Heterologous Effect of Diptheria, Tetanus, Acellular Pertussis Vaccination on Influenza Challenge in the Elderly

Study Overview
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Brief Summary
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Vaccines can have non-targeted or heterologous (also called non-specific) immunological effects on the immune system i.e. effects other than inducing an immune response against the disease targeted by the vaccine. This trial aims to evaluate the non-specific immunological effects of two vaccines - diphtheria-tetanus-acellular pertussis (DTP) vaccine and seasonal influenza vaccine - in a cohort of elderly humans (>65 years of age) and healthy adult control subjects (30-50 years).

Detailed Description
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This prospective randomised study aims to investigate the heterologous immunological effects of DTP and seasonal influenza (Flu) vaccination in an elderly Tasmanian population and healthy adults. The study will assess whether prior or concurrent administration of DTP with seasonal Flu vaccination affects generalised inflammation / immune homeostasis and gene expression, with a particular focus of inflammation reactive cells. It will also analyse for effects of DTP on the induction of vaccine-specific immunity to seasonal influenza vaccination (antibodies and cellular). Volunteers will be randomised to one of three vaccine groups and serial blood samples taken for immunological assays for up to 30 weeks. The study is exploratory and will investigate vaccine effects on multiple immune parameters.

Official Title
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Clifford Craig Vaccine Trial Centre: Heterologous Effect of Diptheria, Tetanus, Acellular Pertussis Vaccination on Influenza Vaccine Challenge in the Elderly

Conditions
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Heterologous Effects of Vaccines

Intervention / Treatment
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* Biological: Seasonal influenza vaccine
* Biological: Diphtheria-tetanus-acellular pertussis vaccine


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Two study groups 30-50 years old >65 years old Exclusion Criteria: Unwell on day of vaccination Temperature >38°C Active cancer Active autoimmune disease Diabetes mellitus Taking immunosuppressive drugs including steroids Any vaccination in last 3 months DT or DTaP vaccination in the last year Known allergy or contraindication to influenza or DTaP vaccination Pregnant or breastfeeding

Ages Eligible for Study
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Minimum Age: 30 Years
Maximum Age: 100 Years

Sexes Eligible for Study
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All

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 |
| --- | --- |
| Active Comparator: Group 1<br>Diphtheria-tetanus-acellular pertussis vaccine administered day 0, followed by seasonal influenza vaccination four weeks later. Blood testing to occur day 0 (prior to vaccine administration), 24 hours, 1 week, 4 weeks, 4 weeks + 24 hours, 5 weeks, 8 weeks and 30 weeks. Stool samples to be taken at day 0 and 1 week post-vaccination. | Biological: Seasonal influenza vaccine<br>* Intramuscular standard seasonal influenza vaccine<br>* Other names: Quadrivalent Influenza Vaccine;Biological: Diphtheria-tetanus-acellular pertussis vaccine<br>* Intramuscular DTaP vaccine<br>* Other names: Boostrix vaccine;|
| Active Comparator: Group 2<br>Seasonal influenza vaccine administered on day 0, to be offered DTP vaccine at week 26. Blood testing to occur day 0 (prior to vaccine administration), 24 hours, 1 week 1, 4 weeks and 26 weeks. Stool samples to be taken at day 0 and 1 week post-vaccination. | Biological: Seasonal influenza vaccine<br>* Intramuscular standard seasonal influenza vaccine<br>* Other names: Quadrivalent Influenza Vaccine;Biological: Diphtheria-tetanus-acellular pertussis vaccine<br>* Intramuscular DTaP vaccine<br>* Other names: Boostrix vaccine;|
| Active Comparator: Group 3<br>Seasonal influenza vaccine and DTP vaccine administered together on day 0. Blood testing to occur day 0 (prior to vaccine administration), 24 hours, 1 week 1, 4 weeks and 26 weeks. Stool samples to be taken at day 0 and 1 week post-vaccination. | Biological: Seasonal influenza vaccine<br>* Intramuscular standard seasonal influenza vaccine<br>* Other names: Quadrivalent Influenza Vaccine;Biological: Diphtheria-tetanus-acellular pertussis vaccine<br>* Intramuscular DTaP vaccine<br>* Other names: Boostrix vaccine;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of inflammation reactive TNFR2+ regulatory T cells per mL of blood | Change over time in different vaccine groups of Tregs measured by flow cytometry. | 24 hours, 1 week, 4 weeks and 26 weeks | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Whole human genome transcription profile by next generation sequencing in log2 expression levels | Differential gene expression 24 hours after vaccination compared to baseline, and vaccine groups compared to see which genes / pathways are affected. Differential transcription determined for each gene, then analysed using modular analysis tools to determine vaccine effects. | 24 hours | 
| Influenza-specific antibody titres to seasonal influenza vaccination | Change over time in the different vaccine groups of titres measured by haemagglutination inhibition assay. | 4 weeks and 26 weeks | 
| Pro-inflammatory (TNF) to anti-inflammatory (IL-10) cytokine ratio in stimulated blood in pg/mL | Change in TNF:IL-10 ratio post-vaccination over time as measured by cytokine multiplex assay of anti-CD3 stimulated PBMC. | 24 hours, 1 week, 4 weeks and 26 weeks | 
| Influenza-specific IFN-g CD4 T cell responses to seasonal influenza vaccination in pg/mL | Change over time in the different vaccine groups of IFN-g levels in supernatants from CD4 T cells cultured with live influenza virus | 4 weeks and 26 weeks |