Cellular Immunity in Adult Hepatitis B-vaccinated Serologic Non-responders

Study Overview
=================
Brief Summary
-----------------
Previous studies have shown that 5-10% of Hepatitis B Virus vaccine recipients produce none or to few antibodies after a standard immunization with 3 vaccines. These individuals are defined as non-responders. The investigators wish to investigate if mounting another kind of immune response, called the cellular immune (CMI) response, protects these non-responders. Aim/Hypothesis Primary aims: To estimate the CMI response in serologic non-responders after receiving a standard course of HBV immunization Secondary aims: To establish the prevalence of serological non-responders after a standard course of HBV vaccination. To assess the safety of the vaccine. Evaluate predictors of serologic non-response in young, healthy individuals receiving a standard course of HBV immunization To compare the immunological profile before and after a standard HBV vaccination regimen on non-responders and responders Establish a rapid test for measuring CMI after being HBV vaccinated. A total of 400 healthy volunteers receive a standard course of immunization with a combined hepatitis A and B vaccine (Twinrix®) at 0, 1, and 6 months. Blood is drawn at 0 and 8 months from all participants. The blood will be analysed to see if there is antibodies or/and if there is mounted a cellular immune response by measuring on parameters called cytokines.

Official Title
-----------------
Cellular Immunity in Adult Hepatitis B-vaccinated Serologic Non-responders

Conditions
-----------------
Hepatitis B

Intervention / Treatment
-----------------
* Biological: Twinrix


Participation Criteria
=================
Eligibility Criteria
-----------------
Inclusion Criteria: Signed participant information and consent Age over 18 years Women of childbearing potential must use effective contraceptives Exclusion Criteria: previous HBV infection previous HBV immunization pregnancy (or planned pregnancy within 6 months) allergy to contents in the vaccine (formaldehyde).

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

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

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

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

Design Details

Primary Purpose: Prevention
Allocation: Non-Randomized
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Other: HBsAg<br> | Biological: Twinrix<br>* A total of 400 healthy volunteers receive a standard course of immunization with a combined hepatitis A and B vaccine (Twinrix®) at 0, 1, and 6 months. Twinrix ® Adult suspension for injection. 1 ml contains 720 ELISA units of hepatitis A virus antigen adsorbed to aluminum hydroxide and 20 micrograms hepatitis B surface antigen (HBsAg) adsorbed to aluminum phosphate in sterile water. Excipient: sodium chloride. Contains traces of neomycin.<br>|

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

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Estimate the CMI response in serologic non-responders after receiving a standard course of HBV immunization | Preparation of peripheral blood mononuclear cells (PBMC) Optimisation of antigen-specific cytokine flow cytometry Quantification of IFN-γ producing CD4+ T cells | within 9. month from 1. vaccination | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Establish the prevalence of serological non-responders after a standard course of HBV vaccination defined by anti-HBs <10 mIU / ml | Antibodies to Hepatitis B surface antigen are detected by use of a comercially available kit at the department of Clinical Immunology, Aarhus University Hospital, Skejby | Within 9 month from 1. vaccination | 
| Assess the safety of the vaccine by evaluating the numbers and intensity of adverse and Serious adverse events | By evaluating adverse events described in Case Report Forms | Within 9 month from 1. vaccination | 
| Evaluate predictors of serologic non-response in young, healthy individuals receiving a standard course of HBV immunization | Questionnaire and *Magnitude of HBsAg-specific cell-mediated immune response.The presence of antigen specifik single, double or triple cytokine-producing T cells. Numbers and fractions of antigen-specific CD4 and CD8 T cells *HBsAg-specific T cell proliferation is quantified*The difference in phenotypic T cell profiles is getting compared at baseline*HBsAg-specific B cells measured by flow cytometry with staining for surface markers*Supernatant from HBsAg-stimulated PBMC is analysed regarding cytokines* Production of pro- og antiinflammatory cytokines is assesed by RT-PCR . | within 9 month from 1. vaccination | 
| Compare the immunological profile before and after a standard HBV vaccination regimen, with com-parison of serological non-responders and serological responders | Magnitude of HBsAg-specific cell-mediated immune response.The presence of antigen specifik single, double or triple cytokine-producing T cells. Numbers and fractions of antigen-specific CD4 and CD8 T cells *HBsAg-specific T cell proliferation is quantified*The difference in phenotypic T cell profiles is getting compared at baseline*HBsAg-specific B cells measured by flow cytometry with staining for surface markers*Supernatant from HBsAg-stimulated PBMC is analysed regarding cytokines* Production of pro- og antiinflammatory cytokines is assesed by RT-PCR . | Within 9. month from 1. vaccination | 
| Establish a rapid test for measuring HBsAg specific CMI by use of an IFN-gamma based assay. | Preparation of peripheral blood mononuclear cells (PBMC) Optimisation of antigen-specific cytokine flow cytometry Quantification of IFN-γ producing CD4+ T cells | 18 month after 1. vaccination | 

 Terms related to the study
=================
Keywords Provided by Centre Hospitalier Valida
-----------------
Hepatitis B, non responders, cellular immune response, cytokines, predictors, HBsAg