Influence of BCG on TDaP-IPV Vaccination

The Influence of BCG Vaccine as a Booster TDaP-IPV Vaccination: an Explorative Study

This study has three purposes:

To investigate whether the immune response to pertussis is increased when TDaP-IPV is given together with BCG vaccine, compared to when it is given alone.

To investigate whether BCG vaccination modulates the immune response to non vaccine target antigens (i.e., antigens/pathogens not used in the vaccine itself).

To investigate whether TDaP-IPV vaccination modulates the immune response to non vaccine target antigens.

Study Overview

• Status: Unknown
• Conditions: Whooping Cough
• Intervention / Treatment: Biological: BCG vaccine (SSI); Biological: TDaP-IPV vaccine

Detailed Description

Rationale: The Bacillus Calmette-Guerin (BCG) vaccine not only protects against Mycobacterium tuberculosis, but has also been shown to reduce morbidity and mortality caused by non-related infections. This effect is likely due to non-specific immunomodulatory effects, at least in part on the innate immune system. Additionally, BCG has been shown to improve immunogenicity of other vaccinations. In contrast, whilst the diphtheria-tetanus-pertussis (DTP) combination vaccine protects against infection with Bordetella pertussis, Clostridium tetani and Corynebacterium diphtheria, it has also been associated with increased mortality due to unrelated infections, particularly in girls in high-mortality countries.

Although widespread DTP vaccination has initially reduced pertussis mortality, the disease has persisted and recently resurged in a number of countries with highly vaccinated populations, including the Netherlands. This has been partially attributed to the switch from a whole-cell vaccine (which is still being used in low-income countries) to a more defined acellular pertussis vaccine, which only protects for a limited period (5-8 years). Strategies to improve the efficacy of pertussis vaccination are therefore urgently required.

As the BCG vaccine has already been used to improve the immunogenicity of other vaccines, the investigators hypothesize that BCG vaccination before or at the same time of DTP vaccination increases the immunogenicity of the DTP vaccine in terms of antibody and T-cell responses to pertussis. Moreover, the investigators aim to assess the effect of DTP vaccination on the known long-term beneficial non-specific effects of BCG on non-mycobacterial infections.

Objective: To examine the effect of BCG as an adjuvant on DTP vaccination, and to investigate the non-specific training effects of BCG and DTP, alone and in combination, on the innate immune system.

Study population: Healthy adult volunteers.

Main study parameters: Comparison of pertussis-specific antibody and T-cell responses, as well as gene transcription between BCG, TDaP-IPV and BCG+TDaP-IPV vaccinated groups. Comparison of cytokine responses to unrelated antigens and/or pathogens before and after BCG, TDaP-IPV or BCG+TDaP-IPV vaccination.

Nature and extent of the burden and risks associated with participation, benefit and group relatedness: There is no direct benefit to the study participants but these results will potentially lead to novel strategies to optimize vaccinations. The risks for participants are negligible, with the only expected risks being minor side-effects from vaccination and local hematoma forming at the site of venepuncture. This will be minimized by the performance of these procedures by experienced personnel.

• Study Type: Interventional
• Enrollment (Anticipated): 75
• Phase: Phase 4

Contacts and Locations

Study Locations

• Netherlands
  • Nijmegen, Netherlands, 6500HB
    • Radbdoudumc

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 55 years (Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: Female

Description

Inclusion Criteria:

• healthy females

Exclusion Criteria:

• systemic medication use other than oral contraceptive drugs
• history of disease resulting in immunodeficiency
• previous vaccination with BCG
• pregnancy
• allergy to neomycin or polymyxin
• known previous allergic reaction to vaccination with diphteria, tetanus, pertussis or polio vaccines
• One of following phenomena after previous vaccination with pertussis containing antigens: Fever >40 °C within 48 hours after vaccination, hypotonous-hyporesponsiveness episode within 48 hours after vaccination, convulsions with or without fever within 3 days after vaccination

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Basic Science
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: None (Open Label)

Number of Arms

3

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: BCG; Subjects are vaccinated with BCG vaccine (SSI) alone, 0,1ml intradermal	Biological: BCG vaccine (SSI)
Experimental: TDaP-IPV; Subjects are vaccinated with TDaP-IPV vaccine (Boostrix Polio) vaccine alone, 0,5ml intramuscular	Biological: TDaP-IPV vaccine
Experimental: BCG+TDaP-IPV; Subjects are vaccinated with BCG vaccine (SSI) (0.1ml intradermal) and TDaP-IPV vaccine Boostrix Polio (0.5ml intramuscular) simultaneously	Biological: BCG vaccine (SSI); Biological: TDaP-IPV vaccine

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Antibody response to TDaP-IPV	antibody titers to antigens in the TDaP-IPV (PT, FHA, Prn, DT, TT) will be measured.	2 weeks
Antibody response to TDaP-IPV	antibody titers to antigens in the TDaP-IPV (PT, FHA, Prn, DT, TT) will be measured.	3 months
Antibody response to TDaP-IPV	antibody titers to antigens in the TDaP-IPV (PT, FHA, Prn, DT, TT) will be measured.	1 year
T-cell response to TDaP-IPV	T-cell responses will be measured by FACS	2 weeks
T-cell response to TDaP-IPV	T-cell responses will be measured by FACS	3 months
T-cell response to TDaP-IPV	T-cell responses will be measured by FACS	1 year
PBMC cytokine response to pertussis related antigens	IL-6, TNF, IL-1b, IL-10, IL-17, IL-22, IFN-g	2 weeks
PBMC cytokine response to pertussis related antigens	IL-6, TNF, IL-1b, IL-10, IL-17, IL-22, IFN-g	3 months
PBMC cytokine response to pertussis related antigens	IL-6, TNF, IL-1b, IL-10, IL-17, IL-22, IFN-g	1 year
B-cell phenotype analysis	pertussis specific B-cells will be analyzed by FACS	2 weeks
B-cell phenotype analysis	pertussis specific B-cells will be analyzed by FACS	3 months
B-cell phenotype analysis	pertussis specific B-cells will be analyzed by FACS	1 year

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
PBMC responses to heterologous antigens	PBMCs will be stimulated with LPS, S. aureus, C.albicans, PHA, S.pneumoniae, zymosan. Responses on cytokine levels (IL-6, TNF, IL-1b, IL-10, IL-17, IL-22, IFN-g) and ROS production will be measured	1 day
PBMC responses to heterologous antigens	PBMCs will be stimulated with LPS, S. aureus, C.albicans, PHA, S.pneumoniae, zymosan. Responses on cytokine levels (IL-6, TNF, IL-1b, IL-10, IL-17, IL-22, IFN-g) and ROS production will be measured	4 days
PBMC responses to heterologous antigens	PBMCs will be stimulated with LPS, S. aureus, C.albicans, PHA, S.pneumoniae, zymosan. Responses on cytokine levels (IL-6, TNF, IL-1b, IL-10, IL-17, IL-22, IFN-g) and ROS production will be measured	2 weeks
PBMC responses to heterologous antigens	PBMCs will be stimulated with LPS, S. aureus, C.albicans, PHA, S.pneumoniae, zymosan. Responses on cytokine levels (IL-6, TNF, IL-1b, IL-10, IL-17, IL-22, IFN-g) and ROS production will be measured	3 months
PBMC responses to heterologous antigens	PBMCs will be stimulated with LPS, S. aureus, C.albicans, PHA, S.pneumoniae, zymosan. Responses on cytokine levels (IL-6, TNF, IL-1b, IL-10, IL-17, IL-22, IFN-g) and ROS production will be measured	1 year
Transcriptional profile of PBMCs	Transcriptional profile of PBMCs will be measured by RNAseq to assess for active gene transcription programs	1 day
Transcriptional profile of PBMCs	Transcriptional profile of PBMCs will be measured by RNAseq to assess for active gene transcription programs	4 days
Transcriptional profile of PBMCs	Transcriptional profile of PBMCs will be measured by RNAseq to assess for active gene transcription programs	2 weeks
Transcriptional profile of PBMCs	Transcriptional profile of PBMCs will be measured by RNAseq to assess for active gene transcription programs	3 months
Epigenetic markers of monocytes	Levels of activating and inhibiting epigenetic marks will be assessed	1 day
Epigenetic markers of monocytes	Levels of activating and inhibiting epigenetic marks will be assessed	4 days
Epigenetic markers of monocytes	Levels of activating and inhibiting epigenetic marks will be assessed	2 weeks
Epigenetic markers of monocytes	Levels of activating and inhibiting epigenetic marks will be assessed	3 months

Other Outcome Measures

Outcome Measure	Measure Description	Time Frame
Leukocyte differential count	Leukocyte differential counts will be performed	1 day,
Leukocyte differential count	Leukocyte differential counts will be performed	4 days
Leukocyte differential count	CBC parameters will be measured before and after vaccination	2 weeks
Leukocyte differential count	Leukocyte differential counts will be performed	3 months
Leukocyte differential count	Leukocyte differential counts will be performed	1 year
NK cell phenotype	NK cell activation markers will be assessed by FACS	2 weeks
NK Cell phenotype	NK cell activation markers will be assessed by FACS	3 months
NK cell phenotype	NK cell activation markers will be assessed by FACS	1 year
NK cell function	degranulation of NK cells upon stimulation with tumor cells will be assessed	2 weeks
NK cell function	degranulation of NK cells upon stimulation with tumor cells will be assessed	3 months
NK cell function	degranulation of NK cells upon stimulation with tumor cells will be assessed	1 year

Collaborators and Investigators

• Sponsor: Radboud University Medical Center
• Collaborators: University of Southern Denmark
• Investigators: Principal Investigator: Mihai Netea, Prof. Dr., Radboud University Medical Center

Publications and helpful links

General Publications

• Blok BA, de Bree LCJ, Diavatopoulos DA, Langereis JD, Joosten LAB, Aaby P, van Crevel R, Benn CS, Netea MG. Interacting, Nonspecific, Immunological Effects of Bacille Calmette-Guerin and Tetanus-diphtheria-pertussis Inactivated Polio Vaccinations: An Explorative, Randomized Trial. Clin Infect Dis. 2020 Jan 16;70(3):455-463. doi: 10.1093/cid/ciz246.

Study record dates

Study Major Dates

• Study Start: January 1, 2015
• Primary Completion (Actual): July 1, 2016
• Study Completion (Anticipated): April 1, 2017

Study Registration Dates

• First Submitted: February 22, 2016
• First Submitted That Met QC Criteria: May 12, 2016
• First Posted (Estimate): May 13, 2016

Study Record Updates

• Last Update Posted (Estimate): October 13, 2016
• Last Update Submitted That Met QC Criteria: October 12, 2016
• Last Verified: April 1, 2016

More Information

Terms related to this study

• Keywords: BCG; TDaP-IPV; DPT Vaccine
• Additional Relevant MeSH Terms: Infections; Respiratory Tract Infections; Respiratory Tract Diseases; Bordetella Infections; Gram-Negative Bacterial Infections; Bacterial Infections; Bacterial Infections and Mycoses; Whooping Cough; Physiological Effects of Drugs; Immunologic Factors; Adjuvants, Immunologic; Vaccines; BCG Vaccine
• Other Study ID Numbers: BCG-DKTP1

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: Undecided