Effects of BCG on Immune Response

NCT02085590 | Completed Phase 2 DMC

• 1 other identifier: BCG-LPS
• Study Type: interventional
• Target: 20
• Locations: 1 country
• Sites: 1

Brief Summary

In the present study, we want to investigate whether BCG-vaccination enhances the innate immune response in humans in vivo during (single) human endotoxemia. In a future experiment we will investigate whether BCG-vaccination can reverse the tolerant state observed upon a second LPS administration. Our goal is to ultimately translate our results into clinic applications to reverse for example sepsis-induced immunoparalysis.

Conditions

Sepsis

Keywords

BCG vaccine; Sepsis; Immunity

Outcome Measures

Primary Outcomes (1)

• To determine the effects of γ-irradiated BCG-vaccination on the in vivo innate immune responses induced by human endotoxemia.

  This will be determined by measuring plasma levels of various pro- and anti-inflammatory cytokines and assessing the difference in the Lipopolysacharide (LPS)-induced cytokine response between γ-irradiated BCG-vaccinated subjects and placebo-treated control subjects.

  Several time points within 1 month after vaccination

Secondary Outcomes (5)

• To determine the effects of γ-irradiated BCG-vaccination on ex vivo responsiveness of leukocytes to various inflammatory stimuli.

  Several time points within 1 month after vaccination

• To determine the effects of γ-irradiated BCG-vaccination on the phenotype of circulating monocytes

  Several time points within 1 month after vaccination

• To determine the effects of γ-irradiated BCG-vaccination on inflammatory transcriptional pathways (by use of qPCR/microarrays)

  Several time points within 1 month after vaccination

• To determine the effects of γ-irradiated BCG-vaccination on epigenetic changes, including H3K4 trimethylation, in circulating immune cells.

  Several time points within 1 month after vaccination

• To determine the effects of γ-irradiated BCG-vaccination on LPS-induced clinical symptoms (illness score) and hemodynamic/temperature changes.

  Several time points within an 8 hour period following LPS-exposure

Study Arms (2)

BCG vaccine

ACTIVE COMPARATOR

BCG vaccine SSI, 0.75mg/ml, injection 0.1 cc intradermal

Biological: BCG vaccine; Biological: Lipopolysaccharide (LPS) E. Coli 1 ng/kg intravenously

NaCl 0.9%

PLACEBO COMPARATOR

injection 0.1 cc intradermal

Biological: Lipopolysaccharide (LPS) E. Coli 1 ng/kg intravenously

Interventions

BCG vaccine BIOLOGICAL

Also known as: BCG vaccine SSI, Bacille Calmette-Guérin, RVG 17661

BCG vaccine

Lipopolysaccharide (LPS) E. Coli 1 ng/kg intravenously BIOLOGICAL

Also known as: Lipopolysaccharide, LPS, Endotoxin derived from E. Coli

BCG vaccine; NaCl 0.9%

Eligibility Criteria

• Age: 18 Years - 35 Years
• Sex: male
• Healthy Volunteers: Yes
• Age Groups: Adult (18-64)

You may qualify if:

• Written informed consent
• Age ≥18 and ≤35 yrs
• Male
• Healthy

You may not qualify if:

• Use of any medication
• History of BCG-vaccination
• Vaccination other than BCG, within 3 months prior to study or within study period
• Tuberculin skin test (Mantoux) in last year
• Smoking
• Previous spontaneous vagal collapse
• History of atrial or ventricular arrhythmia
• (Family) history of myocardial infarction or stroke under the age of 65 years
• Cardiac conduction abnormalities on the ECG consisting of a 2nd degree atrioventricular block or a complex bundle branch block
• Hypertension (defined as RR systolic \> 160 or RR diastolic \> 90)
• Hypotension (defined as RR systolic \< 100 or RR diastolic \< 50)
• Renal impairment (defined as plasma creatinin \>120 μmol/l)
• Liver enzyme abnormalities or positive hepatitis serology
• Medical history of any disease associated with immune deficiency
• CRP \> 20 mg/L, WBC \> 12x109/L, or clinically significant acute illness, including infections, within 4 weeks before endotoxin administration

Sponsors & Collaborators

• Radboud University Medical Center: lead

Study Sites (1)

Radboud University Medical Centre, Intensive Care

Nijmegen, 6525 GA, Netherlands

Location

Related Publications (5)

• Angus DC, Linde-Zwirble WT, Lidicker J, Clermont G, Carcillo J, Pinsky MR. Epidemiology of severe sepsis in the United States: analysis of incidence, outcome, and associated costs of care. Crit Care Med. 2001 Jul;29(7):1303-10. doi: 10.1097/00003246-200107000-00002.

  PMID: 11445675 BACKGROUND

• Leentjens J, Kox M, van der Hoeven JG, Netea MG, Pickkers P. Immunotherapy for the adjunctive treatment of sepsis: from immunosuppression to immunostimulation. Time for a paradigm change? Am J Respir Crit Care Med. 2013 Jun 15;187(12):1287-93. doi: 10.1164/rccm.201301-0036CP.

  PMID: 23590272 BACKGROUND

• Kleinnijenhuis J, Quintin J, Preijers F, Joosten LA, Ifrim DC, Saeed S, Jacobs C, van Loenhout J, de Jong D, Stunnenberg HG, Xavier RJ, van der Meer JW, van Crevel R, Netea MG. Bacille Calmette-Guerin induces NOD2-dependent nonspecific protection from reinfection via epigenetic reprogramming of monocytes. Proc Natl Acad Sci U S A. 2012 Oct 23;109(43):17537-42. doi: 10.1073/pnas.1202870109. Epub 2012 Sep 17.

  PMID: 22988082 BACKGROUND

• Kleinnijenhuis J, Quintin J, Preijers F, Benn CS, Joosten LA, Jacobs C, van Loenhout J, Xavier RJ, Aaby P, van der Meer JW, van Crevel R, Netea MG. Long-lasting effects of BCG vaccination on both heterologous Th1/Th17 responses and innate trained immunity. J Innate Immun. 2014;6(2):152-8. doi: 10.1159/000355628. Epub 2013 Oct 30.

  PMID: 24192057 BACKGROUND

• Hamers LA, Kox M, Arts RJ, Blok B, Leentjens J, Netea MG, Pickkers P. Gamma-irradiated bacille Calmette-Guerin vaccination does not modulate the innate immune response during experimental human endotoxemia in adult males. J Immunol Res. 2015;2015:261864. doi: 10.1155/2015/261864. Epub 2015 Mar 26.

  PMID: 25883989 DERIVED

MeSH Terms

Conditions

Sepsis

Interventions

BCG Vaccine; Lipopolysaccharides

Condition Hierarchy (Ancestors)

Infections; Systemic Inflammatory Response Syndrome; Inflammation; Pathologic Processes; Pathological Conditions, Signs and Symptoms

Intervention Hierarchy (Ancestors)

Tuberculosis Vaccines; Bacterial Vaccines; Vaccines; Biological Products; Complex Mixtures; Glycoconjugates; Carbohydrates; Polysaccharides, Bacterial; Polysaccharides; Lipids; Antigens, Bacterial; Antigens; Biological Factors; Endotoxins; Bacterial Toxins; Toxins, Biological

Study Officials

• Peter Pickkers, Prof.

  Radboud University Medical Center

  STUDY DIRECTOR

Study Design

• Study Type: interventional
• Phase: phase 2
• Allocation: RANDOMIZED
• Masking: QUADRUPLE
• Who Masked: PARTICIPANT, CARE PROVIDER, INVESTIGATOR, OUTCOMES ASSESSOR
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: OTHER
• Responsible Party: PRINCIPAL INVESTIGATOR
• PI Title: Ph.D.

Study Record Dates

• First Submitted: March 11, 2014
• First Posted: March 13, 2014
• Study Start: March 1, 2014
• Primary Completion: October 1, 2014
• Study Completion: November 1, 2014
• Last Updated: May 13, 2015

Record last verified: 2015-05

Locations

NL (1)