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

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

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.

Study Overview

• Status: Completed
• Conditions: Influenza; Herpes Zoster
• Intervention / Treatment: Biological: Herpes zoster vaccination (Shingrix, GSK); Biological: Influenza Vaccine (Fluarix Tetra Northern Hemisphere 2021 or 2022, GSK); Biological: Placebo

Detailed Description

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

• Study Type: Interventional
• Enrollment (Actual): 148
• Phase: Phase 2

Contacts and Locations

Study Locations

• Netherlands
  • Gelderland
    • Nijmegen, Gelderland, Netherlands, 6525GA
      • Radboud University

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 14 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: Yes

Description

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

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

6

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: 1: Young adults herpes zoster vaccination; 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); Shingrix is an ASO1-adjuvanted herpes zoster vaccination used to prevent shingles and its associated complications in at-risk populations
Experimental: 2: Older adults herpes zoster vaccination; 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); Shingrix is an ASO1-adjuvanted herpes zoster vaccination used to prevent shingles and its associated complications in at-risk populations
Experimental: 3: Young adults influenza vaccination; 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); Fluarix Tetra is a quadrivalent inactivated influenza vaccine
Experimental: 4: Older adults influenza vaccination; 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); Fluarix Tetra is a quadrivalent inactivated influenza vaccine
Placebo Comparator: 5: Young adults herpes zoster vaccination related placebo; 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; 0.9% NaCl
Placebo Comparator: 6: Young adults influenza vaccination related placebo; Young adults between 18 and 35 years old will receive the placebo injection (0.9% NaCl).	Biological: Placebo; 0.9% NaCl

What is the study measuring?

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)

Collaborators and Investigators

• Sponsor: Radboud University Medical Center
• Collaborators: GlaxoSmithKline
• Investigators: Principal Investigator: Jaap ten Oever, MD, PhD, Radboud University Medical Center

Study record dates

Study Major Dates

• Study Start (Actual): September 20, 2021
• Primary Completion (Actual): May 17, 2023
• Study Completion (Actual): May 17, 2023

Study Registration Dates

• First Submitted: January 22, 2021
• First Submitted That Met QC Criteria: October 5, 2021
• First Posted (Actual): October 19, 2021

Study Record Updates

• Last Update Posted (Actual): June 29, 2023
• Last Update Submitted That Met QC Criteria: June 28, 2023
• Last Verified: June 1, 2023

More Information

Terms related to this study

• Keywords: Vaccination; Inflammaging; Immunosenescence; Trained immunity
• Additional Relevant MeSH Terms: Skin Diseases; RNA Virus Infections; Virus Diseases; Infections; Respiratory Tract Infections; Respiratory Tract Diseases; DNA Virus Infections; Skin Diseases, Infectious; Skin Diseases, Viral; Orthomyxoviridae Infections; Herpesviridae Infections; Varicella Zoster Virus Infection; Influenza, Human; Herpes Zoster; Herpes Simplex
• Other Study ID Numbers: NL76061.091.20; 2020-005682-13 (EudraCT Number)

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No