Age Differences in Influenza and Herpes Zoster Vaccine Responses (INFLUENZA-SHINGRIX)

Study Overview
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Brief Summary
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Vaccines are used to prevent infectious diseases worldwide. Unfortunately, many vaccines, like the flu vaccine, are less effective in older adults. This single-centre open label partially randomised, partially placebo-controlled trial evaluates the differences in immune response between young and older adults after vaccination with a quadrivalent inactivated influenza vaccine and an adjuvanted herpes zoster vaccination. Exploring the underlying mechanisms between the differences in immunogenicity can provide important information for future vaccine development.

Detailed Description
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Rationale: Vaccination of the older adults is often advised as they are a high-risk population; however, vaccine efficacy generally decreases with age. This is mainly due to a decrease in adaptive immune responses known as immunosenescence, which is a factor influencing the response to influenza vaccination. On the other hand, there are vaccines that show high efficacy (more than 95%) in older adults, one of the most effective being the AS01 adjuvanted herpes zoster vaccine, Shingrix. The differential immune pathways associated with vaccine responsiveness as well as the immune mechanisms by which adjuvants overcome immunosenescence remain poorly understood. Targeting key immune pathways could be a way to improve vaccine efficacy in older adults. Objective: To explore immunological features between young and older adults after administration of an adjuvanted herpes zoster (Shingrix) or influenza unadjuvanted (Fluarix) vaccine that could explain differences in vaccine immunogenicity. Study design: A single centre open label, randomised, and partially placebo-controlled trial Study population: Approximately 140 healthy adults, 80 of which are between 18-35 years old, the other 60 are 60+ years old. Intervention: Two groups of young and elderly volunteers receive recombinant zoster vaccine (Shingrix), while two other groups will receive a quadrivalent influenza vaccine (Fluarix). Two groups of young volunteers will receive a placebo. Main study parameter: To identify immune senescence-related differences contributing to vaccine immunogenicity

Official Title
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Exploratory Study Into Age-related Immunological Differences Related to Immunogenicity in Influenza Vaccination and Herpes Zoster Vaccination

Conditions
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Influenza, Herpes Zoster

Intervention / Treatment
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* Biological: Herpes zoster vaccination (Shingrix, GSK)
* Biological: Influenza Vaccine (Fluarix Tetra Northern Hemisphere 2021 or 2022, GSK)
* Biological: Placebo


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Age between 18-35 years old OR age ≥60 years old Written informed consent Exclusion Criteria: Known allergy to (components of) the influenza or herpes zoster vaccine Immunocompromised subjects and subjects with active malignancy within the last two years Previous herpes zoster vaccination in the last year Receipt of any vaccination 4 weeks prior to the start of the study or plans to receive any other vaccination in the first 2 months after inclusion Use of systemic immunomodulatory drugs:steroids, anti-inflammatory biological treatments (e.g. anti-cytokine monoclonal antibodies) Acute or active illness within two weeks prior to the start of the study Pregnant, breastfeeding or planning to become pregnant during the study period

Ages Eligible for Study
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Minimum Age: 18 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 |
| --- | --- |
| Experimental: 1: Young adults herpes zoster vaccination<br>Young adults between 18 and 35 years old will receive the herpes zoster vaccine (Shingrix). 60 days later, they will receive a booster dose. | Biological: Herpes zoster vaccination (Shingrix, GSK)<br>* Shingrix is an ASO1-adjuvanted herpes zoster vaccination used to prevent shingles and its associated complications in at-risk populations<br>|
| Experimental: 2: Older adults herpes zoster vaccination<br>Adults older than 60 years of age will receive the herpes zoster vaccine (Shingrix). 60 days later, they will receive a booster dose. | Biological: Herpes zoster vaccination (Shingrix, GSK)<br>* Shingrix is an ASO1-adjuvanted herpes zoster vaccination used to prevent shingles and its associated complications in at-risk populations<br>|
| Experimental: 3: Young adults influenza vaccination<br>Young adults between 18 and 35 years old will receive the influenza vaccine (Fluarix Tetra). | Biological: Influenza Vaccine (Fluarix Tetra Northern Hemisphere 2021 or 2022, GSK)<br>* Fluarix Tetra is a quadrivalent inactivated influenza vaccine<br>|
| Experimental: 4: Older adults influenza vaccination<br>Adults older than 60 years of age will receive the influenza vaccine (Fluarix Tetra). | Biological: Influenza Vaccine (Fluarix Tetra Northern Hemisphere 2021 or 2022, GSK)<br>* Fluarix Tetra is a quadrivalent inactivated influenza vaccine<br>|
| Placebo Comparator: 5: Young adults herpes zoster vaccination related placebo<br>Young adults between 18 and 35 years old will receive the placebo injection (0.9% NaCl). 60 days later, they will receive another placebo. | Biological: Placebo<br>* 0.9% NaCl<br>|
| Placebo Comparator: 6: Young adults influenza vaccination related placebo<br>Young adults between 18 and 35 years old will receive the placebo injection (0.9% NaCl). | Biological: Placebo<br>* 0.9% NaCl<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Changes in cytokine productions of PBMCs upon incubation with viral, bacterial, and fungal antigens | IL-6, TNF, IL-1b, IFNg cytokine concentrations will be measured. | 2 months after influenza vaccination | 
| Changes in cytokine productions of PBMCs upon incubation with viral, bacterial, and fungal antigens | IL-6, TNF, IL-1b, IFNg cytokine concentrations will be measured. | 6 months after influenza vaccination | 
| Changes in cytokine productions of PBMCs upon incubation with viral, bacterial, and fungal antigens | IL-6, TNF, IL-1b, IFNg cytokine concentrations will be measured. | 2 months after the first dose of herpes zoster vaccination | 
| Changes in cytokine productions of PBMCs upon incubation with viral, bacterial, and fungal antigens | IL-6, TNF, IL-1b, IFNg cytokine concentrations will be measured. | 2 months after the second dose of herpes zoster vaccination | 
| Changes in cytokine productions of PBMCs upon incubation with viral, bacterial, and fungal antigens | IL-6, TNF, IL-1b, IFNg cytokine concentrations will be measured. | 6 months after the second dose of herpes zoster vaccination | 
| Change in transcriptional profile of individual cells from PBMC population | Gene expression profile of PBMCs will be measured by single cell-RNA sequencing. | 2 months after influenza vaccination | 
| Change in transcriptional profile of individual cells from PBMC population | Gene expression profile of PBMCs will be measured by single cell-RNA sequencing. | 6 months after influenza vaccination | 
| Transcriptional profile of individual cells from PBMC population | Gene expression profile of PBMCs will be measured by single cell-RNA sequencing. | 2 months after the first dose of herpes zoster vaccination | 
| Transcriptional profile of individual cells from PBMC population | Gene expression profile of PBMCs will be measured by single cell-RNA sequencing. | 2 months after the second dose of herpes zoster vaccination | 
| Transcriptional profile of individual cells from PBMC population | Gene expression profile of PBMCs will be measured by single cell-RNA sequencing. | 6 months after the second dose of herpes zoster vaccination | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Changes in the adaptive immune cell populations in blood | Ratio of adaptive immune cells (T and B cells) and their subtypes will be measured by FACS. | 2 months after influenza vaccination | 
| Changes in the adaptive immune cell populations in blood | Ratio of adaptive immune cells (T and B cells) and their subtypes will be measured by FACS. | 6 months after influenza vaccination | 
| Changes in the adaptive immune cell populations in blood | Ratio of adaptive immune cells (T and B cells) and their subtypes will be measured by FACS. | 2 months after the first dose of herpes zoster vaccination | 
| Changes in the adaptive immune cell populations in blood | Ratio of adaptive immune cells (T and B cells) and their subtypes will be measured by FACS. | 2 months after the second dose of herpes zoster vaccination | 
| Changes in the adaptive immune cell populations in blood | Ratio of adaptive immune cells (T and B cells) and their subtypes will be measured by FACS. | 6 months after the second dose of herpes zoster vaccination | 
| Baseline DNA methylation | CpG methylation profile of PBMCs | Baseline (before vaccination) | 
| Changes in B and T cell receptor repertoires | B and T cell receptors will be sequenced. | 2 months after influenza vaccination | 
| Changes in B and T cell receptor repertoires | B and T cell receptors will be sequenced. | 2 months after the first dose of herpes zoster vaccination | 
| Changes in B and T cell receptor repertoires | B and T cell receptors will be sequenced. | 2 months after the second dose of herpes zoster vaccination | 
| Changes in circulating protein concentrations | Concentrations of circulating inflammatory proteins, including TNF, IL-6, IL-8, CCL3, CCL4, CXCL9, CXCL10, CXCL11, will be measured by Olink. | 2 months after influenza vaccination | 
| Changes in circulating protein concentrations | Concentrations of circulating inflammatory proteins, including TNF, IL-6, IL-8, CCL3, CCL4, CXCL9, CXCL10, CXCL11, will be measured by Olink. | 2 months after the first dose of herpes zoster vaccination | 
| Changes in circulating protein concentrations | Concentrations of circulating inflammatory proteins, including TNF, IL-6, IL-8, CCL3, CCL4, CXCL9, CXCL10, CXCL11, will be measured by Olink. | 2 months after the second dose of herpes zoster vaccination | 
| Influenza vaccine-specific antibodies in the serum | HAI titers will be measured. | 2 months after influenza vaccination | 
| Shingles vaccine-specific antibody production in the serum | Anti-gE titers will be measured. | 2 months after the first herpes zoster vaccination | 
| Shingles vaccine-specific antibody production in serum | Anti-gE titers will be measured. | 2 months after the second herpes zoster vaccination | 
| Percentage of participants reporting local reactions | Pain at the injection site, redness, and swelling | 7 days after influenza and herpes zoster vaccination | 
| Percentage of participants reporting systemic events | Fever, fatigue, headache, chills, vomiting, diarrhea | 7 days after influenza and herpes zoster vaccination | 
| Changes in epigenetic markers in PBMCs | ATAC-sequencing will be performed to measure post transcriptional modifications (methylation, acetylation, etc) on histones. | 2 months after influenza vaccination | 
| Changes in epigenetic markers in PBMCs | ATAC-sequencing will be performed to measure post transcriptional modifications (methylation, acetylation, etc) on histones. | 6 months after influenza vaccination | 
| Changes in epigenetic markers in PBMCs | ATAC-sequencing will be performed to measure post transcriptional modifications (methylation, acetylation, etc) on histones. | 2 months after the first herpes zoster vaccination | 
| Changes in epigenetic markers in PBMCs | ATAC-sequencing will be performed to measure post transcriptional modifications (methylation, acetylation, etc) on histones. | 2 months after the second herpes zoster vaccination | 
| Changes in epigenetic markers in PBMCs | ATAC-sequencing will be performed to measure post transcriptional modifications (methylation, acetylation, etc) on histones. | 6 months after the second herpes zoster vaccination | 
| C-reactive protein in the serum | Soluble C-reactive protein (CRP) concentrations will be measured. | Baseline (before vaccination) | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Inflammaging, Vaccination, Trained immunity, Immunosenescence