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Development and preclinical evaluation of safety and immunogenicity of an oral ETEC vaccine containing inactivated E. coli bacteria overexpressing colonization factors CFA/I, CS3, CS5 and CS6 combined with a hybrid LT/CT B subunit antigen, administered alone and together with dmLT adjuvant
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2013 (Engelska)Ingår i: Vaccine, ISSN 0264-410X, E-ISSN 1873-2518, Vol. 31, nr 20, s. 2457-2464Artikel i tidskrift (Refereegranskat) Published
Abstract [en]

A first-generation oral inactivated whole-cell enterotoxigenic Escherichia coli (ETEC) vaccine, comprising formalin-killed ETEC bacteria expressing different colonization factor (CF) antigens combined with cholera toxin B subunit (CTB), when tested in phase III studies did not significantly reduce overall (generally mild) ETEC diarrhea in travelers or children although it reduced more severe ETEC diarrhea in travelers by almost 80%. We have now developed a novel more immunogenic ETEC vaccine based on recombinant non-toxigenic E. coli strains engineered to express increased amounts of CF antigens, including CS6 as well as an ETEC-based B subunit protein (LCTB. A), and the optional combination with a nontoxic double-mutant heat-labile toxin (LT) molecule (dmLT) as an adjuvant.Two test vaccines were prepared under GMP: (1) A prototype E. coli CFA/I-only formalin-killed whole-cell. +. LCTB. A vaccine, and (2) A "complete" inactivated multivalent ETEC-CF (CFA/I, CS3, CS5 and CS6 antigens) whole-cell. +. LCTB. A vaccine. These vaccines, when given intragastrically alone or together with dmLT in mice, were well tolerated and induced strong intestinal-mucosal IgA antibody responses as well as serum IgG and IgA responses to each of the vaccine CF antigens as well as to LT B subunit (LTB). Both mucosal and serum responses were further enhanced (adjuvanted) when the vaccines were co-administered with dmLT. We conclude that the new multivalent oral ETEC vaccine, both alone and especially in combination with the dmLT adjuvant, shows great promise for further testing in humans. 

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2013. Vol. 31, nr 20, s. 2457-2464
Nyckelord [en]
Colonization factors, DmLT, ETEC, Immune responses, Mucosal immunity, Vaccine, bacterial antigen, bacterial vaccine, colonization factor CFA/I, colonization factor CS3, colonization factor CS5, colonization factor CS6, double mutant heat labile toxin, enterotoxigenic Escherichia coli vaccine, hybrid protein, immunoglobulin A antibody, toxin, unclassified drug, adjuvant therapy, animal experiment, animal model, antibody blood level, antibody response, antibody titer, article, bacterial colonization, controlled study, drug safety, Escherichia coli, female, immune response, immunization, immunogenicity, immunological memory, mouse, nonhuman, operon, priority journal, protein subunit, Adjuvants, Immunologic, Administration, Oral, Animals, Antibody Formation, Antigens, Bacterial, Bacterial Toxins, Cholera Toxin, Enterotoxigenic Escherichia coli, Enterotoxins, Escherichia coli Infections, Escherichia coli Proteins, Escherichia coli Vaccines, Fimbriae Proteins, Immunity, Mucosal, Immunoglobulin A, Immunoglobulin G, Intestines, Mice, Mice, Inbred BALB C, Mutant Proteins, Vaccines, Inactivated
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Naturvetenskap
Identifikatorer
URN: urn:nbn:se:ri:diva-56876DOI: 10.1016/j.vaccine.2013.03.027Scopus ID: 2-s2.0-84877034427OAI: oai:DiVA.org:ri-56876DiVA, id: diva2:1612591
Anmärkning

Funding details: PATH; Funding details: Västra Götalandsregionen; Funding details: Vetenskapsrådet, VR; Funding text 1: The skilled technical assistance of Gudrun Wiklund in vaccine development and characterization, and of Margareta Blomquist, Annelie Ekman, Maria Hellman and Madeleine Löfstrand in animal experiments and immunological analyses is gratefully acknowledged. We also gratefully acknowledge the GMP production of PV and EV by Unitech Biopharma, Matfors, Sweden, and of dmLT by the Walter Reed Army Institute of Research Pilot Bioproduction Facility, Silver Spring, MD, USA and the GLP toxicity studies performed by Visonar AB, Stockholm, Sweden. The studies were financially supported by PATH, the Swedish Research Council , and the Västra Götaland Region ALF funds .

Tillgänglig från: 2021-11-18 Skapad: 2021-11-18 Senast uppdaterad: 2021-11-18Bibliografiskt granskad

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