Effectiveness of Two Hepatitis B Vaccines in HIV-negative Youths

Study Overview
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Brief Summary
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This study will evaluate 2 licensed vaccine products (Recombivax and Twinrix) given in a two-dose schedule to youth at risk for hepatitis B and HIV infection to evaluate immunogenicity of the products in this population, barriers to vaccine delivery, and factors which predict a diminished immune response. Since these youths are also potential candidates for future HIV vaccine trials, this study will also include preliminary assessment of youths' understanding of informed consent forms, and willingness to participate in a vaccine trial and return for multiple visits (including blood draws for immunologic assessment).

Detailed Description
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Hepatitis B (HBV) prophylactic immunization has been recommended for at-risk adolescents for more than 10 years although universal coverage has not been achieved. Vaccine response in healthy adolescents has generally been reported to be excellent. But, data from the study Reaching for Excellence in Adolescent Care and Health (REACH) that studied HIV-negative adolescents who were at-risk of acquiring Hepatitis B infection through sexual or needle sharing behaviors has demonstrated a much lower than expected vaccine response rate in this population using standard vaccine dosing. Some data suggest that factors such as gender or body mass index might be responsible for the differences in response to the vaccine observed in individuals. The reason for the diminished vaccine response in this population is unclear. If in fact, Hepatitis B vaccine response is diminished in this population, then efforts to determine correlates of response and to improve the response are warranted. The proposed trial will evaluate 2 licensed vaccine products given in a two-dose schedule in youth at risk for hepatitis B and HIV infection to evaluate immunogenicity of the products in this population, barriers to vaccine delivery, and factors which predict a diminished immune response. Since these youths are also potential candidates for future HIV vaccine trials, participation in such trials will require ability to understand and willingness to volunteer for such trials, ability to return for multiple vaccinations and blood draws to assess vaccine response, and willingness to participate in HIV prevention education. A hepatitis B vaccine trial will provide a licensed vaccine to youth in whom the vaccine is indicated and will allow preliminary assessment of youth's willingness to participate in a vaccine trial that involves blood draws for immunologic assessment. Tools that will be necessary for HIV vaccine trials in youth include a youth-friendly simplified vaccine trial education component with a required written test for the participant, a standardized risk reduction education program, and a computer-assisted assessment of youth behaviors. These tools can be finalized and field tested in youth participating in the hepatitis B vaccine trial without promoting a false sense of protection from HIV. Secondary objectives of this trial will include assessment of a number of ancillary tools crucial for future HIV vaccine trials. This Hepatitis B vaccine trial will also serve as a HIV vaccine preparedness trial for youth at risk for both Hepatitis B and HIV. Design: This is a phase II, randomized, single-blinded trial of two hepatitis B immunization regimens in 150 HIV-negative, hepatitis B core antibody, hepatitis B surface antigen and surface antibody negative youth. Vaccinations will be given in a two-dose regimen at 0 and six months (75 subjects in each arm) and the primary outcome will be seroresponsiveness one month after the 6-month dose. Safety and tolerability will also be assessed.

Official Title
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Hepatitis B Vaccination in Youth at Adolescent Trial Network Sites: Effectiveness of Two Strategies and Evaluation of Tools To be Used in Future HIV Prevention Trials.

Conditions
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Hepatitis B

Intervention / Treatment
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* Biological: Recombivax
* Biological: Twinrix


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: HIV negative youth age 12-17 years (No serologic evidence of HIV infection). Negative hepatitis B serology. (No serologic evidence of hepatitis B surface antigen (HBSAg), hepatitis B surface antibody (HBsAb or anti-HBs) and hepatitis B core antibody (HBcAb or anti-HBc)). Either no prior hepatitis B immunizations or unknown or incomplete hepatitis B immunization status. Willing to participate in HIV risk-reduction counseling and computer assisted measurement of behaviors. Parent or legal guardian willing to provide written permission Females of childbearing potential must have a negative pregnancy test at screening and should agree to avoid pregnancy through the end of the vaccine phase of the study. Females who are engaging in sexual intercourse must be willing to practice a reliable method of birth control through the end of the vaccine-phase of the study (approximately 6 months). The decision of what is reliable is at the discretion of the site investigator. Exclusion Criteria: Presence of any serious illness requiring treatment with systemic medications, excluding treatment for asthma. Previous allergic reaction to any vaccines or to constituents of these vaccines (yeast, thimerosal or aluminum) Pregnancy Current immunomodulator therapy Receipt of immunosuppressor therapy (more than 10 mg/day of prednisone or equivalent for >1 week) in the 6 months preceding entry or anticipated long-term corticosteroid therapy in the above dose and duration. Short term (< 7 days) steroid use for the treatment of asthma is not an exclusion. Receipt of any vaccine within 2 weeks preceding study entry.

Ages Eligible for Study
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Minimum Age: 12 Years
Maximum Age: 17 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: Single


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Active Comparator: 1<br>Participants receive doses of Recombivax at weeks 0 and 24. A risk-behavior assessment is administered at week 12 and post-vaccination follow-up visits and bloodwork occur at weeks 28 and 76. | Biological: Recombivax<br>* Participants receive doses of Recombivax at weeks 0 and 24.<br>|
| Experimental: 2<br>Participants receive doses of Twinrix at weeks 0 and 24. A risk-behavior assessment is administered at week 12 and post-vaccination follow-up visits and bloodwork occur at weeks 28 and 76. | Biological: Twinrix<br>* Participants receive doses of Twinrix at weeks 0 and 24.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Qualitative Seroresponsiveness to Hepatitis B Surface Antigen | Seroresponsiveness to Hepatitis B Surface Antigen is defined as follows: Responder: serum antibody level is greater than or equal to 10 mIU/mL. Non-responder: serum antibody level is less than 10 mIU/mL. | Week (Wk) 28 (One month after the second immunization) | 
| Safety and Tolerability of Vaccine Regimens of Recombivax and Twinrix (Number of Participants With >=1 Adverse Event (AE)) | Frequency Distribution of AEs by Study Arm and Preferred Term. The safety and tolerability of each vaccine was assessed by measuring reactogenicity. The reactions were coded as Any vs. None. In summarizing the distribution of AEs, the number of subjects with at least one event by preferred term and study arm were reported. | Week 12, Week 24, Week 28, Week 76 | 
| Safety and Tolerability of Vaccine Regimens of Recombivax and Twinrix: Serious Adverse Events (SAE)(Number of Subjects With >= 1 SAE) | Frequency Distribution of SAE by Study Arm and Preferred Term. The safety and tolerability of each vaccine was assessed by measuring reactogenicity. The reactions were coded as Any vs. None. The number of participants with at least one SAE is reported. | Week 12, Week 24, Week 28, Week 76 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Quantitative Vaccine Response | The Log10 titer was used as the quantitative vaccine response. | Week 28 | 
| Unadjusted Relationship of Hepatitis B Vaccine Response (Log10 Titer) and Potential Impact Factors Among Subjects Whose Week 28 Antibody Results Are Within Week 28 Visit Window. | The Log10 titer at Week 28 was used as the quantitative continuous vaccine response. | Week 28 | 
| Outcome Measure: Qualitative Vaccine Response to Hepatitis B (Hep B) Surface Antigen (Binary); Predictor: STUDY ARM. | Qualitative Vaccine Response to Hepatitis B Surface Antigen is defined as a Responder if serum a'body level is >= 10 mIU/mL and a Non- Responder if a serum antibody level is < 10 mIU/mL. Study arm was analyzed as a potential impact factor and was measured and examined for the association with both the presence of adequate response as well as the quantitative titer one month post 2 vaccine doses. | Week 28 | 
| Outcome Measure: Qualitative Vaccine Response to Hepatitis B Surface Antigen (Binary); Predictor: SITE EFFECT | Qualitative Vaccine Response to Hepatitis B Surface Antigen is defined as a Responder if serum antibody level is >= 10 mIU/mL and a Non- Responder if a serum a'body level is < 10 mIU/mL. Site effect was analyzed as a potential impact factor and was measured and examined for the association with both the presence of adequate response as well as the quantitative titer one month post 2 vaccine doses. | Week 28 | 
| Outcome Measure: Qualitative Vaccine Response to Hepatitis B Surface Antigen (Binary); Predictor: AGE | Qualitative Vaccine Response to Hepatitis B (Hep B)Surface Antigen is defined as a Responder if serum a'body level is >= 10 mIU/mL and a Non- Responder if a serum antibody level is < 10 mIU/mL. Age was analyzed as a potential impact factor and was measured and examined for the association with both the presence of adequate response as well as the quantitative titer one month post 2 vaccine doses. | Week 28 | 
| Outcome Measure: Qualitative Vaccine Response to Hepatitis B Surface Antigen (Binary); Predictor: GENDER | Qualitative Vaccine Response to Hepatitis B (Hep B) Surface Antigen is defined as a Responder if serum a'body level is >= 10 mIU/mL and a Non- Responder if a serum a'body level is < 10 mIU/mL. Gender was analyzed as a potential impact factor and was measured and examined for the association with both the presence of adequate response as well as the quantitative titer one month post 2 vaccine doses. | Week 28 | 
| Outcome Measure: Qualitative Vaccine Response to Hepatitis B Surface Antigen (Binary); Predictor: HISPANIC ETHNICITY | Qualitative Vaccine Response to Hepatitis B (Hep B) Surface Antigen is defined as a Responder if serum a'body level is >= 10 mIU/mL and a Non- Responder if a serum antibody level is < 10 mIU/mL. Hispanic ethnicity was analyzed as a potential impact factor and was measured and examined for the association with both the presence of adequate response as well as the quantitative titer one month post 2 vaccine doses. | Week 28 | 
| Outcome Measure: Qualitative Vaccine Response to Hepatitis B Surface Antigen (Binary); Predictor: RACE | Qualitative Vaccine Response to Hepatitis B (Hep B) Surface Antigen is defined as a Responder if serum a'body level is >= 10 mIU/mL and a Non- Responder if a serum antibody level is < 10 mIU/mL. Race was analyzed as a potential impact factor and was measured and examined for the association with both the presence of adequate response as well as the quantitative titer one month post 2 vaccine doses. | Week 28 | 
| Outcome Measure: Qualitative Vaccine Response to Hepatitis B Surface Antigen (Binary); Predictor: TANNER STAGE FOR FEMALES | Qualitative Vaccine Response to Hepatitis B (Hep B) Surface Antigen is defined as a Responder if serum a'body level is >= 10 mIU/mL and a Non- Responder if a serum antibody level is < 10 mIU/mL. Tanner stage by gender was analyzed as a potential impact factor and was measured and examined for the association with both the presence of adequate response as well as the quantitative titer one month post 2 vaccine doses. | Week 28 | 
| Outcome Measure: Qualitative Vaccine Response to Hepatitis B Surface Antigen (Binary); Predictor: TANNER STAGE FOR MALES | Qualitative Vaccine Response to Hepatitis B (Hep B) Surface Antigen is defined as a Responder if serum a'body level is >= 10 mIU/mL and a Non- Responder if a serum antibody level is < 10 mIU/mL. Tanner stage by gender was analyzed as a potential impact factor and was measured and examined for the association with both the presence of adequate response as well as the quantitative titer one month post 2 vaccine doses. | Week 28 | 
| Outcome Measure: Qualitative Vaccine Response to Hepatitis B Surface Antigen (Binary); Predictor: BMI at Baseline | Qualitative Vaccine Response to Hepatitis B (Hep B) Surface Antigen is defined as a Responder if serum a'body level is >= 10 mIU/mL and a Non- Responder if a serum antibody level is < 10 mIU/mL. BMI at baseline was analyzed as a potential impact factor and was measured and examined for the association with both the presence of adequate response as well as the quantitative titer one month post 2 vaccine doses. | Week 28 | 
| Outcome Measure: Qualitative Vaccine Response to Hepatitis B Surface Antigen (Binary); Predictor: EVER SMOKED CIGARETTES | Qualitative Vaccine Response to Hepatitis B (Hep B) Surface Antigen is defined as a Responder if serum a'body level is >= 10 mIU/mL and a Non- Responder if a serum antibody level is < 10 mIU/mL. Whether participants ever smoked cigarettes was analyzed as a potential impact factor and was measured and examined for the association with both the presence of adequate response as well as the quantitative titer one month post 2 vaccine doses. | Week 28 | 
| Outcome Measure: Qualitative Vaccine Response to Hepatitis B Surface Antigen (Binary); Predictor: SEXUAL IDENTITY | Qualitative Vaccine Response to Hepatitis B (Hep B) Surface Antigen is defined as a Responder if serum a'body level is >= 10 mIU/mL and a Non- Responder if a serum antibody level is < 10 mIU/mL. Sexual identity was analyzed as a potential impact factor and was measured and examined for the association with both the presence of adequate response as well as the quantitative titer one month post 2 vaccine doses. | Week 28 | 
| Outcome Measure: Qualitative Vaccine Response to Hepatitis B Surface Antigen (Binary); Predictor: AGE AT WHICH SUBJECT FIRST HAD SEX (NOT FORCED) | Qualitative Vaccine Response to Hepatitis B (Hep B) Surface Antigen is defined as a Responder if serum a'body level is >= 10 mIU/mL and a Non- Responder if a serum antibody level is < 10 mIU/mL. Age of participants' first unforced sexual encounter was analyzed as a potential impact factor and was measured and examined for the association with both the presence of adequate response as well as the quantitative titer one month post 2 vaccine doses. | Week 28 | 
| Outcome Measure: Qualitative Vaccine Response to Hepatitis B Surface Antigen (Binary); Predictor: TOTAL LIFETIME SEX PARTNERS | Qualitative Vaccine Response to Hepatitis B (Hep B) Surface Antigen is defined as a Responder if serum a'body level is >= 10 mIU/mL and a Non- Responder if a serum antibody level is < 10 mIU/mL. Total number of lifetime sex partners was analyzed as a potential impact factor and was measured and examined for the association with both the presence of adequate response as well as the quantitative titer one month post 2 vaccine doses. | Week 28 | 
| Outcome Measure: Qualitative Vaccine Response to Hepatitis B Surface Antigen (Binary); Predictor: TOTAL LIFETIME MALE SEX PARTNERS | Qualitative Vaccine Response to Hepatitis B (Hep B) Surface Antigen is defined as a Responder if serum a'body level is >= 10 mIU/mL and a Non- Responder if a serum antibody level is < 10 mIU/mL. Total number of lifetime male sex partners was analyzed as a potential impact factor and was measured and examined for the association with both the presence of adequate response as well as the quantitative titer one month post 2 vaccine doses. | Week 28 | 
| Outcome Measure: Qualitative Vaccine Response to Hepatitis B Surface Antigen (Binary); Predictor: TOTAL LIFETIME FEMALE SEX PARTNERS | Qualitative Vaccine Response to Hepatitis B (Hep B) Surface Antigen is defined as a Responder if serum a'body level is >= 10 mIU/mL and a Non- Responder if a serum antibody level is < 10 mIU/mL. Total number of lifetime female sex partners was analyzed as a potential impact factor and was measured and examined for the association with both the presence of adequate response as well as the quantitative titer one month post 2 vaccine doses. | Week 28 | 
| Outcome Measure: Qualitative Vaccine Response to Hepatitis B Surface Antigen (Binary); Predictor: EVER DRANK ALCOHOL | Qualitative Vaccine Response to Hepatitis B (Hep B) Surface Antigen is defined as a Responder if serum a'body level is >= 10 mIU/mL and a Non- Responder if a serum antibody level is < 10 mIU/mL. Whether participants ever drank alcohol was analyzed as a potential impact factor and was measured and examined for the association with both the presence of adequate response as well as the quantitative titer one month post 2 vaccine doses. | Week 28 | 
| Outcome Measure: Qualitative Vaccine Response to Hepatitis B Surface Antigen (Binary); Predictor: EVER SMOKED MARIJUANA | Qualitative Vaccine Response to Hepatitis B (Hep B) Surface Antigen is defined as a Responder if serum a'body level is >= 10 mIU/mL and a Non- Responder if a serum antibody level is < 10 mIU/mL. Whether participants ever smoked marijuana was analyzed as a potential impact factor and was measured and examined for the association with both the presence of adequate response as well as the quantitative titer one month post 2 vaccine doses. | Week 28 | 
| Outcome Measure: Qualitative Vaccine Response to Hepatitis B Surface Antigen (Binary); Predictor: EVER USED DRUGS NOT PRESCRIBE | Qualitative Vaccine Response to Hepatitis B (Hep B) Surface Antigen is defined as a Responder if serum a'body level is >= 10 mIU/mL and a Non- Responder if a serum antibody level is < 10 mIU/mL. Whether participants ever used drugs not prescribed was analyzed as a potential impact factor and was measured and examined for the association with both the presence of adequate response as well as the quantitative titer one month post 2 vaccine doses. | Week 28 | 
| Immunogenicity to Hep B 18 Months After First Immunization | Persistence of protective antibody response was measured by presence or absence of 10 mIU/ml HepB surface antibody and geometric mean titer of the same antibody at Week 76 | Week 76 | 
| Immunogenicity to Hep A in the Twinrix Arm: One Month Post 2nd Vaccination | Hepatitis A antibody response in those subjects in the combined vaccine arm (Twinrix) at 1 month after the 2nd vaccination. Immunogenicity to Hepatitis is given as a positive or negative response. If the Hepatitis A serology was reactive, then the participant was considered to have a positive response; if the Hepatitis A serology was non-reactive, then the participant was considered to have a negative response. | Week 28 | 
| Immunogenicity to Hep A in Twinrix Arm: Twelve Months Post 2nd Vaccination | Hepatitis A antibody response in those subjects in the combined vaccine arm (Twinrix) at 12 months after the 2nd vaccination. Immunogenicity to Hepatitis is given as a positive or negative response. | Week 76 | 
| Immunogenicity to Hep A in Twinrix Arm: Overall Response (1-month or 12-month After 2nd Vaccination) | Hepatitis A antibody response in those subjects in the combined vaccine arm (Twinrix) at two time points: 1 and 12 months after the 2nd vaccination. Immunogenicity to Hepatitis is given as a positive or negative response. | Week 28 and Week 76 | 
| As Treated Analysis - Adequate Antibody Response to Hep B Surface Antigen | The subject was considered seroresponsive to Hepatitis B Surface Antigen if the serum antibody level was greater than or equal to 10 mIU/mL. Those who received only a single vaccination, whose second vaccination was outside of the specified time window, or other cases of protocol violations were excluded from the analysis. | Week 28 | 
| Assessment of Youth Understanding of Vaccine Trial and Informed Consent | Assessment of understanding was measured by a questionnaire containing six questions. The summary score is the sum of correct answers from six questions. | Screening | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Hepatitis B, HIV vaccine trial