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

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ClinicalTrials.gov Identifier: NCT02378207
Recruitment Status : Completed
First Posted : March 4, 2015
Results First Posted : November 18, 2019
Last Update Posted : November 18, 2019
Sponsor:
Collaborators:
HIV Vaccine Trials Network
Sanofi Pasteur, a Sanofi Company
Statens Serum Institut
Information provided by (Responsible Party):
Aeras

Tracking Information
First Submitted Date  ICMJE February 12, 2015
First Posted Date  ICMJE March 4, 2015
Results First Submitted Date  ICMJE September 3, 2019
Results First Posted Date  ICMJE November 18, 2019
Last Update Posted Date November 18, 2019
Study Start Date  ICMJE May 2015
Actual Primary Completion Date October 31, 2016   (Final data collection date for primary outcome measure)
Current Primary Outcome Measures  ICMJE
 (submitted: October 28, 2019)
  • Number of Participants With Adverse Events [ Time Frame: 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 [ Time Frame: 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.
Original Primary Outcome Measures  ICMJE
 (submitted: February 26, 2015)
  • Safety and tolerability of the different vaccine regimens in adolescents [ Time Frame: Up to 8 months ]
    The number and percentage of solicited and unsolicited adverse events (AEs), recorded postvaccination for all participants.
  • Cellular immune responses of the different vaccine regimens in adolescents compared to those measured at baseline. [ Time Frame: Up to day 70 ]
    T-cell responses by flow cytometric intracellular cytokine staining (ICS) of CD4+ T cells after stimulation with a pool of mycobacterial peptides and/or PPD (purified protein derivative) using cryopreserved peripheral blood mononuclear cells (PBMC).
  • Cellular immune responses of the different vaccine regimens in adolescents compared to those measured at baseline. [ Time Frame: Up to day 70 ]
    T-cell responses by flow cytometric intracellular cytokine staining (ICS) of CD8+ T cells after stimulation with a pool of mycobacterial peptides and/or PPD (purified protein derivative) using cryopreserved peripheral blood mononuclear cells (PBMC).
Change History
Current Secondary Outcome Measures  ICMJE
 (submitted: October 28, 2019)
  • Evaluate Humoral Responses Elicited by the Different Vaccine Regimens. [ Time Frame: 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 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. [ Time Frame: 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 Changes in Innate Cells in Response to the Vaccine Regimens [ Time Frame: 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). [ Time Frame: 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
  • Evaluate QFT-GIT and ESAT-6 Free IGRA Discordance and Conversion/Reversion Rate During the Course of the Trial. [ Time Frame: 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.
Original Secondary Outcome Measures  ICMJE Not Provided
Current Other Pre-specified Outcome Measures Not Provided
Original Other Pre-specified Outcome Measures Not Provided
 
Descriptive Information
Brief Title  ICMJE Safety and Immunogenicity Study of BCG, H4:IC31, and H56:IC31 Revaccination in Healthy Adolescents
Official Title  ICMJE 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
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.

Study Type  ICMJE Interventional
Study Phase  ICMJE Phase 1
Study Design  ICMJE Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
Primary Purpose: Prevention
Condition  ICMJE Tuberculosis
Intervention  ICMJE
  • Biological: H4:IC31
    H4 contains Mtb antigens Ag85B and TB10.4
  • Biological: H56:IC31
    H56 contains Mtb antigens ESAT-6, and Rv2660c
  • Biological: BCG
  • Biological: Control Sodium Chloride 0.9%
Study Arms  ICMJE
  • Experimental: Group 1 H4:IC31
    15 mcg H4/500 nmol IC31 administered IM as 0.5 mL in alternating deltoid muscle at Days 0 and 56.
    Intervention: Biological: H4:IC31
  • Experimental: Group 2 H56:IC31
    5 mcg H56/500 nmol IC31 administered IM as 0.5 mL in alternating deltoid muscle at Days 0 and 56.
    Intervention: Biological: H56:IC31
  • Active Comparator: Group 3 BCG (2-8 x 105 CFU)
    Administered IM as 0.1 mL in either deltoid muscle at Day 0.
    Intervention: Biological: BCG
  • Placebo Comparator: Group 4 Control Sodium Chloride 0.9%
    Administered IM as 0.5 mL in alternating deltoid muscle at Days 0 and 56.
    Intervention: Biological: Control Sodium Chloride 0.9%
Publications * Bekker LG, Dintwe O, Fiore-Gartland A, Middelkoop K, Hutter J, Williams A, Randhawa AK, Ruhwald M, Kromann I, Andersen PL, DiazGranados CA, Rutkowski KT, Tait D, Miner MD, Andersen-Nissen E, De Rosa SC, Seaton KE, Tomaras GD, McElrath MJ, Ginsberg A, Kublin JG; HVTN 602/Aeras A-042 Protocol Team. A phase 1b randomized study of the safety and immunological responses to vaccination with H4:IC31, H56:IC31, and BCG revaccination in Mycobacterium tuberculosis-uninfected adolescents in Cape Town, South Africa. EClinicalMedicine. 2020 Mar 18;21:100313. doi: 10.1016/j.eclinm.2020.100313. eCollection 2020 Apr.

*   Includes publications given by the data provider as well as publications identified by ClinicalTrials.gov Identifier (NCT Number) in Medline.
 
Recruitment Information
Recruitment Status  ICMJE Completed
Actual Enrollment  ICMJE
 (submitted: February 26, 2015)
84
Original Estimated Enrollment  ICMJE Same as current
Actual Study Completion Date  ICMJE December 9, 2016
Actual Primary Completion Date October 31, 2016   (Final data collection date for primary outcome measure)
Eligibility Criteria  ICMJE

Inclusion Criteria:

  1. Age of 12 to ≤ 17 years at enrollment
  2. Minimum weight ≥ 40 kg
  3. Previous BCG vaccination at least 5 years ago documented by scarification or medical card
  4. No evidence of active TB disease, as determined by history, physical examination and, if deemed appropriate, sputum investigation and / or chest x-ray.
  5. Negative QFT-GIT test at screening, using the manufacturer's recommended threshold of 0.35 IU/mL
  6. Assessed by the clinic staff as being at low risk for HIV infection
  7. Hemoglobin ≥ 11.7 g/dL for females, ≥ 12.5 g/dL for males
  8. Negative HIV-1 and -2 blood test
  9. 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:

  1. Blood products received within 120 days before first vaccination
  2. Investigational research agents received within 182 days before first vaccination
  3. Intent to participate in another study of an investigational research agent during the planned duration of the HVTN 602 / AERAS A-042 study
  4. Pregnant or breastfeeding
  5. History of alcohol or drug abuse
  6. 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
  7. TB prophylaxis within 90 days prior to enrollment
  8. History of treatment for active TB disease or latent Mtb infection
  9. Positive and indeterminate QFT-GIT result
  10. Received a tuberculin skin test (TST) within 90 days prior to enrollment
  11. Vaccines and other Injections
  12. Immunosuppressive medications received within 168 days before first vaccination.
  13. Serious adverse reactions to vaccines including history of anaphylaxis and related symptoms such as hives, respiratory difficulty, angioedema, and/or abdominal pain.
  14. Immunoglobulin received within 60 days before first vaccination
  15. Autoimmune disease Not excluded: mild, well-controlled psoriasis
  16. 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)

Sex/Gender  ICMJE
Sexes Eligible for Study: All
Ages  ICMJE 12 Years to 17 Years   (Child)
Accepts Healthy Volunteers  ICMJE Yes
Contacts  ICMJE Contact information is only displayed when the study is recruiting subjects
Listed Location Countries  ICMJE South Africa
Removed Location Countries  
 
Administrative Information
NCT Number  ICMJE NCT02378207
Other Study ID Numbers  ICMJE HVTN 602 / AERAS A-042
Has Data Monitoring Committee Yes
U.S. FDA-regulated Product Not Provided
IPD Sharing Statement  ICMJE
Plan to Share IPD: No
Responsible Party Aeras
Study Sponsor  ICMJE Aeras
Collaborators  ICMJE
  • HIV Vaccine Trials Network
  • Sanofi Pasteur, a Sanofi Company
  • Statens Serum Institut
Investigators  ICMJE
Study Chair: Linda-Gail Bekker, MD Desmond Tutu HIV Centre
Study Chair: Jim Kublin, MD HVTN Core, FHCRC
PRS Account Aeras
Verification Date January 2018

ICMJE     Data element required by the International Committee of Medical Journal Editors and the World Health Organization ICTRP