The Influence of Trained Immunity in COVID-19 Vaccinated Individuals

Study Overview
=================
Brief Summary
-----------------
The concept of trained immunity defines the long-term functional reprogramming of innate immune cells, which is evoked by exogenous or endogenous insults and leads to an altered response towards a second challenge after return to a non-activated state and is characterized by several markers, such as specific cytokines, activation markers of innate immune cells and epigenetic modifications, e.g. H3K4me3. Vaccinations have been shown to induce trained immunity and to have heterologous effects on other infections or vaccinations. A recent article showed, that individuals who had received recombinant adjuvanted zoster vaccine (RZV) before the pandemic had a 16% lower risk of COVID-19 diagnosis and a 32% lower risk of hospitalization suggesting a protective heterologous effect of RVZ on COVID19 infections. So far, the mechanisms behind these add-on benefits of RZV vaccination are on the hypothetical level and need further experimental evidence. Therefore, we aim to investigate the specific humoral and cellular immune response towards COVID-19 vaccine in healthy individuals who were exposed to RZV 1 to 12 months before COVID-19 vaccination compared to individuals who did not receive RZV before. Particular emphasis is layed on COVID-19 vaccine non-responders and individuals with breakthrough infections indicating lower vaccine efficacy compared to those who had no breakthrough infection. The primary objective is the cytokine profile of spike protein-stimulated T, NK and NKT cells. Spike protein stimulated T, NK and NKT cells are characterized by cell surface markers, transcription factor expression, chemokine receptor expression, activation and proliferation markers and by their lineage-specific cytokine pattern. CD14+ monocytes are magnetically isolated and further characterized by cell-culture experiments imitating a training and resting period after stimulation. Epigenetic modifications by methylation of CpG regions are assessed at promoter, enhancer and regulatory gene regions of immune cell characteristic transcription factors by bisulfite conversion and pyrosequencing. Chromatin immunoprecipitation and ChIP-seq will be performed for analysis H3K4me3 associated with trained immunity. Humoral and cellular reactivity to spike protein is analyzed by adapted ELISA and neutralisation assays and by ELISpot and flow cytometry, respectively, and correlated. From our findings we expect to learn about the role of previous RZV on immunogenicity and efficacy of COVID-19 vaccination and whether mechanisms of trained immunity play a role for better responses towards COVID-19 vaccination.

Official Title
-----------------
The Influence of Trained Immunity in COVID-19 Vaccinated Individuals

Conditions
-----------------
Zoster Varicella, Vaccination; Infection

Intervention / Treatment
-----------------
* Biological: recombinant adjuvanted zoster vaccine


Participation Criteria
=================
Eligibility Criteria
-----------------
Inclusion Criteria: Group 1, retrospective (samples already stored, CoVaKo study cohort): healthy (n=420) Group 2, prospective (samples to be recruited, CoVaKo study cohort): healthy (n=180) Age 18-90 years, stratified into <60 and ≥60 years at least 2 COVID-19-mRNA vaccinations as equivalent to primary immunization and the third and/or fourth dose considered as booster, as recommended for all individuals >12 years (third dose) and for risk groups, medical staff, nursing home residents (fourth dose) in Germany Only individuals naive for SARS-CoV-2 (negative N-specific and S-specific-IgG antibody status, no history of PCR+ swab) before COVID-19 vaccination will be included. Exclusion Criteria: High-dose glucocorticoids >10 mg/day Immunosuppressive therapy Biologics or immunomodulators Transplantation Cancer Autoimmunity RZV after COVID-19 vaccination COVID-19 PCR+ before COVID-19 vaccination Other types of COVID-19 vaccines than mRNA vaccines

Ages Eligible for Study
-----------------
Minimum Age: 18 Years
Maximum Age: 90 Years

Sexes Eligible for Study
-----------------
All

Accepts Healthy Volunteers
-----------------
Accepts Healthy Volunteers

Study Plan
=================
How is the study designed?
-----------------

Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| A Retrospective samples<br>Retrospective (samples already stored, CoVaKo study cohort): Retrospective samples were consecutively collected during March 2020 and March 2022 (n=420). Group 1A: RZV 1-12 months before COVID-19 -mRNA vaccination Group 1B: no RZV (control arm) | Biological: recombinant adjuvanted zoster vaccine<br>* vaccination with recombinant adjuvantes zoster vaccine<br>|
| B Prospective samples<br>Prospective (samples to be recruited, CoVaKo study cohort): Prospective samples will be collected April 2022 to July 2022 (n=180). Group 2A: RZV 1-12 months before COVID-19 -mRNA vaccination Group 2B: no RZV (control arm) | Biological: recombinant adjuvanted zoster vaccine<br>* vaccination with recombinant adjuvantes zoster vaccine<br>|

What is the study measuring?
-----------------
Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Interferon-gamma | Spot forming units in Interferon-gamma ELISpot assay | 12 months | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Spike-specific IgG antibodies | Spike-specific IgG antibodies measured in BAU/ml | 12 months | 
| Spike-specific IgG antibody avidity | Spike-specific IgG antibody avidity measured in relative avidity by adapted ELISA | 12 months |