@article{f21fbf57fd1b4cb1b250fccf3ea7dad7,
title = "Evaluation of the safety and immunogenicity of the oral inactivated multivalent enterotoxigenic Escherichia coli vaccine ETVAX in Bangladeshi adults in a double-blind, randomized, placebo-controlled Phase I trial using electrochemiluminescence and ELISA assays for immunogenicity analyses",
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.",
keywords = "Adult, Antibodies in lymphocyte supernatant, Antibody-secreting cell, ELISA, ETEC, Electrochemiluminescence, IgA, Vaccine",
author = "Marjahan Akhtar and Chowdhury, {Mohiul I.} and Bhuiyan, {Taufiqur R.} and Joanna Kaim and Tasnuva Ahmed and Rafique, {Tanzeem A.} and Arifuzzaman Khan and Rahman, {Sadia I.A.} and Farhana Khanam and Begum, {Yasmin A.} and Sharif, {Mir Z.} and Islam, {Laila N.} and Nils Carlin and Nicole Maier and Alan Fix and Wierzba, {Thomas F.} and Walker, {Richard I.} and Bourgeois, {A. Louis} and Svennerholm, {Ann Mari} and Firdausi Qadri and Anna Lundgren",
note = "Funding Information: We acknowledge the support of the study participants as well as the dedicated field and laboratory workers in this study at icddr,b. The work was supported by icddr,b with funding from PATH through its enteric vaccine project (grant no. GR01263) from the Bill and Melinda Gates Foundation, the Swedish Research Council (grant number VR 348-2013-6615), the British Department of International Development (program number 300341-107) and the Swedish Foundation for Strategic Research (grant number SB12-0072). icddr,b is thankful to the institutional donors for their support to its research efforts. icddr,b is also grateful to the governments of Bangladesh, Canada, Sweden and the UK for providing core/unrestricted support. AMS, FQ, AL, TRB, NC, NM, AF, RW, LB and TW designed the studies. MIC, TA, FK, AK, and MZS performed the clinical work. MA, JK, TAR, YAB and SIAR performed the immunological analyses. MA, AL, FQ, LNI and AMS wrote the manuscript. All authors contributed to the interpretation of results and critical review and revision of the manuscript and have approved the final version. The nonprofit organization PATH Vaccine Solution participated in the design of the studies, interpretation of results and reviewed the manuscript. The other funding sources only contributed financially to the study. NC is employee and minority shareholder of Scandinavian Biopharma Holding AB, which holds certain commercial rights to the vaccine tested in this study. NC has patents PCT/EP2012/067598 and PCT/EP2011/065784. A-M Svennerholm is shareholder of the biotech company Gotovax AB that may receive a small royalty on sales of the ETEC vaccine if it becomes a commercial product. The other authors declare that they have no conflicts of interest. Funding Information: We acknowledge the support of the study participants as well as the dedicated field and laboratory workers in this study at icddr,b. The work was supported by icddr,b with funding from PATH through its enteric vaccine project (grant no. GR01263 ) from the Bill and Melinda Gates Foundation , the Swedish Research Council (grant number VR 348-2013-6615 ), the British Department of International Development (program number 300341-107 ) and the Swedish Foundation for Strategic Research (grant number SB12-0072 ). icddr,b is thankful to the institutional donors for their support to its research efforts. icddr,b is also grateful to the governments of Bangladesh, Canada, Sweden and the UK for providing core/unrestricted support. Publisher Copyright: {\textcopyright} 2018 The Authors",
year = "2019",
month = sep,
day = "3",
doi = "10.1016/j.vaccine.2018.11.040",
language = "English (US)",
volume = "37",
pages = "5645--5656",
journal = "Vaccine",
issn = "0264-410X",
publisher = "Elsevier BV",
number = "37",
}