Safety and Immunogenicity Study of BCG, H4:IC31, and H56:IC31 Revaccination in Healthy Adolescents

Study Overview
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Brief Summary
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The aims of the phase 1b trial described here are to facilitate identification of assays and immune responses that could then be evaluated as correlates of risk and correlates of protection in efficacy studies and ultimately to provide leads for biomarkers of protection against tuberculosis. This study will complement one ongoing study (NCT02075203) evaluating the prevention of M. Tuberculosis infection using H4:IC31 (also known as AERAS-404).

Detailed Description
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This study proposes to further evaluate the safety and immunogenicity of H4:IC31, H56:IC31, and BCG revaccination. The study will be conducted in previously BCG vaccinated healthy adolescents, and will entail a thorough immunogenicity evaluation of these regimens incorporating unbiased systems vaccinology approaches and novel assessments of baseline and elicited responses that may impact vaccine responses. A major goal for this study is to generate immunological data on a wide range of immune responses using a variety of approaches including validated assessments, unbiased strategies, and novel exploratory assays to increase the likelihood of detecting responses correlating with risk or protection in the prevention of infection study. Investigators contributing to the proposed study have participated in a correlates analysis for an HIV vaccine exhibiting modest efficacy in which 2 correlates of risk were identified. An additional aim of this study is to explore factors affecting vaccine induced responses that may also impact efficacy. For example, it is hypothesized that exposure to environmental mycobacteria may alter protection provided by BCG vaccination. Reagents for evaluating levels of exposure to environmental mycobacteria are in development as part of a concurrent collaborative study. An exploratory objective for this trial is to apply these reagents to examine whether such exposures influence immune responses elicited by the study vaccine and regimens.

Official Title
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A Randomized, Placebo-controlled, Partially Blinded Phase 1b Clinical Trial to Evaluate the Safety and Immunogenicity of BCG Revaccination, H4:IC31, and H56:IC31 in Healthy, HIV-1-Uninfected Adolescent Participants

Conditions
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Tuberculosis

Intervention / Treatment
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* Biological: H4:IC31
* Biological: H56:IC31
* Biological: BCG
* Biological: Control Sodium Chloride 0.9%


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Age of 12 to ≤ 17 years at enrollment Minimum weight ≥ 40 kg Previous BCG vaccination at least 5 years ago documented by scarification or medical card No evidence of active TB disease, as determined by history, physical examination and, if deemed appropriate, sputum investigation and / or chest x-ray. Negative QFT-GIT test at screening, using the manufacturer's recommended threshold of 0.35 IU/mL Assessed by the clinic staff as being at low risk for HIV infection Hemoglobin ≥ 11.7 g/dL for females, ≥ 12.5 g/dL for males Negative HIV-1 and -2 blood test Agree to consistently use effective contraception for sexual activity that could lead to pregnancy from at least 20 days prior to enrollment through the last required protocol clinic visit. (additional minor criteria not added due to space constraints) Exclusion Criteria: Blood products received within 120 days before first vaccination Investigational research agents received within 182 days before first vaccination Intent to participate in another study of an investigational research agent during the planned duration of the HVTN 602 / AERAS A-042 study Pregnant or breastfeeding History of alcohol or drug abuse A significant contact with active TB disease: for example, shared residency with an individual receiving anti-TB treatment, or with an individual known to have incompletely treated culture or smear positive TB TB prophylaxis within 90 days prior to enrollment History of treatment for active TB disease or latent Mtb infection Positive and indeterminate QFT-GIT result Received a tuberculin skin test (TST) within 90 days prior to enrollment Vaccines and other Injections Immunosuppressive medications received within 168 days before first vaccination. Serious adverse reactions to vaccines including history of anaphylaxis and related symptoms such as hives, respiratory difficulty, angioedema, and/or abdominal pain. Immunoglobulin received within 60 days before first vaccination Autoimmune disease Not excluded: mild, well-controlled psoriasis Clinically significant medical condition, physical examination findings, clinically significant abnormal laboratory results, or past medical history with clinically significant implications for current health. Including but not limited to: Diabetes mellitus type 1 or type 2, Thyroidectomy, or Thyroid disease, Asthma, Asplenia, Bleeding disorders, malignancy, Seizure disorder, and Angioedema (additional minor criteria not added due to space constraints)

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: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Group 1 H4:IC31<br>15 mcg H4/500 nmol IC31 administered IM as 0.5 mL in alternating deltoid muscle at Days 0 and 56. | Biological: H4:IC31<br>* H4 contains Mtb antigens Ag85B and TB10.4<br>|
| Experimental: Group 2 H56:IC31<br>5 mcg H56/500 nmol IC31 administered IM as 0.5 mL in alternating deltoid muscle at Days 0 and 56. | Biological: H56:IC31<br>* H56 contains Mtb antigens ESAT-6, and Rv2660c<br>|
| Active Comparator: Group 3 BCG (2-8 x 105 CFU)<br>Administered IM as 0.1 mL in either deltoid muscle at Day 0. | Biological: BCG<br> <br> |
| Placebo Comparator: Group 4 Control Sodium Chloride 0.9%<br>Administered IM as 0.5 mL in alternating deltoid muscle at Days 0 and 56. | Biological: Control Sodium Chloride 0.9%<br> <br> |

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of Participants With Adverse Events | The number of solicited and unsolicited adverse events (AEs), including serious adverse events (SAEs), recorded post-vaccination for all participants. | Up to 8 months | 
| Percentage of Participants With Response Rates to TB Antigens as Compared to Baseline | Flow cytometry was used to examine TB Mb-specific CD4+ and CD8+ T-cell responses using the ICS assay. The antigens used to stimulate cells in this assay included peptide pools for the vaccine-matched proteins (Ag85B, ESAT-6, Rv2660c, and TB 10.4) as well as complex TB antigens (TB whole cell lysate [TB WCL], and BCG Pasteur strain. | Days 70 and 168 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Evaluate Humoral Responses Elicited by the Different Vaccine Regimens. | Vaccine-specific binding antibodies elicited by the vaccine regimens as determined by multiplex antibody assay and/or enzyme-linked immunosorbent assay (ELISA). | Up to day 168. | 
| * Evaluate Immune Response From Vaccine Regimens by Measuring Early (Innate) Vaccine-induced Peripheral Blood Transcription Profiles; Determine Which Responses Are Associated With Antigen-specific Adaptive Responses * Evaluate Adaptive Immune Response. | Changes in gene expression measured in longitudinally-collected blood samples relative to samples collected at baseline. The transcriptional profiles will be correlated with antigen-specific adaptive responses measured in Primary objective 2. Transcriptional analysis of antigen-stimulated peripheral blood mononuclear cells (PBMC) at 2 weeks post vaccination will be performed.. | Up to day 168 | 
| Evaluate Changes in Innate Cells in Response to the Vaccine Regimens | Blood concentrations of innate immune cell populations including lymphocyte populations, dendritic cells, monocytes, and granulocytes before and after vaccination | Up to day 168 | 
| Measure Non-classical Major Histocompatibility Complex (MHC)-Restricted T-cell Vaccine-induced Responses, Such as to Mycobacterial Lipids (CD1-restricted) and Metabolites (MR1-restricted). | Frequency of CD4+, CD8+, and CD4/CD8 double-negative T-cell responses restricted by CD1 (recognizing specific Mtb lipids) before and after BCG revaccination in Group 3 participants. Frequency of mucosal-associated invariant T-cells (MAIT) restricted by MR1 (recognizing vitamin B metabolites) before and after BCG revaccination in Group 3 participants | Up to day 168 | 
| Evaluate QFT-GIT and ESAT-6 Free IGRA Discordance and Conversion/Reversion Rate During the Course of the Trial. | Magnitude and positivity of interferon (IFN)-γ release using QFT-GIT ELISA in QFT-GIT tests. Magnitude and positivity of IFN-γ release using QFT-GIT ELISA in ESAT-6 free IGRAs. | Up to day 168 |