Tuberculosis
Conditions
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.
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%
Sponsors
HIV Vaccine Trials Network
Sanofi Pasteur, a Sanofi Company
Statens Serum Institut
Aeras
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
PREVENTION
Masking
QUADRUPLE (Subject, Caregiver, Investigator, Outcomes Assessor)
Eligibility
Sex/Gender
ALL
Age
12 Years to 17 Years
Healthy volunteers
Yes
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)
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| 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
| Measure | Time frame | Description |
|---|---|---|
| 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 |
| 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 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. |
| 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 |
| * 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.. |
Countries
South Africa
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| 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.
n=24 | 24 |
| 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.
n=24 | 24 |
| Group 3 BCG (2-8 x 105 CFU) Administered ID as 0.1 mL in either deltoid muscle at Day 0.
n=24 | 24 |
| Group 4 Control Sodium Chloride 0.9% Administered IM as 0.5 mL in alternating deltoid muscle at Days 0 and 56.
n=24 | 12 |
| Total | 84 |
Baseline characteristics
| Characteristic | Group 1 H4:IC31 | Group 2 H56:IC31 | Group 3 BCG (2-8 x 105 CFU) | Group 4 Control Sodium Chloride 0.9% | Total |
|---|---|---|---|---|---|
| Age, Categorical <=18 years | 24 Participants | 24 Participants | 24 Participants | 12 Participants | 84 Participants |
| Age, Categorical >=65 years | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Age, Categorical Between 18 and 65 years | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Age, Continuous | 13.8 years STANDARD_DEVIATION 1.42 | 13.7 years STANDARD_DEVIATION 1.46 | 14.5 years STANDARD_DEVIATION 1.47 | 13.2 years STANDARD_DEVIATION 1.11 | 13.9 years STANDARD_DEVIATION 1.45 |
| Participants: QuantiFERON-TB Gold In-Tube (QFT-GIT)-negative, HIV-negative, and BCG vaccinated | 24 Participants | 24 Participants | 24 Participants | 12 Participants | 84 Participants |
| Region of Enrollment South Africa | 24 participants | 24 participants | 24 participants | 12 participants | 84 participants |
| Sex: Female, Male Female | 15 Participants | 13 Participants | 11 Participants | 6 Participants | 45 Participants |
| Sex: Female, Male Male | 9 Participants | 11 Participants | 13 Participants | 6 Participants | 39 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk | EG003 affected / at risk |
|---|---|---|---|---|
| deaths Total, all-cause mortality | 0 / 24 | 0 / 24 | 0 / 24 | 0 / 12 |
| other Total, other adverse events | 22 / 24 | 20 / 24 | 24 / 24 | 10 / 12 |
| serious Total, serious adverse events | 0 / 24 | 1 / 24 | 1 / 24 | 0 / 12 |
Outcome results
Primary
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
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Group 1 H4:IC31 | Number of Participants With Adverse Events | 22 participants |
| Group 2 H56:IC31 | Number of Participants With Adverse Events | 20 participants |
| Group 3 BCG (2-8 x 105 CFU) | Number of Participants With Adverse Events | 24 participants |
| Group 4 Control Sodium Chloride 0.9% | Number of Participants With Adverse Events | 10 participants |
Primary
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
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Group 1 H4:IC31 | Percentage of Participants With Response Rates to TB Antigens as Compared to Baseline | Response rates to Ag85B on Day 70 | 40.0 percentage of participants |
| Group 1 H4:IC31 | Percentage of Participants With Response Rates to TB Antigens as Compared to Baseline | Response rates to TB10.4 on Day 70 | 21.1 percentage of participants |
| Group 1 H4:IC31 | Percentage of Participants With Response Rates to TB Antigens as Compared to Baseline | Response rates to Ag85B on Day 168 | 21.7 percentage of participants |
| Group 1 H4:IC31 | Percentage of Participants With Response Rates to TB Antigens as Compared to Baseline | Response rate to TB10.4 on Day 168 | 8.7 percentage of participants |
| Group 2 H56:IC31 | Percentage of Participants With Response Rates to TB Antigens as Compared to Baseline | Response rates to Ag85B on Day 70 | 45.0 percentage of participants |
| Group 2 H56:IC31 | Percentage of Participants With Response Rates to TB Antigens as Compared to Baseline | Response rates to Ag85B on Day 168 | 9.5 percentage of participants |
| Group 2 H56:IC31 | Percentage of Participants With Response Rates to TB Antigens as Compared to Baseline | Response rates to TB10.4 on Day 70 | 5.6 percentage of participants |
| Group 2 H56:IC31 | Percentage of Participants With Response Rates to TB Antigens as Compared to Baseline | Response rate to TB10.4 on Day 168 | 0.0 percentage of participants |
| Group 3 BCG (2-8 x 105 CFU) | Percentage of Participants With Response Rates to TB Antigens as Compared to Baseline | Response rates to TB10.4 on Day 70 | 5.9 percentage of participants |
| Group 3 BCG (2-8 x 105 CFU) | Percentage of Participants With Response Rates to TB Antigens as Compared to Baseline | Response rates to Ag85B on Day 70 | 0.0 percentage of participants |
| Group 3 BCG (2-8 x 105 CFU) | Percentage of Participants With Response Rates to TB Antigens as Compared to Baseline | Response rate to TB10.4 on Day 168 | 0.0 percentage of participants |
| Group 3 BCG (2-8 x 105 CFU) | Percentage of Participants With Response Rates to TB Antigens as Compared to Baseline | Response rates to Ag85B on Day 168 | 4.3 percentage of participants |
| Group 4 Control Sodium Chloride 0.9% | Percentage of Participants With Response Rates to TB Antigens as Compared to Baseline | Response rates to Ag85B on Day 70 | 0.0 percentage of participants |
| Group 4 Control Sodium Chloride 0.9% | Percentage of Participants With Response Rates to TB Antigens as Compared to Baseline | Response rates to TB10.4 on Day 70 | 0.0 percentage of participants |
| Group 4 Control Sodium Chloride 0.9% | Percentage of Participants With Response Rates to TB Antigens as Compared to Baseline | Response rates to Ag85B on Day 168 | 0.0 percentage of participants |
| Group 4 Control Sodium Chloride 0.9% | Percentage of Participants With Response Rates to TB Antigens as Compared to Baseline | Response rate to TB10.4 on Day 168 | 0.0 percentage of participants |
Secondary
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
Secondary
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.
Secondary
* 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
Secondary
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
Secondary
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