vaccine antigens were considered. Responses in placebo recipients were infrequent and mainly detected against single antigens.The promising results in adults supported testing ETVAX in descending age groups of children.ClinicalTrials.gov Identifier: NCT02531802.
Highlights
Enterotoxigenic Escherichia coli (ETEC) remains one of the most common bacterial pathogens causing diarrhea in children as well as adults in developing countries [1,2,3]
We show that two full doses of ETVAX, both when administered alone and with 10 mg double mutant heat labile toxin (LT) (dmLT) adjuvant, were safe and well tolerated in the healthy Bangladeshi adults tested, confirming previous safety data from studies in Swedish adults [15,16,18]
We further demonstrate that the vaccine is highly immunogenic in Bangladeshi adults, inducing intestine-derived antibodysecreting cell (ASC) responses as detected by the antibodies in lymphocyte supernatants (ALS) method in all, and plasma antibody responses in a majority, of the vaccinees to all primary vaccine antigens
Summary
Enterotoxigenic Escherichia coli (ETEC) remains one of the most common bacterial pathogens causing diarrhea in children as well as adults in developing countries [1,2,3]. The vaccine did not confer protection in 6–24 months old Egyptian children, but both vaccinated and unvaccinated children experienced mainly mild disease during the study period and the impact on moderate/severe diarrhea could not be evaluated [7] Based on these results, an improved second generation multivalent oral ETEC vaccine (ETVAX) was developed, containing inactivated E. coli strains over-expressing CFA/I, CS3, CS5 and CS6 antigens at significantly higher levels than the bacteria in the first generation vaccine [14]. Our recent results demonstrated that ETVAX may induce IgA antibody responses that cross-react with CFs belonging to the same CF families, possibly expanding the coverage of the vaccine [19] These successful results have led to clinical evaluation of ETVAX in a large phase I/II trial in adults and lower age groups (5 years to 6 months) in Bangladesh. The study included establishment of an ECL assay based on the MSD ECL technology for detection of ALS responses against multiple ETVAX antigens in small sample volumes for subsequent use in studies in younger age groups
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