Clinical trial NCT02771782: Influence of BCG on TDaP-IPV Vaccination
Official title: The Influence of BCG Vaccine as a Booster TDaP-IPV Vaccination: an Explorative Study
Study type: INTERVENTIONAL
Overall status: UNKNOWN
Phase: PHASE4
Conditions: Whooping Cough
Keywords: BCG
TDaP-IPV
DPT Vaccine
Lead sponsor: Radboud University Medical Center
Sponsor class: OTHER
Collaborators: name: University of Southern Denmark
First posted: 2016-05-13
Enrollment: 75
Sex: FEMALE
Minimum age (years): 18
Maximum age (years): 55
Standard ages: ADULT
Accepts healthy volunteers: yes
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: BASIC_SCIENCE

Brief summary: 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: 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.

Eligibility criteria: 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

Primary outcomes:
measure: Antibody response to TDaP-IPV
timeFrame: 2 weeks
measure: Antibody response to TDaP-IPV
timeFrame: 3 months
measure: Antibody response to TDaP-IPV
timeFrame: 1 year
measure: T-cell response to TDaP-IPV
timeFrame: 2 weeks
measure: T-cell response to TDaP-IPV
timeFrame: 3 months
measure: T-cell response to TDaP-IPV
timeFrame: 1 year
measure: PBMC cytokine response to pertussis related antigens
timeFrame: 2 weeks
measure: PBMC cytokine response to pertussis related antigens
timeFrame: 3 months
measure: PBMC cytokine response to pertussis related antigens
timeFrame: 1 year
measure: B-cell phenotype analysis
timeFrame: 2 weeks
measure: B-cell phenotype analysis
timeFrame: 3 months
measure: B-cell phenotype analysis
timeFrame: 1 year
Secondary outcomes:
measure: PBMC responses to heterologous antigens
timeFrame: 1 day
measure: PBMC responses to heterologous antigens
timeFrame: 4 days
measure: PBMC responses to heterologous antigens
timeFrame: 2 weeks
measure: PBMC responses to heterologous antigens
timeFrame: 3 months
measure: PBMC responses to heterologous antigens
timeFrame: 1 year
measure: Transcriptional profile of PBMCs
timeFrame: 1 day
measure: Transcriptional profile of PBMCs
timeFrame: 4 days
measure: Transcriptional profile of PBMCs
timeFrame: 2 weeks
measure: Transcriptional profile of PBMCs
timeFrame: 3 months
measure: Epigenetic markers of monocytes
timeFrame: 1 day
measure: Epigenetic markers of monocytes
timeFrame: 4 days
measure: Epigenetic markers of monocytes
timeFrame: 2 weeks
measure: Epigenetic markers of monocytes
timeFrame: 3 months
Other outcomes:
measure: Leukocyte differential count
timeFrame: 1 day,
measure: Leukocyte differential count
timeFrame: 4 days
measure: Leukocyte differential count
timeFrame: 2 weeks
measure: Leukocyte differential count
timeFrame: 3 months
measure: Leukocyte differential count
timeFrame: 1 year
measure: NK cell phenotype
timeFrame: 2 weeks
measure: NK Cell phenotype
timeFrame: 3 months
measure: NK cell phenotype
timeFrame: 1 year
measure: NK cell function
timeFrame: 2 weeks
measure: NK cell function
timeFrame: 3 months
measure: NK cell function
timeFrame: 1 year
Locations:
city: Nijmegen
country: Netherlands
facility: Radbdoudumc
Study officials:
affiliation: Radboud University Medical Center
name: Mihai Netea, Prof. Dr.
role: PRINCIPAL_INVESTIGATOR
References:
citation: 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.