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

Phase 1

Completed

Conditions: Tuberculosis

Interventions: Biological: BCG
Biological: Control Sodium Chloride 0.9%

Registration Number: NCT02378207

Lead Sponsor: Aeras

Brief Summary: 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: 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.

Recruitment & Eligibility

Status: COMPLETED

Sex: All

Target Recruitment: 84

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)

Study & Design

Study Type: INTERVENTIONAL

Study Design: PARALLEL

Arm && Interventions

Group	Intervention	Description
Group 3 BCG (2-8 x 105 CFU)	BCG	Administered IM as 0.1 mL in either deltoid muscle at Day 0.
Group 4 Control Sodium Chloride 0.9%	Control Sodium Chloride 0.9%	Administered IM as 0.5 mL in alternating deltoid muscle at Days 0 and 56.

Primary Outcome Measures

Name	Time	Method
Number of Participants With Adverse Events	Up to 8 months	The number of solicited and unsolicited adverse events (AEs), including serious adverse events (SAEs), recorded post-vaccination for all participants.
Percentage of Participants With Response Rates to TB Antigens as Compared to Baseline	Days 70 and 168	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.

Secondary Outcome Measures

Name	Time	Method
* 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.	Up to day 168	* 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..
Evaluate QFT-GIT and ESAT-6 Free IGRA Discordance and Conversion/Reversion Rate During the Course of the Trial.	Up to day 168	* 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.
Evaluate Humoral Responses Elicited by the Different Vaccine Regimens.	Up to day 168.	Vaccine-specific binding antibodies elicited by the vaccine regimens as determined by multiplex antibody assay and/or enzyme-linked immunosorbent assay (ELISA).
Evaluate Changes in Innate Cells in Response to the Vaccine Regimens	Up to day 168	Blood concentrations of innate immune cell populations including lymphocyte populations, dendritic cells, monocytes, and granulocytes before and after vaccination
Measure Non-classical Major Histocompatibility Complex (MHC)-Restricted T-cell Vaccine-induced Responses, Such as to Mycobacterial Lipids (CD1-restricted) and Metabolites (MR1-restricted).	Up to day 168	* 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