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      Intradermal or Sublingual Delivery and Heat-Labile Enterotoxin Proteins Shape Immunologic Responses to a CFA/I Fimbria-Derived Subunit Antigen Vaccine against Enterotoxigenic Escherichia coli

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          Abstract

          Enterotoxigenic Escherichia coli (ETEC) is a major cause of infectious diarrhea in children, travelers, and deployed military personnel. As such, development of a vaccine would be advantageous for public health. One strategy is to use subunits of colonization factors combined with antigen/adjuvant toxoids as an ETEC vaccine.

          ABSTRACT

          Enterotoxigenic Escherichia coli (ETEC) is a major cause of infectious diarrhea in children, travelers, and deployed military personnel. As such, development of a vaccine would be advantageous for public health. One strategy is to use subunits of colonization factors combined with antigen/adjuvant toxoids as an ETEC vaccine. Here, we investigated the intradermal (i.d.) or sublingual (s.l.) delivery of CFA/I fimbrial antigens, including CfaEB and a CfaE-heat-labile toxin B subunit (LTB) chimera admixed with double mutant heat-labile toxin (LT) LT-R192G/L211A (dmLT). In addition, we compared dmLT with other LT proteins to better understand the generation of adjuvanted fimbrial and toxoid immunity as well as the influence on any local skin reactogenicity. We demonstrate that immunization with dmLT admixed with CfaEB induces robust serum and fecal antibody responses to CFA/I fimbriae and LT but that i.d. formulations are not optimal for s.l. delivery. Improved s.l. vaccination outcomes were observed when higher doses of dmLT (1 to 5 μg) were admixed with CfaEB or, even better, when a CfaE-LTB chimera antigen was used instead. Serum anti-CFA/I total antibodies, detected by enzyme-linked immunosorbent assay, were the best predictor of functional antibodies, based on the inhibition of red blood cell agglutination by ETEC. Immunization with other LT proteins or formulations with altered B-subunit binding during i.d. immunization (e.g., by addition of 5% lactose, LTA1, or LT-G33D) minimally altered the development of antibody responses and cytokine recall responses but reduced skin reactogenicity at the injection site. These results reveal how formulations and delivery parameters shape the adaptive immune responses to a toxoid and fimbria-derived subunit vaccine against ETEC.

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          Author and article information

          Contributors
          Role: Editor
          Journal
          Infect Immun
          Infect. Immun
          iai
          iai
          IAI
          Infection and Immunity
          American Society for Microbiology (1752 N St., N.W., Washington, DC )
          0019-9567
          1098-5522
          19 August 2019
          18 October 2019
          November 2019
          : 87
          : 11
          : e00460-19
          Affiliations
          [a ] Henry M. Jackson Foundation for the Advancement of Military Medicine, Bethesda, Maryland, USA
          [b ] Department of Microbiology and Immunology, Uniformed Services University of the Health Sciences, Bethesda, Maryland, USA
          [c ] Department of Microbiology and Immunology, Tulane University School of Medicine, New Orleans, Louisiana, USA
          [d ] Subunit Enteric Vaccines and Immunology, Walter Reed Army Institute of Research, Silver Spring, Maryland, USA
          [e ] Enteric Diseases Department, Naval Medical Research Center, Silver Spring, Maryland, USA
          University of California San Diego School of Medicine
          Author notes
          Address correspondence to Elizabeth B. Norton, enorton@ 123456tulane.edu .
          [*]

          Present address: Stephen J. Savarino, Sanofi Pasteur, Swiftwater, Pennsylvania, USA.

          M.M. and D.B. are co-first authors.

          Citation Maciel M, Jr, Bauer D, Baudier RL, Bitoun J, Clements JD, Poole ST, Smith MA, Kaminski RW, Savarino SJ, Norton EB. 2019. Intradermal or sublingual delivery and heat-labile enterotoxin proteins shape immunologic responses to a CFA/I fimbria-derived subunit antigen vaccine against enterotoxigenic Escherichia coli. Infect Immun 87:e00460-19. https://doi.org/10.1128/IAI.00460-19.

          Author information
          https://orcid.org/0000-0001-7110-2328
          https://orcid.org/0000-0002-4015-5694
          Article
          PMC6803349 PMC6803349 6803349 00460-19
          10.1128/IAI.00460-19
          6803349
          31427449
          05971cb4-3151-452d-9736-a7d0431c3a78
          Copyright © 2019 American Society for Microbiology.

          All Rights Reserved.

          History
          : 14 June 2019
          : 31 July 2019
          : 8 August 2019
          Page count
          supplementary-material: 1, Figures: 7, Tables: 0, Equations: 0, References: 62, Pages: 17, Words: 10534
          Funding
          Funded by: HHS | NIH | National Institute of Allergy and Infectious Diseases (NIAID), https://doi.org/10.13039/100000060;
          Award ID: R01AI114697
          Award Recipient :
          Categories
          Microbial Immunity and Vaccines
          Custom metadata
          November 2019

          vaccine,sublingual,intradermal,dmLT,LTA1,ETEC,CFA/I
          vaccine, sublingual, intradermal, dmLT, LTA1, ETEC, CFA/I

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