Tuberculosis, HIV Infections
Conditions
Keywords
HIV, Tuberculosis, Vaccine
Brief summary
This was a Phase II, randomized, double-blind, placebo-controlled trial conducted at 1 site in South Africa. A total of 26 subjects were randomized 1:1 to receive 2 doses of either AERAS-402 at 3 x 10\^10 vp (N=13) or placebo (N=13) on Study Days 0 and 28. Dose-escalation to a second group of 40 subjects was planned, but although no safety concerns were identified, the sponsor decided not to continue the study.
Detailed description
Further study details as provided by Aeras.
Interventions
BIOLOGICALAERAS-402
AERAS-402 is a replication-deficient serotype 35 adenovirus containing DNA that expresses a fusion protein of three Mycobacterium tuberculosis (Mtb) antigens: 85A, 85B and TB10.4.
BIOLOGICALPlacebo
Placebo was the identical buffer solution in which AERAS-402 is formulated.
Sponsors
Crucell Holland BV
Aeras
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
PREVENTION
Masking
QUADRUPLE (Subject, Caregiver, Investigator, Outcomes Assessor)
Eligibility
Sex/Gender
ALL
Age
21 Years to 45 Years
Healthy volunteers
No
Inclusion criteria
1. Age 21 years through 45 years (i.e., subject had not yet reached his/her 46th birthday at day of randomization). 2. Had completed the written informed consent process prior to undergoing any screening evaluations. 3. Had BCG vaccination at least 5 years previously, documented by medical history or presence of scar. 4. Females: Ability to avoid pregnancy for at least 6 months after receiving the last study vaccination: Women physically capable of pregnancy (not sterilized and still menstruating or within 1 year of the last menses if menopausal) must have avoided pregnancy from 28 days prior to administration of the study vaccine and must have agreed to avoid pregnancy through at least 6 months after receiving the last study vaccination. Acceptable methods of avoiding pregnancy included a sterile sexual partner, sexual abstinence (not engaging in sexual intercourse), or use of a combination of at least two forms of acceptable contraception: hormonal contraceptives (oral, injection, transdermal patch, or implant), vaginal ring, intrauterine device (IUD), and the use of a condom or a diaphragm; or the use of a condom or a diaphragm combined with spermicide. 5. Was able to carry out activities of daily living independently. 6. Had Body Mass Index (BMI) of at least 19 (wt./ht.2) by nomogram. 7. Had ability to complete follow-up period as required by the protocol. 8. Was able and willing to commit to avoiding elective surgery for at least 6 months after receiving the last study vaccination. 9. Was able and willing to stay in contact with the study site for the duration of the study. 10. Had committed to simultaneous enrollment in Aeras Vaccine Development Registry Protocol. 11. Had laboratory evidence of human immunodeficiency virus (HIV) infection, defined as a positive HIV-1 ELISA test plus a positive confirmatory test (e.g., a second HIV-1 ELISA, PCR, or rapid ELISA). 12. Had four (4) (for Group 1) or three (3) (for Group 2)\* CD4+ lymphocyte count tests, each performed at least four days apart within the 42-day screening period, with at least three (for Group 1) or two (for Group 2) CD4+ lymphocyte count results greater than 350 cells / mm3. 13. Not currently receiving antiretroviral drugs. 14. Committed to not participate in any other clinical trials during the first 12 months of participation in this study.
Exclusion criteria
1. Acute illness. 2. Fever ≥37.5°C. 3. Significant symptomatic infection. 4. Used immunosuppressive medication within 42 days prior to randomization (inhaled and topical corticosteroids were permitted). 5. Received immunoglobulin or blood products within 42 days prior to randomization. 6. Received any investigational drug therapy or vaccine within 182 days prior to randomization. 7. History of having received any adenovirus-vector-based vaccine. 8. Medical history that may have compromised the evaluation of safety of the subject in the study (e.g., diabetes, seizure disorder, sickle cell disease). 9. Pregnant or breastfeeding female, or intention to become pregnant during the study within 6 months after receiving the last study vaccination. 10. Liver function tests \>Grade 2 per the toxicity table. 11. Currently receiving treatment for TB, or evidence of active TB disease based on history, physical examination, chest X-ray, or laboratory evaluation (INH prophylaxis was permitted).
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| CD4+ Lymphocyte Count | CD4+ counts from samples collected on Study days 0 and 182. | Assess the effect of AERAS-402 on the CD4+ lymphocyte count after 6 months in HIV-infected, BCG-vaccinated adult subjects with no evidence of active tuberculosis (TB disease) Change in cells/mm\^3 pre-vaccination to Study Day 182 |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Change in HIV Viral Load in HIV-infected, BCG-vaccinated Adult Subjects Before and After Administration of AERAS-402 (From Day 1 to Day 182) | 6 months (day 182) post Study Day 0 vaccination. | — |
| Mtb-specific T Cell Response in HIV-infected BCG-vaccinated Adult Subjects With no Evidence of TB Disease | Study days 28 and 56 | Intracellular cytokine staining (ICS) assay immune response was expressed as the percentage of CD4+ and CD8+ T cells producing any one of three cytokines (IFN-γ, TNF-α, or IL-2) or any combination of the three cytokines simultaneously after stimulation with Ag85A, Ag85B, and TB10.4 peptide pools. |
Countries
South Africa
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| Placebo Placebo Control: Placebo was the identical buffer solution in which AERAS-402 is formulated. | 13 |
| Investigational Vaccine AERAS-402: AERAS-402 is a replication-deficient serotype 35 adenovirus containing DNA that expresses a fusion protein of three Mycobacterium tuberculosis (Mtb) antigens: 85A, 85B and TB10.4. | 13 |
| Total | 26 |
Baseline characteristics
| Characteristic | Placebo | Investigational Vaccine | Total |
|---|---|---|---|
| Age, Categorical <=18 years | 0 Participants | 0 Participants | 0 Participants |
| Age, Categorical >=65 years | 0 Participants | 0 Participants | 0 Participants |
| Age, Categorical Between 18 and 65 years | 13 Participants | 13 Participants | 26 Participants |
| Age, Continuous | 30.8 years STANDARD_DEVIATION 6.49 | 30.5 years STANDARD_DEVIATION 5.88 | 30.7 years STANDARD_DEVIATION 6.07 |
| Region of Enrollment South Africa | 13 participants | 13 participants | 26 participants |
| Sex: Female, Male Female | 11 Participants | 12 Participants | 23 Participants |
| Sex: Female, Male Male | 2 Participants | 1 Participants | 3 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — |
| other Total, other adverse events | 13 / 13 | 13 / 13 |
| serious Total, serious adverse events | 1 / 13 | 1 / 13 |
Outcome results
Primary
CD4+ Lymphocyte Count
Assess the effect of AERAS-402 on the CD4+ lymphocyte count after 6 months in HIV-infected, BCG-vaccinated adult subjects with no evidence of active tuberculosis (TB disease) Change in cells/mm\^3 pre-vaccination to Study Day 182
Time frame: CD4+ counts from samples collected on Study days 0 and 182.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Placebo | CD4+ Lymphocyte Count | -136.0 cells/mm^3 |
| Investigational Vaccine | CD4+ Lymphocyte Count | -107.0 cells/mm^3 |
Secondary
Change in HIV Viral Load in HIV-infected, BCG-vaccinated Adult Subjects Before and After Administration of AERAS-402 (From Day 1 to Day 182)
Time frame: 6 months (day 182) post Study Day 0 vaccination.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Placebo | Change in HIV Viral Load in HIV-infected, BCG-vaccinated Adult Subjects Before and After Administration of AERAS-402 (From Day 1 to Day 182) | -0.163 Change in copies/mL over time |
| Investigational Vaccine | Change in HIV Viral Load in HIV-infected, BCG-vaccinated Adult Subjects Before and After Administration of AERAS-402 (From Day 1 to Day 182) | -0.011 Change in copies/mL over time |
Secondary
Mtb-specific T Cell Response in HIV-infected BCG-vaccinated Adult Subjects With no Evidence of TB Disease
Intracellular cytokine staining (ICS) assay immune response was expressed as the percentage of CD4+ and CD8+ T cells producing any one of three cytokines (IFN-γ, TNF-α, or IL-2) or any combination of the three cytokines simultaneously after stimulation with Ag85A, Ag85B, and TB10.4 peptide pools.
Time frame: Study days 28 and 56
Population: percentage of CD4 or CD8 T-cell response
| Arm | Measure | Group | Value (MEDIAN) |
|---|---|---|---|
| Placebo | Mtb-specific T Cell Response in HIV-infected BCG-vaccinated Adult Subjects With no Evidence of TB Disease | CD4+ TB10.4 response at study day 28 | 0.0196 percentage of T-cell response |
| Placebo | Mtb-specific T Cell Response in HIV-infected BCG-vaccinated Adult Subjects With no Evidence of TB Disease | CD4+ Ag85A response at study day 28 | 0.0103 percentage of T-cell response |
| Placebo | Mtb-specific T Cell Response in HIV-infected BCG-vaccinated Adult Subjects With no Evidence of TB Disease | CD4+ Ag85A response at study day 56 | 0.0199 percentage of T-cell response |
| Placebo | Mtb-specific T Cell Response in HIV-infected BCG-vaccinated Adult Subjects With no Evidence of TB Disease | CD4+ Ag85B response at study day 28 | 0.0011 percentage of T-cell response |
| Placebo | Mtb-specific T Cell Response in HIV-infected BCG-vaccinated Adult Subjects With no Evidence of TB Disease | CD4+ Ag85B response at study day 56 | 0.0083 percentage of T-cell response |
| Placebo | Mtb-specific T Cell Response in HIV-infected BCG-vaccinated Adult Subjects With no Evidence of TB Disease | CD4+ TB10.4 response at study day 56 | 0.0281 percentage of T-cell response |
| Placebo | Mtb-specific T Cell Response in HIV-infected BCG-vaccinated Adult Subjects With no Evidence of TB Disease | CD8+ Ag85A response at study day 28 | 0.0002 percentage of T-cell response |
| Placebo | Mtb-specific T Cell Response in HIV-infected BCG-vaccinated Adult Subjects With no Evidence of TB Disease | CD8+ Ag85A response at study day 56 | 0.0027 percentage of T-cell response |
| Placebo | Mtb-specific T Cell Response in HIV-infected BCG-vaccinated Adult Subjects With no Evidence of TB Disease | CD8+ Ag85B response at study day 28 | 0.0000 percentage of T-cell response |
| Placebo | Mtb-specific T Cell Response in HIV-infected BCG-vaccinated Adult Subjects With no Evidence of TB Disease | CD8+ Ag85B response at study day 56 | 0.0040 percentage of T-cell response |
| Placebo | Mtb-specific T Cell Response in HIV-infected BCG-vaccinated Adult Subjects With no Evidence of TB Disease | CD8+ TB10.4 response at study day 28 | 0.0000 percentage of T-cell response |
| Placebo | Mtb-specific T Cell Response in HIV-infected BCG-vaccinated Adult Subjects With no Evidence of TB Disease | CD8+ TB10.4 response at study day 56 | 0.0051 percentage of T-cell response |
| Investigational Vaccine | Mtb-specific T Cell Response in HIV-infected BCG-vaccinated Adult Subjects With no Evidence of TB Disease | CD8+ TB10.4 response at study day 28 | 0.0000 percentage of T-cell response |
| Investigational Vaccine | Mtb-specific T Cell Response in HIV-infected BCG-vaccinated Adult Subjects With no Evidence of TB Disease | CD8+ Ag85A response at study day 28 | 0.0127 percentage of T-cell response |
| Investigational Vaccine | Mtb-specific T Cell Response in HIV-infected BCG-vaccinated Adult Subjects With no Evidence of TB Disease | CD4+ Ag85A response at study day 28 | 0.0908 percentage of T-cell response |
| Investigational Vaccine | Mtb-specific T Cell Response in HIV-infected BCG-vaccinated Adult Subjects With no Evidence of TB Disease | CD8+ Ag85B response at study day 56 | 0.0846 percentage of T-cell response |
| Investigational Vaccine | Mtb-specific T Cell Response in HIV-infected BCG-vaccinated Adult Subjects With no Evidence of TB Disease | CD4+ Ag85A response at study day 56 | 0.1248 percentage of T-cell response |
| Investigational Vaccine | Mtb-specific T Cell Response in HIV-infected BCG-vaccinated Adult Subjects With no Evidence of TB Disease | CD8+ Ag85A response at study day 56 | 0.0300 percentage of T-cell response |
| Investigational Vaccine | Mtb-specific T Cell Response in HIV-infected BCG-vaccinated Adult Subjects With no Evidence of TB Disease | CD4+ Ag85B response at study day 28 | 0.0819 percentage of T-cell response |
| Investigational Vaccine | Mtb-specific T Cell Response in HIV-infected BCG-vaccinated Adult Subjects With no Evidence of TB Disease | CD8+ TB10.4 response at study day 56 | 0.0094 percentage of T-cell response |
| Investigational Vaccine | Mtb-specific T Cell Response in HIV-infected BCG-vaccinated Adult Subjects With no Evidence of TB Disease | CD4+ Ag85B response at study day 56 | 0.0769 percentage of T-cell response |
| Investigational Vaccine | Mtb-specific T Cell Response in HIV-infected BCG-vaccinated Adult Subjects With no Evidence of TB Disease | CD4+ TB10.4 response at study day 28 | 0.0364 percentage of T-cell response |
| Investigational Vaccine | Mtb-specific T Cell Response in HIV-infected BCG-vaccinated Adult Subjects With no Evidence of TB Disease | CD8+ Ag85B response at study day 28 | 0.0317 percentage of T-cell response |
| Investigational Vaccine | Mtb-specific T Cell Response in HIV-infected BCG-vaccinated Adult Subjects With no Evidence of TB Disease | CD4+ TB10.4 response at study day 56 | 0.0443 percentage of T-cell response |