Influence of BCG on TDaP-IPV Vaccination

Study Overview
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Brief Summary
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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.

Detailed Description
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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.

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

Conditions
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Whooping Cough

Intervention / Treatment
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* Biological: BCG vaccine (SSI)
* Biological: TDaP-IPV vaccine


Participation Criteria
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Eligibility Criteria
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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

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 55 Years

Sexes Eligible for Study
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Female

Accepts Healthy Volunteers
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Accepts Healthy Volunteers

Study Plan
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How is the study designed?
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Design Details

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


Arms and Interventions

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

What is the study measuring?
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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 | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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BCG, TDaP-IPV, DPT Vaccine