Safety and Immunogenicity Study of AERAS-456 Vaccine for Tuberculosis

Study Overview
=================
Brief Summary
-----------------
This is a Phase I, open-label, dose-escalation study with three study groups. This study will be conducted in 25 HIV negative subjects, 17 of whom will have Latent Tuberculosis Infection (LTBI) and 8 of whom will not have LTBI at study enrollment. The investigational product is AERAS-456 at a dose of 15 ug of H56 antigen with IC31 500 nmol KLK (15/500), and a dose of 50 ug of H56 antigen with IC31 500 nmol KLK (50/500). The vaccine is administered by intramuscular injection.

Detailed Description
-----------------
This is a Phase I, open-label, dose-escalation study with three study groups. This study will be conducted in 25 HIV negative subjects, 17 of whom will have Latent Tuberculosis Infection (LTBI) and 8 of whom will not have LTBI at study enrollment. The investigational product is H56:IC31 (AERAS-456) at a dose of 15 ug of H56 antigen with IC31 500 nmol KLK (15/500), and a dose of 50 ug of H56 antigen with IC31 500 nmol KLK (50/500). The vaccine is administered by intramuscular (IM) injection. Subjects will be assigned to a study group based on LTBI status at enrollment and time of completion of screening. Subjects without LTBI will be assigned to Group 1. Subjects with LTBI will be sequentially assigned to Groups 2 and 3 based on the order in which they complete screening. All subjects will receive a first dose of study vaccine on Study Day 0, a second dose of study vaccine on Study Day 56, and a third dose of study vaccine on Study Day 112. Enrollment of subjects into Group 2 will begin only after a review of safety data from the 14-day period after initial vaccination of all subjects in Group 1. Likewise, enrollment of subjects into Group 3 will begin only after the corresponding review of safety data from Group 2. The total duration of study follow-up for all subjects is 210 days. Study groups 1-2 will enroll 8 subjects each and study group 3 will enroll 9 subjects. This study is planned at a single clinical site in South Africa. The sizes specified for each study group were selected because they are judged to be adequate for preliminary safety and immunogenicity evaluations for a Phase I study rather than for statistical reasons.

Official Title
-----------------
Phase I Open Label Dose-Escalation Study to Evaluate the Safety and Immunogenicity of H56:IC31 (AERAS-456) in HIV-negative Adults With and Without Latent Tuberculosis Infection

Conditions
-----------------
Latent Tuberculosis, Latent Tuberculosis Bacteriology and Histology Unknown

Intervention / Treatment
-----------------
* Biological: H56:IC31


Participation Criteria
=================
Eligibility Criteria
-----------------
Inclusion Criteria: Has completed the written informed consent process Is male or female Is aged 18 through 50 years on Study Day 0 Females: Ability to avoid pregnancy during the trial: Women physically capable of pregnancy (not sterilized and still menstruating or within 1 year of the last menses if menopausal) in sexual relationships with men must avoid pregnancy with an acceptable method of avoiding pregnancy from 28 days prior to administration of the study vaccine through the end of the study. Has general good health, confirmed by medical history and physical examination Is able and willing to complete the full follow-up period of 210 days as required by the protocol Is able and willing to commit to avoiding elective surgery for the duration of the study Is able and willing to stay in contact with the study site for the duration of the study [Groups 2 & 3] Has latent tuberculosis infection (LTBI), diagnosed by a positive Quantiferon (QFT) Has completed simultaneous enrollment in the Registry Protocol Exclusion Criteria: Axillary temperature 37.5 C Abnormal laboratory values from blood collected within 7 days prior to Study Day 0 vaccination as follows: hemoglobin, hematocrit, platelet count, absolute neutrophil count, or absolute lymphocyte count below lower limit of normal (LLN). white blood cell count above upper limit of normal (ULN) or below LLN alanine aminotransferase (ALT), aspartate aminotransferase (AST), total bilirubin, alkaline phosphatase (ALP), or creatinine above ULN. Abnormal urinalysis that, in the opinion of the investigator, indicates systemic or local disease. History or evidence of tuberculosis disease, including but not limited to pulmonary tuberculosis, pleural tuberculosis, lymph node tuberculosis or tuberculosis meningitis. [Group 1] Evidence of latent tuberculosis infection (LTBI), defined as a positive screening QFT or a history of a positive TST or QFT. Received a tuberculin skin test (TST) or bacillus Calmette-Guerin (BCG) within 45 days prior to Study Day 0. Received investigational Mtb vaccine at any time prior to Study Day 0. History or evidence of autoimmune disease. History or laboratory evidence of HIV infection. History or laboratory evidence of Hepatitis B or C. Used immunosuppressive medication (other than inhaled or topical immunosuppressants) within 45 days prior to Study Day 0. Received immunoglobulin or blood products within 45 days prior to Study Day 0 Received any investigational product within 45 days prior to Study Day 0, or plans to participate in any other study involving administration of investigational product during the study period. Inability to discontinue daily medications, except contraceptives, inhaled or topical immunosuppressants, or nutritional supplements, during the study period. Documented history of allergic reaction or hypersensitivity to any component of the study vaccine. Female subjects: currently pregnant or lactating/nursing; or positive serum pregnancy test during screening; or positive urine pregnancy test on the day of Study Day 0, Study Day 56, or Study Day 112 vaccination. History or evidence of any systemic disease or any acute or chronic illness that, in the opinion of the investigator, may compromise the safety of the subject in the study or interfere with the evaluation of the safety or immunogenicity of the vaccine. History of dermatologic disease or skin features that, in the opinion of the investigator, may interfere with the assessment of injection site reactions. History or evidence of any medical, psychiatric, occupational, or substance abuse problems that, in the opinion of the investigator, will make it unlikely that the subject will comply with the protocol.

Ages Eligible for Study
-----------------
Minimum Age: 18 Years
Maximum Age: 50 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: Sequential Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: H56:IC31 (50 ug H56) LTBI Neg<br>LTBI Negative 3 Doses | Biological: H56:IC31<br>* H56:IC31 contains a fusion protein (referred to as H56 antigen, or H56) of 3 mycobacterial antigens (the early secreted antigens Ag85B and ESAT-6, and the latency antigen Rv2660c) formulated in the Th1-stimulating IC31 adjuvant.<br>* Other names: AERAS 456;|
| Experimental: H56:IC31 (15 ug H56) LTBI Pos<br>LTBI Positive 3 Doses | Biological: H56:IC31<br>* H56:IC31 contains a fusion protein (referred to as H56 antigen, or H56) of 3 mycobacterial antigens (the early secreted antigens Ag85B and ESAT-6, and the latency antigen Rv2660c) formulated in the Th1-stimulating IC31 adjuvant.<br>* Other names: AERAS 456;|
| Experimental: H56:IC31 (50 ug H56) LTBI Pos<br>LTBI Positive 3 Doses | Biological: H56:IC31<br>* H56:IC31 contains a fusion protein (referred to as H56 antigen, or H56) of 3 mycobacterial antigens (the early secreted antigens Ag85B and ESAT-6, and the latency antigen Rv2660c) formulated in the Th1-stimulating IC31 adjuvant.<br>* Other names: AERAS 456;|

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

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of Participants With at Least One Adverse Event (AE) Through Day 210 | Solicited AEs: through 14 days after each vaccination Unsolicited AEs: post-vaccination on Study Days 0, 56, and 112 through 28 days after vaccination Injection site reactions and axillary lymphadenopathy: post-injection on the day of each vaccination, and Study Days 2 , 7, 14, and 28 days after each vaccination Serious adverse events (SAE): through Study Day 210 | Through Study Day 210 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Median % Change in Response to Peptides From Vaccine Antigen Ag85B From Pre-vaccination to Day 70 in Participants Who Received Two Vaccinations | Whole blood ICS Percent Antigen-Specific T Cell UNS-subtracted Cytokine Response Antigen: Ag85B Cytokine(s): G+2+17+T+ %CD4+ T Cell Response | Study Day 70 | 
| Median % Change in Response to Peptides From Vaccine Antigen ESAT-6 From Pre-vaccination to Day 70 in Participants Who Received Two Vaccinations | Percent Antigen-Specific T Cell UNS-subtracted Cytokine Response 12-Hour Whole Blood Intracellular Cytokine Staining (ICS) Assay Antigen: ESAT6 Cytokine(s): G+2+17+T+ %CD4+ T Cell Response | Study Day 70 | 
| Number of Participants Who Received at Least Two Vaccinations and Tested Positive for Mtb Infection on Day 210 | Measure of Mtb positivity by QuantiFERON-TB Gold In-Tube Number of Positive Responses and Shift from Screening to Study Day 210 Post-Vaccination Responses | Study Day 210 | 
| Median % Change in Response to Peptides From Vaccine Antigen Ag85AB From Pre-vacc to Day 210 | Responses to vaccine antigen Ag85B measure by Interferon gamma (IFN-γ) ELISpot assay Unstimulated-subtracted IFN-γ ELISpot Response (Spot forming units/10^6 PBMC) Antigen: Ag85B | Study Day 210 | 

 Terms related to the study
=================
Keywords Provided by Centre Hospitalier Valida
-----------------
HIV Negative