How to develop a controlled human infection model for Clostridioides difficile

Clinical Microbiology and Infection, vol. 31, pp. 373–379

Abstract

BACKGROUND: Clostridioides difficile (C. difficile) remains the leading cause of healthcare-associated diarrhoea, posing treatment challenges because of antibiotic resistance and high relapse rates. Faecal microbiota transplantation is a novel treatment strategy to prevent relapses of C. difficile infection (CDI), however, the exact components conferring colonization resistance are unknown, hampering its translation to a medicinal product. The development of novel products independent of antibiotics, which increase colonization resistance or induce protective immune mechanisms is urgently needed. OBJECTIVES: To establish a framework for a Controlled Human Infection Model (CHIM) of C. difficile, in which healthy volunteers are exposed to toxigenic C. difficile spores, offering the possibility to test novel approaches and identify microbiota and immunological targets. Whereas experimental exposure to non-toxigenic C. difficile has been done before, a toxigenic C. difficile CHIM faces ethical, scientific, logistical, and biosafety challenges. SOURCES: Specific challenges in developing a C. difficile CHIM were discussed by a group of international experts during a workshop organized by Inno4Vac, an Innovative Health Initiative-funded consortium. CONTENT: The experts agreed that the main challenges are: developing a clinically relevant CHIM that induces mild to moderate CDI symptoms but not severe CDI, determining the optimal C. difficile inoculum dose, and understanding the timing and duration of antibiotic pretreatment in inducing susceptibility to CDI in healthy volunteers. IMPLICATIONS: Should these challenges be tackled, a C. difficile CHIM will not only provide a way forward for the testing of novel products but also offer a framework for a better understanding of the pathophysiology, pathogenesis, and immunology of C. difficile colonization and infection.

Authors 18

1. Annefleur D. O. Hensen Aachen

   Leiden University · Leiden University Medical Center

   Affiliation as printed

   Leiden University Center for Infectious Diseases (LUCID), Leiden University Medical Center (LUMC), Leiden, The Netherlands

2. Maria J. G. T. Vehreschild

   University of Cologne · German Center for Infection Research · University Hospital Cologne

   Affiliation as printed

   Department of Internal Medicine, Division of Infectious Diseases, Faculty of Medicine and University Hospital Cologne, University of Cologne, Cologne, Germany; German Center for Infection Research (DZIF), Cologne, Germany

   Department of Internal Medicine, Division of Infectious Diseases, Faculty of Medicine and University Hospital Cologne, University of Cologne, Cologne, Germany

   German Center for Infection Research (DZIF), Cologne, Germany

3. Dale N. Gerding

   Edward Hines, Jr. VA Hospital

   Affiliation as printed

   Department of Veterans Affairs, Edward Hines Jr VA Hospital, Hines, IL, United States

4. Oleg Krut

   Paul Ehrlich Institut

   Affiliation as printed

   Paul-Ehrlich-Institut (PEI), Langen, Germany

5. Wilbur H. Chen

   University of Maryland, Baltimore

   Affiliation as printed

   Center for Vaccine Development and Global Health, University of Maryland School of Medicine, Baltimore, MD, United States

6. Vincent Bensan Young

   University of Michigan · Michigan Medicine

   Affiliation as printed

   Department of Internal Medicine/Infectious Diseases Division and the Department of Microbiology & Immunology, The University of Michigan, Ann Arbor, MI, United States

7. Saul Tzipori

   Tufts University

   Affiliation as printed

   Division of Infectious Disease and Global Health, Tufts University, Medford, MA, United States

8. Philipp Solbach

   University Hospital Schleswig-Holstein

   Affiliation as printed

   First Department of Medicine, University Medical Center Schleswig-Holstein, Kiel, Germany

9. Malick M. Gibani

   Imperial College London

   Affiliation as printed

   Department of Infectious Disease, Imperial College London (ICL), London, United Kingdom

10. Christopher Chiu

    Imperial College London

    Affiliation as printed

    Department of Infectious Disease, Imperial College London (ICL), London, United Kingdom

11. Sigrid C. J. De Keersmaecker

    Sciensano (Belgium)

    Affiliation as printed

    Transversal Activities in Applied Genomics, Sciensano, Brussels, Belgium

12. Dileep Dasyam

    GlaxoSmithKline (Belgium)

    Affiliation as printed

    GSK, Rixensart, Belgium

13. Sandra Morel

    GlaxoSmithKline (Belgium)

    Affiliation as printed

    GSK, Rixensart, Belgium

14. Jeanne‐Marie Devaster

    GlaxoSmithKline (Belgium)

    Affiliation as printed

    GSK, Rixensart, Belgium

15. Nicoletta Corti

    European Vaccine Initiative

    Affiliation as printed

    European Vaccine Initiative (EVI), Heidelberg, Germany

16. Ed J. Kuijper Aachen

    Leiden University · Leiden University Medical Center

    Affiliation as printed

    Leiden University Center for Infectious Diseases (LUCID), Leiden University Medical Center (LUMC), Leiden, The Netherlands

17. Meta Roestenberg corresponding Aachen

    Leiden University · Leiden University Medical Center

    Affiliation as printed

    Leiden University Center for Infectious Diseases (LUCID), Leiden University Medical Center (LUMC), Leiden, The Netherlands. Electronic address: m.roestenberg@lumc.nl

    Leiden University Center for Infectious Diseases (LUCID), Leiden University Medical Center (LUMC), Leiden, The Netherlands

18. Wiep Klaas Smits Aachen

    Leiden University · Leiden University Medical Center

    Affiliation as printed

    Leiden University Center for Infectious Diseases (LUCID), Leiden University Medical Center (LUMC), Leiden, The Netherlands