Safety and Efficacy Study of Adjuvanted Prophylactic Hepatitis B Vaccine

Study Overview
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Brief Summary
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There is a need for more effective and better-tolerated hepatitis B vaccines for low responder high-risk populations including patients with renal impairment and/or diabetes mellitus and those aged over 40 years. Several approaches are available to enhance the potency of hepatitis B virus vaccines including use of the more highly immunogenic antigens, replacing alum with potentially more effective adjuvants, and increasing the dose of vaccine antigen. A combination of these strategies is being tested in this study to identify the most promising candidate approaches to take forward into advanced clinical development

Detailed Description
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Adjuvants are a critical ingredient in most vaccines and act by boosting the immune response to the target protein (e.g. hepatitis B surface antigen (HBsAg)). Despite considerable research, aluminium hydroxide or phosphate compounds (collectively referred to as alum) remain the dominant adjuvants used in human hepatitis B virus vaccines. There is thus an unmet need for new HBV vaccine adjuvants, in particular, for adjuvants capable of boosting cell-mediated immunity (this is a particular type of immune response where killer T cells are activated that are then able to attack and destroy the infection) as alum, although good at stimulating antibodies is very poor at stimulating cell-mediated immunity. Alum, whilst generally accepted as safe, can be associated with significant local vaccine reactions and this is another reason why newer better-tolerated vaccine adjuvants would be beneficial. This study will compare a range of experimental adjuvant formulations to identify those that provide the safest and most effective enhancement of T- and B-cell immunity against hepatitis B

Official Title
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Phase 1 Randomized, Controlled, Double-blind Study to Compare the Safety and Effectiveness of Hepatitis B Vaccines in Individuals With Renal Impairment, Diabetes Mellitus or Age Greater Than 40 Years

Conditions
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Exposure to Hepatitis B Virus

Intervention / Treatment
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* Drug: HBsAg
* Biological: PreS HBsAg
* Biological: Advax-1(TM)
* Biological: Advax-2(TM)
* Biological: Advax-3(TM)
* Biological: Alum


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Age 18 years and above Male or female Able to provide written informed consent Willing and able to comply with the protocol for the duration of the study. Has one or more of Age 40 years or above Impaired renal function (creatinine >120 mmol/L or calculated glomerular filtration rate <60mls/min) Diagnosis of diabetes mellitus (any type) Exclusion Criteria: History of prior hepatitis B vaccination History of serious vaccine allergy if in the opinion of the Investigator this represents a contraindication to hepatitis B vaccination Women of childbearing potential unless using a reliable and appropriate contraceptive method, specifically oral contraceptive pill, intrauterine device or mechanical barrier device. Pregnant or lactating women. History of systemic autoimmune disease including Wegener's granulomatosis, systemic lupus erythematosus, Guillain-Barre, scleroderma or multiple sclerosis. Participation in another clinical trial with an investigational agent within 28 days of the scheduled date of first immunization. Any other serious medical, social or mental condition that, in the opinion of the investigator, would be detrimental to the subjects or the study.

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: Prevention
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Double


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Active Comparator: HBsAg + alum adjuvant<br>HBsAg + standard alum adjuvant | Drug: HBsAg<br>* Standard hepatitis B vaccine antigen<br>* Other names: hepatitis B vaccine based on hepatitis B surface antigen;Biological: Alum<br>* Adjuvant formulated with vaccine antigen<br>* Other names: Aluminium hydroxide;|
| Experimental: HBsAg + Advax-1(TM)<br>HBsAg + Advax-1 | Drug: HBsAg<br>* Standard hepatitis B vaccine antigen<br>* Other names: hepatitis B vaccine based on hepatitis B surface antigen;Biological: Advax-1(TM)<br>* Adjuvant formulated with vaccine antigen<br>* Other names: Delta inulin adjuvant;|
| Experimental: HBsAg + Advax-2(TM)<br>HBsAg + Advax-2 | Drug: HBsAg<br>* Standard hepatitis B vaccine antigen<br>* Other names: hepatitis B vaccine based on hepatitis B surface antigen;Biological: Advax-2(TM)<br>* Adjuvant formulated with vaccine antigen<br>* Other names: Supermix;|
| Experimental: HBsAg + Advax-3(TM)<br>HBsAg + Advax-3 | Drug: HBsAg<br>* Standard hepatitis B vaccine antigen<br>* Other names: hepatitis B vaccine based on hepatitis B surface antigen;Biological: Advax-3(TM)<br>* Adjuvant formulated with vaccine antigen<br>|
| Active Comparator: preS HBsAg + alum adjuvant<br>preS HBsAg + alum adjuvant | Biological: PreS HBsAg<br>* preS hepatitis B surface antigen<br>* Other names: preS hepatitis B surface antigen;Biological: Alum<br>* Adjuvant formulated with vaccine antigen<br>* Other names: Aluminium hydroxide;|
| Experimental: preS HBsAg + Advax-1(TM)<br>preS HBsAg + Advax-1 | Biological: PreS HBsAg<br>* preS hepatitis B surface antigen<br>* Other names: preS hepatitis B surface antigen;Biological: Advax-1(TM)<br>* Adjuvant formulated with vaccine antigen<br>* Other names: Delta inulin adjuvant;|
| Experimental: preS HBsAg + Advax-2(TM)<br>preS HBsAg + Advax-2 | Biological: PreS HBsAg<br>* preS hepatitis B surface antigen<br>* Other names: preS hepatitis B surface antigen;Biological: Advax-2(TM)<br>* Adjuvant formulated with vaccine antigen<br>* Other names: Supermix;|
| Experimental: preS HBsAg + Advax-3(TM)<br>preS HBsAg + Advax-3 | Biological: PreS HBsAg<br>* preS hepatitis B surface antigen<br>* Other names: preS hepatitis B surface antigen;Biological: Advax-3(TM)<br>* Adjuvant formulated with vaccine antigen<br>|
| Active Comparator: high dose preS HBsAg + alum adjuvant<br>high dose preS HBsAg + alum adjuvant | Biological: PreS HBsAg<br>* preS hepatitis B surface antigen<br>* Other names: preS hepatitis B surface antigen;Biological: Alum<br>* Adjuvant formulated with vaccine antigen<br>* Other names: Aluminium hydroxide;|
| Experimental: high dose preS HBsAg + Advax-1(TM)<br>high dose preS HBsAg + Advax-1 | Biological: PreS HBsAg<br>* preS hepatitis B surface antigen<br>* Other names: preS hepatitis B surface antigen;Biological: Advax-1(TM)<br>* Adjuvant formulated with vaccine antigen<br>* Other names: Delta inulin adjuvant;|
| Experimental: high dose preS HBsAg + Advax-2(TM)<br>high dose preS HBsAg + Advax-2(TM) | Biological: PreS HBsAg<br>* preS hepatitis B surface antigen<br>* Other names: preS hepatitis B surface antigen;Biological: Advax-2(TM)<br>* Adjuvant formulated with vaccine antigen<br>* Other names: Supermix;|
| Experimental: high dose preS HBsAg + Advax-3(TM)<br>high dose preS HBsAg + Advax-3 | Biological: PreS HBsAg<br>* preS hepatitis B surface antigen<br>* Other names: preS hepatitis B surface antigen;Biological: Advax-3(TM)<br>* Adjuvant formulated with vaccine antigen<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Safety | Safety as assessed by incidence of adverse events | 12 months | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Hepatitis B surface antibody geometric mean titer | Geometric mean titer of HBsAg titers | one-month post each immunization and 10 months post-final immunization | 
| T cell responses | HBsAg-specific T cell responses as measured by cytokine enzyme-linked immunospot and carboxyfluorescein diacetate succinimidyl ester T-cell proliferation assay will be compared between groups | 7 days and one month post each immunization and 10 months post-final immunization | 
| Efficacy | Seroconversion and seroprotection rates will be compared between groups using titers of antibodies to hepatitis B surface antigen at each major time point | one month post each immunization and 10 months post final immunization | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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hepatitis B virus, vaccine, adjuvant, prophylaxis