Non Inferiority Trial of Locally Manufactured 'Hepa-B' Vaccine in Bangladesh.

Research Protocol Title: A randomized observer-blinded non inferiority trial to evaluate the immunogenicity and safety of locally manufactured Hepatitis B Vaccine 'Hepa B' in Bangladeshi healthy adults.

Background (brief):

• Burden: Hepatitis B is a serious and common infectious disease of the liver, affecting millions of people throughout the world1. The severe pathological consequences of persistent Hepatitis B virus (HBV) infections include the development of chronic hepatic insufficiency, cirrhosis and hepatocellular carcinoma (HCC) 1. More than 2000 million people alive today have been infected with HBV at some time in their lives. 1 Of these, about 350 million remain infected chronically and become carriers of the virus. 1 Three quarters of the world's population live in areas where there are high levels of infection 1. Every year there are over 4 million acute clinical cases of HBV and about 25% of carriers, 1 million people a year, die from chronic active hepatitis, cirrhosis or primary liver cancer 1. HBV prevalence in Bangladesh is 2.3 to 9.7 percent with an approximate carrier pool of 10 million. These include healthy adult population 4.4 to 9.7%, healthy children 3%, school girls 2.3%, a rural community 6.4%, and slum communities 3.8%.2,3 About 25-30% population of Bangladesh do not test positive for HBsAg rather test positive for another marker of HBV that is with anti HBc4. Thus about 50 million Bangladeshi people are infected with HBV and transmission of their blood and body fluids may transmit HBV to healthy uninfected person4.
• Knowledge gap: The prevention of chronic HBV infection has become a high priority in the global community. Immunization with hepatitis B vaccine is the most effective means of preventing HBV infection and its consequence. Vaccine against hepatitis B was introduced in the early 1980s. Recombinant vaccines became available in the mid 1980s.1 Bangladesh introduced Hepatitis B vaccine in the EPI, immunization schedule in a small scale from 2003 but nationwide it was available from 20095 .The HBV prevalence in Bangladesh is 2.3 to 9.7 percent with an approximate carrier pool of 10 million. These include healthy adult population 4.4 to 9.7%, healthy children 3%, school girls 2.3%, a rural community 6.4%, and slum communities 3.8%2,3 . WHO recommended to vaccinate all children and adolescents younger than 18 years-old living in low or intermediate endemicity and also in these settings to vaccinate people in high-risk groups who may acquire the infection6. Currently there is no locally manufactured Hepatitis B vaccine available in Bangladesh. The results of this study will provide information regarding the immunogenicity and safety of the locally manufactured Hepatitis B vaccine 'Hepa B' as a test vaccine using 'Engerix B' as a comparator vaccine in a non inferiority study design.
• Relevance: The study of this locally manufactured Hepatitis B vaccine, 'Hepa B' among adults will be able to give us information regarding the safety and immunogenicity of the vaccine and compare this locally produced Hepatitis B vaccine 'Hepa B' with 'Engerix B' vaccine. Hepa B has undergone technology transfer from BioBridge company in Pune, India. Incepta and BioBridge entered into an agreement for transfer of technology for manufacture of locally produced 'Hepa- B' in Bangladesh. The regulatory requirements as well as licensure of the vaccine will be initiated in Bangladesh. Currently there are no locally manufactured Bulk of Hepatitis B available in Bangladesh. Once these clinical trials will be completed, Incepta will apply for licensure of Hepa B to the Bangladesh DGDA. This will significantly reduce the cost of vaccine and ensure availability to the people of Bangladesh. Currently the imported vaccine "Engerix B 1 ml" is sold at a price of 608 taka where as Incepta can sell the product at 500 taka. So, in each unit price difference is 108 taka. As each individual needs 3 doses, so it will be 324 taka saved for each subject. Thus the vaccine cost could be significantly reduced and save a large amount of foreign currency of Bangladesh Government.

Hypothesis (if any): Locally produced intramuscular non-infectious recombinant DNA vaccine Hepa-B is non inferior in terms of immunogenicity and safety among adults in Bangladesh as compared to Engerix-B.

Objectives:

Primary Objective

• To evaluate and compare the immunogenicity and safety of locally produced Hepatitis B vaccine 'Hepa-B' with Engerix-B among healthy adults in Bangladesh.

Methods:

This will be a randomized observer-blinded and comparative study on a total of 158 healthy adult participants. Hepa B (Test group) and Engerix B (Comparator Group) controlled non inferiority study in healthy adult (20-45 years of age). 79 participants will receive Hepa B 1.0 ml and another 79 participants will receive Engerix B 1.0 ml Outcome measures/variables: To evaluate and compare the immunogenicity and safety of locally produced Hepa B with Engerix B.

Primary Objective:

• To evaluate and compare the immunogenicity and safety of locally produced Hepatitis B vaccine 'Hepa B' with 'Engerix B' in healthy adults in Bangladesh.

Primary end points:

• The test vaccine will induce similar seroprotection rates to hepatitis B one month post vaccination and at 7 months, one month after the third dose of vaccine compared to comparator vaccine. This will be done by comparing the percentage of participants with ≥10 mIU/ml anti HBs after vaccination with either Hepa B or Engerix B vaccine. The non inferiority margin will be 10%.
• Number of immediate reactions reported within 30 minutes after vaccination
• Number of solicited adverse events (prelisted in the participant's memory aid) occurring up to 4 days following vaccination.
• Number of unsolicited AEs up to 30 days after each dose of vaccination.
• Occurrence of serious adverse events (SAEs) throughout the trial.

Secondary end points:

• The Ratio of the GMTs of test and comparator vaccines in different time points.

Inclusion criteria

• Considered healthy as per medical judgment of the investigator
• Age: 20 to 45 years
• Sex: Male, Female and Transgender
• For married women, a negative urine pregnancy test (Rapid Diagnostic Test) during screening and prior to first, second and third dose of vaccination.Moreover, medical history will be taken thoroughly by study physician from the woman of childbearing age to completely exclude the probability of pregnancy.The women who are married and living with a partner must agree to use a reliable contraceptive method to prevent pregnancy until final follow-up following vaccination. However abstinence is also acceptable.

Exclusion criteria

• Prior history of hepatitis B infection
• Vaccination with any hepatitis B vaccine
• Recent febrile illness (within 2 weeks)
• Known or suspected hypersensitivity to any component of Hepatitis B vaccine (e.g., aluminium, yeast).
• History of received hepatitis B immune globulin (HBIG), serum immune globulin, or any other blood-derived product.
• Known or suspected impairment of immunologic function or recent use of immunomodulatory medications (e.g., systemic corticosteroids) more than 14 days with in last 6 months. Does not include topical and inhaled steroids.
• Receipt of investigational drugs or other investigational vaccines within 3 months prior to first injection with the study vaccine.
• Pregnant women, nursing mothers, and women planning to become pregnant within the study period.
• HBsAg reactive, anti-HBs antibody (≥10mlU/ml), anti-HBc (total) reactive, and abnormal liver function test [serum alanine aminotransferase (ALT) level], serum creatinine and CBC (As mentioned in Appendix IV).