Hepatitis B Vaccine for Non-responders

Rationale:

Worldwide, people are suffering from the consequences of Hepatitis B (HB) virus infection. Currently available vaccines are protective in most of the vaccinees, however, a small part of the population does not respond to these vaccines (non-responders). A new adjuvant (AI20) has been developed by CyTuVax to improve the standard Hepatitis B vaccine for the protection of non-responders. The AI20 adjuvant consists of depot-attached rhuIL-2 (aggregated Interleukin-2 (IL-2) molecules attached to alum), facilitating the slow release of highly concentrated IL-2 nano aggregates. In preclinical experiments, vaccination of mice, rats, and rabbits with the new HBAI20 vaccine results in higher and earlier immune responses to HBsAg compared to vaccination with one of the standard Hepatitis B vaccines. The phase 1 clinical trial showed that the HBAI20 vaccine was well tolerated and it induced protective anti Hepatitis B antibody titers in 9 out of 10 non-responders (subjects vaccinated at least 6 times with the Hepatitis B vaccine). The phase 2 clinical trial will be conducted in order to assess the immunogenicity and safety of the AI20 adjuvant and further test if the AI20 adjuvanted Hepatitis B vaccine induces protective antibody titers in the vaccinated non-responders.

Objective: In the current study, the investigators study the efficacy of the HBAI20 vaccine to induce seroprotection. Furthermore, the investigators will compare the safety of the HBAI20 vaccine with the HBVaxPro-10μg.

Study design:

Multicenter double blinded randomized controlled intervention phase II study.

Study population:

Registered non-responders after at least 3 HBV vaccinations (n=132- 140) 18-59 years of age, males and females.

Intervention:

The study will include 2 groups. HB vaccine registered non-responder subjects after at least 3 vaccinations are randomized into group 1 (n= 33 to 35) or 2 (n= 99 to 105) at a 1 to 3 ratio. No less than 40% of the subjects of each group should have received only 1 series of Hepatitis B vaccination. "Group 1" subjects receive the standard HB vaccine (HBVaxPro-10μg) and "Group 2" subjects receive the HBAI20 vaccine. All study subjects will receive 3 vaccinations separated by one month (0, 1, and 2 months) in accordance with the recommended vaccination schedule for non-responders in the Netherlands.

Main study parameters/endpoints:

The primary study parameter is the immunogenicity of the adjuvanted vaccine. The immunogenicity of the adjuvanted vaccine is measured as the percentage of subjects that attain seroprotection after the first vaccination at 1, 2, and 3,5 months (HBsAg antibodies ≥10 mIU/ml measure by the COBAS system). The secondary study parameter is the safety of the vaccination. The safety of the vaccination is the number and severity of the local and systemic adverse reactions.

Nature and extent of the burden and risks associated with participation, benefit and group relatedness:

Study subjects will be vaccinated 3 times at 0, 1, and 2 months from the beginning of the study and invited to the hospital or vaccination centre for 4 or 5 visits. The risks associated with participation in this study are considered to be low and comparable with standard vaccines. Physical discomfort after vaccine administration can occur at the injection site (redness, swelling, etc.) and systemically (fever, fatigue, headache). Effects are expected to occur for a short period of time (within the first 4 days after the first and second injection). In addition subjects may experience adverse reactions to the cytokine component of the adjuvant. Because of the very low dose of the cytokine component of the adjuvant, which will be gradually released, the risks are expected to be low. The potential risks of venepuncture for blood sampling are mild pain and haematoma, and are considered low. Subjects may benefit from this study by becoming immunized (seroprotected) against Hepatitis B. Becoming seroprotected is important for the non-responder subjects because most of the registered non-responders are healthcare workers who can be exposed to the Hepatitis B virus.

Inclusion criteria

• In good health as determined by the outcome of medical history, physical examination screening/baseline labs and clinical judgment of the clinical investigator
• Age 18 to 59 years, inclusive at the time of enrollment
• Willing and able to adhere to the study regimen
• Willing to adhere to a highly effective birth control method during the duration of the study
• Having a signed informed consent form
• Documented non-responders: Subjects with documented one or more cycles of Hepatitis B vaccination (total of 3 or more vaccinations) and titer analysis 1 to 3 months after the last vaccination that show that they have not developed the Hepatitis B antibody titer recommended after standard vaccination: HBsAg antibody titer superior to 10mIU/ml. In case the subjects do not have a titer analysis performed 1 to 3 months after their last recorded vaccination, the potential subject can be included after permission from the project leader after analysis of the case file.

Exclusion criteria

• Any infectious disease at the time of screening and/or enrollment
• Positive HIV, Hepatitis B virus or Hepatitis C virus serology
• Known or suspected immune deficiency
• Known or suspected disease that influences the immune system including chronic allergies that require frequent anti-allergy medication - excluding anti-histaminics -, cancer and transplantation recipients
• Known or suspected allergy to any of the vaccine components
• Dialysis patient
• History of unusual or severe reactions to any previous vaccination
• History of any neurologic disorder, including epilepsy and autism
• Use of medication that influences the immune system (immune suppressive treatment or daily use of corticosteroids, including chronic use of local corticosteroids)
• Any vaccination within 3 months before screening excluding flu vaccination
• Blood donation within 1 month before screening
• Administration of plasma (incl. immunoglobulins) or blood products within 12 months before screening
• Participation in another clinical trial within 3 months before screening
• Abnormal pre-treatment laboratory parameters which are clinically relevant according to the investigator
• Bleeding disorders. Participants on coumadins anticoagulants and participants receiving 2 platelet aggregation inhibitors can not be included in the study. People on the direct oral anticoagulant dabigatran, apixaban, edoxaban, and rivaroxaban and participants using only one platelet aggregation inhibitor can be included.
• Female subjects planning to become pregnant or breastfeeding babies until visit 4
• Females: positive pregnancy test at screening date
• Excessive alcohol or controlled drug use - More than 2 alcohol measures per day (one alcohol measure is a beer (250ml) or one glass of wine (125ml) or one strong measure (35ml) or one port/sherry (75ml)). Regular use of controlled drugs
• Any Hepatitis B vaccination in the last 3 months Temporary exclusion criterion for vaccination
• Temperature > 38.4°C will lead to postponement of participation and vaccination.

Screening may continue when the temperature has normalized.