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

Primary Purpose

Tuberculosis

Status

Completed

Phase

Phase 1

Locations

South Africa

Study Type

Interventional

Intervention

H4:IC31

H56:IC31

BCG

Control Sodium Chloride 0.9%

About this trial

This is an interventional prevention trial for Tuberculosis

Eligibility Criteria

12 Years - 17 Years (Child)All SexesAccepts Healthy Volunteers

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)

Sites / Locations

Desmond Tutu HIV Foundation

Arms of the Study

Arm 1

Arm 2

Arm 3

Arm 4

Arm Type

Experimental

Active Comparator

Placebo Comparator

Arm Label

Group 1 H4:IC31

Group 2 H56:IC31

Group 3 BCG (2-8 x 105 CFU)

Group 4 Control Sodium Chloride 0.9%

Arm Description

15 mcg H4/500 nmol IC31 administered IM as 0.5 mL in alternating deltoid muscle at Days 0 and 56.

5 mcg H56/500 nmol IC31 administered IM as 0.5 mL in alternating deltoid muscle at Days 0 and 56.

Administered IM as 0.1 mL in either deltoid muscle at Day 0.

Administered IM as 0.5 mL in alternating deltoid muscle at Days 0 and 56.

Outcomes

Primary Outcome Measures

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.

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.

Secondary Outcome Measures

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).

* 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..

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

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

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.

Full Information

NCT ID

NCT02378207

First Posted

February 12, 2015

Last Updated

October 28, 2019

Sponsor

Aeras

Collaborators

HIV Vaccine Trials Network, Sanofi Pasteur, a Sanofi Company, Statens Serum Institut

1. Study Identification

Unique Protocol Identification Number

NCT02378207

Brief Title

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

Official Title

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

Study Type

Interventional

2. Study Status

Record Verification Date

January 2018

Overall Recruitment Status

Completed

Study Start Date

May 2015 (undefined)

Primary Completion Date

October 31, 2016 (Actual)

Study Completion Date

December 9, 2016 (Actual)

3. Sponsor/Collaborators

Responsible Party, by Official Title

Sponsor

Name of the Sponsor

Aeras

Collaborators

HIV Vaccine Trials Network, Sanofi Pasteur, a Sanofi Company, Statens Serum Institut

4. Oversight

Data Monitoring Committee

Yes

5. Study Description

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.

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study

Tuberculosis

7. Study Design

Primary Purpose

Prevention

Study Phase

Phase 1

Interventional Study Model

Parallel Assignment

Masking

ParticipantCare ProviderInvestigatorOutcomes Assessor

Allocation

Randomized

Enrollment

84 (Actual)

8. Arms, Groups, and Interventions

Arm Title

Group 1 H4:IC31

Arm Type

Experimental

Arm Description

15 mcg H4/500 nmol IC31 administered IM as 0.5 mL in alternating deltoid muscle at Days 0 and 56.

Arm Title

Group 2 H56:IC31

Arm Type

Experimental

Arm Description

5 mcg H56/500 nmol IC31 administered IM as 0.5 mL in alternating deltoid muscle at Days 0 and 56.

Arm Title

Group 3 BCG (2-8 x 105 CFU)

Arm Type

Active Comparator

Arm Description

Administered IM as 0.1 mL in either deltoid muscle at Day 0.

Arm Title

Group 4 Control Sodium Chloride 0.9%

Arm Type

Placebo Comparator

Arm Description

Administered IM as 0.5 mL in alternating deltoid muscle at Days 0 and 56.

Intervention Type

Biological

Intervention Name(s)

H4:IC31

Intervention Description

H4 contains Mtb antigens Ag85B and TB10.4

Intervention Type

Biological

Intervention Name(s)

H56:IC31

Intervention Description

H56 contains Mtb antigens ESAT-6, and Rv2660c

Intervention Type

Biological

Intervention Name(s)

BCG

Intervention Type

Biological

Intervention Name(s)

Control Sodium Chloride 0.9%

Primary Outcome Measure Information:

Title

Number of Participants With Adverse Events

Description

The number of solicited and unsolicited adverse events (AEs), including serious adverse events (SAEs), recorded post-vaccination for all participants.

Time Frame

Up to 8 months

Title

Percentage of Participants With Response Rates to TB Antigens as Compared to Baseline

Description

Time Frame

Days 70 and 168

Secondary Outcome Measure Information:

Title

Evaluate Humoral Responses Elicited by the Different Vaccine Regimens.

Description

Vaccine-specific binding antibodies elicited by the vaccine regimens as determined by multiplex antibody assay and/or enzyme-linked immunosorbent assay (ELISA).

Time Frame

Up to day 168.

Title

Description

Time Frame

Up to day 168

Title

Evaluate Changes in Innate Cells in Response to the Vaccine Regimens

Description

Blood concentrations of innate immune cell populations including lymphocyte populations, dendritic cells, monocytes, and granulocytes before and after vaccination

Time Frame

Up to day 168

Title

Measure Non-classical Major Histocompatibility Complex (MHC)-Restricted T-cell Vaccine-induced Responses, Such as to Mycobacterial Lipids (CD1-restricted) and Metabolites (MR1-restricted).

Description

Time Frame

Up to day 168

Title

Evaluate QFT-GIT and ESAT-6 Free IGRA Discordance and Conversion/Reversion Rate During the Course of the Trial.

Description

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.

Time Frame

Up to day 168

10. Eligibility

Sex

All

Minimum Age & Unit of Time

12 Years

Maximum Age & Unit of Time

17 Years

Accepts Healthy Volunteers

Eligibility Criteria

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)

Overall Study Officials:

First Name & Middle Initial & Last Name & Degree

Linda-Gail Bekker, MD

Organizational Affiliation

Desmond Tutu HIV Centre

Official's Role

Study Chair

First Name & Middle Initial & Last Name & Degree

Jim Kublin, MD

Organizational Affiliation

HVTN Core, FHCRC

Official's Role

Study Chair

Facility Information:

Facility Name

Desmond Tutu HIV Foundation

City

Cape Town

Country

South Africa

12. IPD Sharing Statement

Plan to Share IPD

Citations:

PubMed Identifier

32382714

Citation

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.

Results Reference

derived

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

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