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Genetically modified enterotoxigenic Escherichia coli vaccines induce mucosal immune responses without inflammation
  1. Alexandra Daley1,
  2. Roger Randall2,
  3. Michael Darsley2,*,
  4. Naheed Choudhry1,
  5. Nicola Thomas2,
  6. Ian R Sanderson1,
  7. Nick M Croft1,
  8. Paul Kelly1
  1. 1
    Centre for Adult & Paediatric Gastroenterology, Institute of Cell and Molecular Science, Barts & The London, Queen Mary’s School of Medicine and Dentistry, London, UK
  2. 2
    Acambis Research Limited, Peterhouse Technology Park, Fulbourn Road, Cambridge, UK
  1. Dr Paul Kelly , MD, FRCP, Centre for Adult & Paediatric Gastroenterology, Institute of Cell and Molecular Science, Barts & The London School of Medicine, Turner Street, London E1 2AD, UK; m.p.kelly{at}


Objective: Enterotoxigenic Escherichia coli (ETEC) is a major cause of acute diarrhoea in children in the developing world, in travellers and in the military. Safe, effective vaccines could reduce morbidity and mortality. As immunity to ETEC is strain specific, the ability to create vaccines in vitro which express multiple antigens would be desirable. It was hypothesised that three genetically attenuated ETEC strains, one with a genetic addition, would be immunogenic and safe, and they were evaluated in the first licensed UK release of genetically modified oral vaccines.

Methods: Phase 1 studies of safety and immunogenicity were carried out at a Teaching Hospital in London. Varying oral doses of any of three oral vaccines, or placebo, were administered to volunteers of both sexes (n = 98). Peripheral blood responses were measured as serum antibodies (IgG or IgA) by ELISA, antibody-secreting cell (ASC) responses by enzyme-linked immunospot (ELISPOT), and antibody in lymphocyte supernatant (ALS) by ELISA. Mucosal antibody secretion was measured by ELISA for specific IgG and IgA in whole gut lavage fluids (WGLFs).

Results: Significant mucosal IgA responses were obtained to colonisation factors CFA/I, CS1, CS2 and CS3, both when naturally expressed and when genetically inserted. Dose–response relationships were most clearly evident in the mucosal IgA in WGLF. Vaccines were well tolerated and did not elicit interleukin (IL) 8 or IL6 secretion in WGLF.

Conclusions: Genetically modified ETEC vaccines are safe and induce significant mucosal IgA responses to important colonisation factors. Mucosal IgA responses were clearly seen in WGLF, which is useful for evaluating oral vaccines.

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  • Present address: ACE BioSciences A/S, Unsbjergvej 2A, Odense, DK-5220, Denmark

  • Funding: Acambis plc provided a research grant for Dr Daley to carry out these studies.

  • Competing interests: None.

  • Abbreviations:
    adverse event
    antibody in lymphocyte supernatant
    antibody-secreting cell
    colonisation factor antigen
    CS antigen
    coli surface antigen
    Department of the Environment, Food and Rural Affairs
    enzyme-linked immunospot
    enterotoxigenic Escherichia coli
    hepatitis B virus
    hepatitis C virus
    heat-labile toxin of ETEC
    peripheral blood mononuclear cells
    heat-stable toxin of ETEC
    whole gut lavage fluid

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