CompletedNCT02378207Updated Nov 18, 2019Results posted

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

A Phase 1 interventional study of H4:IC31 and H56:IC31 in Tuberculosis, sponsored by Aeras. Completed at 1 site in South Africa. Open to participants aged 12 Years to 17 Years, including healthy volunteers. Per ClinicalTrials.gov, last updated 2019-11-18.

Sponsored by Aeras · Phase 1, Interventional, and Prevention

Phase: Phase 1
Study type: Interventional
Enrollment: 84
Allocation: Randomized
Ages: 12 Years to 17 Years
Sex: All

Study 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).

Read the 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.

Conditions studied

Tuberculosis

Browse trials for

Tuberculosis 1,417

In context

Tuberculosis

1,417 studies on the registry are indexed under Tuberculosis; 208 are open to participants now.

This study's enrollment of 84 is below the median of 150 across 952 interventional studies indexed under Tuberculosis.

Browse Tuberculosis studies →

Lead sponsor

Aeras is the lead sponsor of 22 studies on the registry; none are open to participants now.

Counted across the registry records on this site, refreshed daily.

Who can participate

Ages eligible: 12 Years to 17 Years
Sexes eligible: All
Accepts healthy volunteers: Yes

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

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

Phase: Phase 1
Primary purpose: Prevention
Allocation: Randomized
Intervention model: Parallel assignment
Masking: Quadruple (Participant, Care provider, Investigator, Outcomes assessor)
Enrollment: 84 participants (actual)

Study arms

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
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
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%

Interventions

BiologicalH4:IC31
H4 contains Mtb antigens Ag85B and TB10.4
BiologicalH56:IC31
H56 contains Mtb antigens ESAT-6, and Rv2660c
BiologicalBCG
BiologicalControl Sodium Chloride 0.9%

What researchers measure

Primary outcomes

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.
Time frame: 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.
Time frame: Days 70 and 168

Secondary outcomes

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).
Time frame: 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..
Time frame: 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
Time frame: 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
Time frame: 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.
Time frame: Up to day 168

Results

Posted Nov 18, 2019

Participant flow

Participant flow — Overall Study
Milestone	Group 1 H4:IC31	Group 2 H56:IC31	Group 3 BCG (2-8 x 105 CFU)	Group 4 Control Sodium Chloride 0.9%
Started	24	24	24	12
Completed	24	21	22	11
Not completed	0	3	2	1

Outcome measures

PrimaryNumber 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.

Time frame:: Up to 8 months
Reported as:: Number · participants

Number of Participants With Adverse Events
participants	Group 1 H4:IC31	Group 2 H56:IC31	Group 3 BCG (2-8 x 105 CFU)	Group 4 Control Sodium Chloride 0.9%
Number of Participants With Adverse Events	22	20	24	10

PrimaryPercentage 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.

Time frame:: Days 70 and 168
Reported as:: Number · percentage of participants

Percentage of Participants With Response Rates to TB Antigens as Compared to Baseline
percentage of participants	Group 1 H4:IC31	Group 2 H56:IC31	Group 3 BCG (2-8 x 105 CFU)	Group 4 Control Sodium Chloride 0.9%
Response rates to Ag85B on Day 70	40.0 (21.9 to 61.3)	45.0 (25.8 to 65.8)	0.0 (0.0 to 17.6)	0.0 (0.0 to 25.95)
Response rates to TB10.4 on Day 70	21.1 (8.5 to 43.3)	5.6 (1.0 to 25.8)	5.9 (1.0 to 27.0)	0.0 (0.0 to 25.9)
Response rates to Ag85B on Day 168	21.7 (9.7 to 41.9)	9.5 (2.7 to 28.9)	4.3 (0.8 to 21.0)	0.0 (0.0 to 27.8)
Response rate to TB10.4 on Day 168	8.7 (2.4 to 26.8)	0.0 (0.0 to 15.5)	0.0 (0.0 to 14.3)	0.0 (0.0 to 27.8)

SecondaryEvaluate 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).

Time frame:: Up to day 168.