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

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

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).

Study Overview

• Status: Completed
• Conditions: Tuberculosis
• Intervention / Treatment: Biological: BCG; Biological: H4:IC31; Biological: H56:IC31; Biological: Control Sodium Chloride 0.9%

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: Interventional
• Enrollment (Actual): 84
• Phase: Phase 1

Contacts and Locations

Study Locations

• South Africa
  • Cape Town, South Africa
    • Desmond Tutu HIV Foundation

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 8 years to 13 years (Child)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

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)

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Prevention
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Quadruple

Number of Arms

4

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
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.	Biological: H4:IC31; H4 contains Mtb antigens Ag85B and TB10.4
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.	Biological: H56:IC31; H56 contains Mtb antigens ESAT-6, and Rv2660c
Active Comparator: Group 3 BCG (2-8 x 105 CFU); Administered IM as 0.1 mL in either deltoid muscle at Day 0.	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.	Biological: Control Sodium Chloride 0.9%

What is the study measuring?

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

Collaborators and Investigators

• Sponsor: Aeras
• Collaborators: Sanofi Pasteur, a Sanofi Company; Statens Serum Institut; HIV Vaccine Trials Network
• Investigators: Study Chair: Linda-Gail Bekker, MD, Desmond Tutu HIV Centre; Study Chair: Jim Kublin, MD, HVTN Core, FHCRC

Publications and helpful links

General 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.

Study record dates

Study Major Dates

• Study Start: May 1, 2015
• Primary Completion (Actual): October 31, 2016
• Study Completion (Actual): December 9, 2016

Study Registration Dates

• First Submitted: February 12, 2015
• First Submitted That Met QC Criteria: February 26, 2015
• First Posted (Estimate): March 4, 2015

Study Record Updates

• Last Update Posted (Actual): November 18, 2019
• Last Update Submitted That Met QC Criteria: October 28, 2019
• Last Verified: January 1, 2018

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Infections; Bacterial Infections; Bacterial Infections and Mycoses; Gram-Positive Bacterial Infections; Actinomycetales Infections; Mycobacterium Infections; Tuberculosis
• Other Study ID Numbers: HVTN 602 / AERAS A-042

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: No