HIV Infections, Tuberculosis
Conditions
Keywords
HIV, Tuberculosis, Vaccine
Brief summary
This is a phase II, proof of concept, randomized, double-blind, placebo-controlled study to evaluate the protective efficacy against TB disease, safety, and immunogenicity of MVA85A/AERAS-485 in healthy, HIV-infected adults. This study consists of 650 adults subjects (ages 18-50 years of age inclusive) who will receive study vaccine or placebo at Study Day 0 and again 6-9 months later. Samples for real-time evaluation of immunogenicity were to be collected from 70 subjects (immunogenicity analysis set).
Detailed description
This Phase II multi-country trial was conducted as a randomized, double-blind, placebo-controlled trial in 650 HIV-positive adults with no evidence of active TB disease. Subjects were stratified at the time of randomization by whether or not they were receiving anti-retroviral therapy (ART) and then randomized in a ratio of 1:1 to receive either MVA85A/AERAS-485 at 1 x 10\^8 plaque forming units (pfu) or placebo (Candin). Randomization of each group was capped so that at least 50% of the subjects randomized were receiving ART at randomization. Subjects were to receive an intradermal injection of MVA85A/AERAS-485 or placebo on Study Day 0, followed 6-9 months later by a booster injection of MVA85A/AERAS-485 or placebo. The minimum follow-up period for each subject was 6 months after their last vaccination, during which subjects were followed for safety, clinical signs and symptoms of TB, and immunogenicity. All subjects were to continue to be followed every 3 months until the last subject enrolled had been followed for 6 months after their last vaccination.
Interventions
BIOLOGICALMVA85A/AERAS-485
Subjects received intradermal injection of MVA85A/AERAS-485 on Study Day 0, followed 6-9 months later by a booster injection of MVA85A/AERAS-485.
BIOLOGICALPlacebo
Subjects received an intradermal injection placebo on Study Day 0, followed 6-9 months later by a booster injection of placebo.
Sponsors
University of Oxford
European and Developing Countries Clinical Trials Partnership (EDCTP)
Aeras
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
PREVENTION
Masking
QUADRUPLE (Subject, Caregiver, Investigator, Outcomes Assessor)
Eligibility
Sex/Gender
ALL
Age
18 Years to 50 Years
Healthy volunteers
No
Inclusion criteria
* Has completed the written informed consent process prior to undergoing any screening evaluations. * Either males or females aged 18-50 years (inclusive) on Study Day 0 * In general good health, confirmed by medical history and physical examination * Has ability to complete follow-up period as required by the protocol * Has 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, polymerase chain reaction (PCR), or rapid ELISA) diagnosed prior to randomization * Is willing to allow the investigators to discuss the subject's medical history with the subject's HIV physician * Has 2 CD4+ lymphocyte count test results \>350 cells/mm3, performed at least 4 weeks apart, one performed within 6 months prior to randomization and one within 30 days prior to randomization * Has either: a) a negative QuantiFERON-TB Gold In-Tube test result and tuberculin purified protein derivative (PPD) skin test ≤5 mm induration within 30 days prior to randomization or; b) a positive QuantiFERON-TB Gold In-Tube test result and/or tuberculin PPD skin test \>5 mm and has completed 6 months of isoniazid preventive therapy prior to randomization or; c) a positive QuantiFERON-TB Gold In-Tube test result and/or tuberculin PPD skin test \>5 mm and has completed treatment for TB disease within 3 year prior to randomization * Females: Ability to avoid pregnancy during the trial. Women physically capable of pregnancy (not sterilized and still menstruating or within 1 year of the last menses if menopausal) in sexual relationships with men must avoid pregnancy by using an acceptable method of avoiding pregnancy from 28 days prior to administration of the study vaccine through the end of the study. Acceptable methods of avoiding pregnancy include a sterile sexual partner, sexual abstinence (not engaging in sexual intercourse), hormonal contraceptives (oral, injection, transdermal patch, or implant), vaginal ring, intrauterine device (IUD), or the use of a condom or a diaphragm combined with spermicide. * Has completed the written informed consent process for simultaneous enrollment in Aeras Vaccine Development Registry protocol
Exclusion criteria
* Acute illness * Fever (temperature \> 37.5°C) * Significant symptomatic infection * Any evidence of active tuberculosis (TB) disease, as determined by any clinical, radiological, or microbiology measurements. * Any AIDS defining illness by WHO criteria * Has received antiretroviral therapy (ART) in the two months prior to study entry (women who have received ART as part of the Prevention of Mother-to-Child Transmission \[PMTCT\] program and completed this more than 2 months prior to randomization ARE eligible) * Use of any investigational or non-registered drug, vaccine or medical device other than the study vaccine within 182 days preceding dosing of study vaccine, or planned use during the study period * Previous receipt of a recombinant modified vaccinia Ankara (MVA) or fusion protein (FP) vector at any time. * Is enrolled in any other clinical product trial * Administration of methotrexate, azathioprine, cyclophosphamide, oral corticosteroids (for corticosteroids, this will mean prednisolone, or equivalent, ≥0.5 mg/kg/day; inhaled and topical steroids are allowed) and other immunosuppressive therapies, or blood products or blood derivatives within the six months prior to randomization * History of allergic disease or reactions likely to be exacerbated by any component of the vaccine, e.g. egg products * Presence of any history of cancer \[except basal cell carcinoma of the skin and cervical carcinoma in situ\], or renal failure * Evidence of severe depression, schizophrenia or mania * Pregnant females and females who are breast-feeding * Any history of anaphylaxis in reaction to vaccination * Principal investigator assessment of lack of willingness to participate and comply with the protocol, or increase in the participant's risk of adverse outcome
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Percentage of Participants With Adverse Events | Adverse Events (AEs) are recorded for 28 days post vaccination, Serious Adverse Events (SAEs) for at least 6 months post second vaccination. | The primary objective of this study is to evaluate the safety of MVA85A/AERAS-485 compared to placebo in HIV-infected, African adult subjects without active TB disease. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| CD4+ Lymphocyte Counts Before and After Administration of MVA85A/AERAS-485 Compared to Placebo in Anti-retroviral Therapy Negative (ART -)Subjects | Up to 6 months post second vaccination. | — |
| CD4+ Lymphocyte Counts Before and After Administration of MVA85A/AERAS-485 Compared to Placebo in ART+ Subjects | Up to 6 months post second vaccination. | — |
| HIV-1 Viral Load Before and After Administration of MVA85A/AERAS-485 Compared to Placebo in ART - Participants | Up to 6 months post second vaccination. | — |
| Number of TB Cases | For at least 6 months post second vaccination up to 33 months total follow-up. | Efficacy of MVA85A/AERAS-485 in the prevention of TB disease compared to control subjects who received placebo in HIV-infected, African adult subjects without active TB disease. |
| Counts of Spot-forming Units After Stimulation With AG85A Peptide Pool. | 28 days post second vaccination. | Immunogenicity of MVA85A/AERAS-485 compared to placebo as described by the ex vivo interferon (IFN)-γ enzyme linked immunospot (ELISpot). |
| Immunogenicity of MVA85A/AERAS-485 Compared to Placebo as Described by Flow Cytometric Intracellular Cytokine Staining (ICS) of CD4+ and CD8+ T Cells After Stimulation With a Peptide Pool of Mycobacterial Antigens. | 7 days post second vaccination. | The antigen-specific negative control-subtracted response for any cytokine (Interferon gamma \[INFγ\] , Interleukin 2 \[IL2\], Interleukin 17 \[IL17\] and tumor necrosis factor \[TNF\]). |
| QuantiFERON (QFN) Conversion Rate in MVA85A/AERAS-485 Recipients Compared to Control Subjects Without a Diagnosis of Tuberculosis During the Trial. | For at least 6 months post second vaccination up to 33 months total follow-up. | — |
| HIV-1 Viral Load Before and After Administration of MVA85A/AERAS-485 Compared to Placebo in ART+ Participants. | Up tp 6 months post second vaccination | — |
Countries
Senegal, South Africa
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| Placebo Placebo: Subjects were to receive an intradermal injection placebo on Study Day 0, followed 6-9 months later by a booster injection of placebo. | 325 |
| MVA85A/AERAS-485 MVA85A/AERAS-485 is a recombinant modified vaccinia virus Ankara expressing the M. tuberculosis antigen, Ag85A. Dosage of the study vaccine to be administered will be 1x10\^8 pfu.
MVA85A/AERAS-485: Subjects received intradermal injection of MVA85A/AERAS-485 on Study Day 0, followed 6-9 months later by a booster injection of MVA85A/AERAS-485. | 324 |
| Total | 649 |
Baseline characteristics
| Characteristic | Placebo | MVA85A/AERAS-485 | Total |
|---|---|---|---|
| Age, Continuous | 37.8 years STANDARD_DEVIATION 6.61 | 37.7 years STANDARD_DEVIATION 6.69 | 37.7 years STANDARD_DEVIATION 6.65 |
| Race/Ethnicity, Customized Asian | 0 participants | 0 participants | 0 participants |
| Race/Ethnicity, Customized Black | 304 participants | 302 participants | 606 participants |
| Race/Ethnicity, Customized Coloured | 21 participants | 22 participants | 43 participants |
| Race/Ethnicity, Customized White | 0 participants | 0 participants | 0 participants |
| Region of Enrollment Senegal | 179 participants | 178 participants | 357 participants |
| Region of Enrollment South Africa | 146 participants | 146 participants | 292 participants |
| Sex: Female, Male Female | 255 Participants | 265 Participants | 520 Participants |
| Sex: Female, Male Male | 70 Participants | 59 Participants | 129 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — |
| other Total, other adverse events | 310 / 325 | 320 / 324 |
| serious Total, serious adverse events | 17 / 325 | 17 / 324 |
Outcome results
Primary
Percentage of Participants With Adverse Events
The primary objective of this study is to evaluate the safety of MVA85A/AERAS-485 compared to placebo in HIV-infected, African adult subjects without active TB disease.
Time frame: Adverse Events (AEs) are recorded for 28 days post vaccination, Serious Adverse Events (SAEs) for at least 6 months post second vaccination.
Population: Safety:~All randomized subjects who received a dose of study vaccine, based on actual treatment received.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Placebo | Percentage of Participants With Adverse Events | 96.0 percentage of participants with an AE |
| MVA85A/AERAS-485 | Percentage of Participants With Adverse Events | 99.1 percentage of participants with an AE |
Secondary
CD4+ Lymphocyte Counts Before and After Administration of MVA85A/AERAS-485 Compared to Placebo in Anti-retroviral Therapy Negative (ART -)Subjects
Time frame: Up to 6 months post second vaccination.
Population: Safety:~All randomized ART negative subjects who received a dose of study vaccine, based on actual treatment received.
| Arm | Measure | Group | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|---|
| Placebo | CD4+ Lymphocyte Counts Before and After Administration of MVA85A/AERAS-485 Compared to Placebo in Anti-retroviral Therapy Negative (ART -)Subjects | Baseline | 540.60 cells/mm^3 | Standard Deviation 1.333 |
| Placebo | CD4+ Lymphocyte Counts Before and After Administration of MVA85A/AERAS-485 Compared to Placebo in Anti-retroviral Therapy Negative (ART -)Subjects | Study Visit 8 | 557.39 cells/mm^3 | Standard Deviation 1.395 |
| MVA85A/AERAS-485 | CD4+ Lymphocyte Counts Before and After Administration of MVA85A/AERAS-485 Compared to Placebo in Anti-retroviral Therapy Negative (ART -)Subjects | Baseline | 541.10 cells/mm^3 | Standard Deviation 1.394 |
| MVA85A/AERAS-485 | CD4+ Lymphocyte Counts Before and After Administration of MVA85A/AERAS-485 Compared to Placebo in Anti-retroviral Therapy Negative (ART -)Subjects | Study Visit 8 | 484.64 cells/mm^3 | Standard Deviation 1.43 |
Secondary
CD4+ Lymphocyte Counts Before and After Administration of MVA85A/AERAS-485 Compared to Placebo in ART+ Subjects
Time frame: Up to 6 months post second vaccination.
Population: Safety:~All randomized ART positive subjects who received a dose of study vaccine, based on actual treatment received.
| Arm | Measure | Group | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|---|
| Placebo | CD4+ Lymphocyte Counts Before and After Administration of MVA85A/AERAS-485 Compared to Placebo in ART+ Subjects | Baseline | 568.07 cells/mm^3 | Standard Deviation 1.387 |
| Placebo | CD4+ Lymphocyte Counts Before and After Administration of MVA85A/AERAS-485 Compared to Placebo in ART+ Subjects | Study Visit 8 | 606.07 cells/mm^3 | Standard Deviation 1.43 |
| MVA85A/AERAS-485 | CD4+ Lymphocyte Counts Before and After Administration of MVA85A/AERAS-485 Compared to Placebo in ART+ Subjects | Baseline | 564.27 cells/mm^3 | Standard Deviation 1.395 |
| MVA85A/AERAS-485 | CD4+ Lymphocyte Counts Before and After Administration of MVA85A/AERAS-485 Compared to Placebo in ART+ Subjects | Study Visit 8 | 604.24 cells/mm^3 | Standard Deviation 1.449 |
Secondary
Counts of Spot-forming Units After Stimulation With AG85A Peptide Pool.
Immunogenicity of MVA85A/AERAS-485 compared to placebo as described by the ex vivo interferon (IFN)-γ enzyme linked immunospot (ELISpot).
Time frame: 28 days post second vaccination.
Population: First 70 patients enrolled who also had pre-vaccination results available were analyzed.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Placebo | Counts of Spot-forming Units After Stimulation With AG85A Peptide Pool. | 9.00 SFU - background/10^6 PBMC |
| MVA85A/AERAS-485 | Counts of Spot-forming Units After Stimulation With AG85A Peptide Pool. | 254.00 SFU - background/10^6 PBMC |
Secondary
HIV-1 Viral Load Before and After Administration of MVA85A/AERAS-485 Compared to Placebo in ART - Participants
Time frame: Up to 6 months post second vaccination.
Population: Safety:~All randomized ART - subjects who received a dose of study vaccine, based on actual treatment received.
| Arm | Measure | Group | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|---|
| Placebo | HIV-1 Viral Load Before and After Administration of MVA85A/AERAS-485 Compared to Placebo in ART - Participants | Baseline | 6918.76 copies/mL | Standard Deviation 8.673 |
| Placebo | HIV-1 Viral Load Before and After Administration of MVA85A/AERAS-485 Compared to Placebo in ART - Participants | Study Visit 8 | 9090.32 copies/mL | Standard Deviation 14.101 |
| MVA85A/AERAS-485 | HIV-1 Viral Load Before and After Administration of MVA85A/AERAS-485 Compared to Placebo in ART - Participants | Baseline | 9616.55 copies/mL | Standard Deviation 9.783 |
| MVA85A/AERAS-485 | HIV-1 Viral Load Before and After Administration of MVA85A/AERAS-485 Compared to Placebo in ART - Participants | Study Visit 8 | 6437.59 copies/mL | Standard Deviation 25.781 |
Secondary
HIV-1 Viral Load Before and After Administration of MVA85A/AERAS-485 Compared to Placebo in ART+ Participants.
Time frame: Up tp 6 months post second vaccination
Population: Safety:~All randomized ART + subjects who received a dose of study vaccine, based on actual treatment received.
| Arm | Measure | Group | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|---|
| Placebo | HIV-1 Viral Load Before and After Administration of MVA85A/AERAS-485 Compared to Placebo in ART+ Participants. | Baseline | 26.32 copies/mL | Standard Deviation 1.339 |
| Placebo | HIV-1 Viral Load Before and After Administration of MVA85A/AERAS-485 Compared to Placebo in ART+ Participants. | Study visit 8 | 27.30 copies/mL | Standard Deviation 1.58 |
| MVA85A/AERAS-485 | HIV-1 Viral Load Before and After Administration of MVA85A/AERAS-485 Compared to Placebo in ART+ Participants. | Baseline | 26.87 copies/mL | Standard Deviation 1.5 |
| MVA85A/AERAS-485 | HIV-1 Viral Load Before and After Administration of MVA85A/AERAS-485 Compared to Placebo in ART+ Participants. | Study visit 8 | 29.39 copies/mL | Standard Deviation 2.04 |
Secondary
Immunogenicity of MVA85A/AERAS-485 Compared to Placebo as Described by Flow Cytometric Intracellular Cytokine Staining (ICS) of CD4+ and CD8+ T Cells After Stimulation With a Peptide Pool of Mycobacterial Antigens.
The antigen-specific negative control-subtracted response for any cytokine (Interferon gamma \[INFγ\] , Interleukin 2 \[IL2\], Interleukin 17 \[IL17\] and tumor necrosis factor \[TNF\]).
Time frame: 7 days post second vaccination.
Population: First 70 patients enrolled who also had pre-vaccination results available were analyzed.
| Arm | Measure | Group | Value (MEDIAN) |
|---|---|---|---|
| Placebo | Immunogenicity of MVA85A/AERAS-485 Compared to Placebo as Described by Flow Cytometric Intracellular Cytokine Staining (ICS) of CD4+ and CD8+ T Cells After Stimulation With a Peptide Pool of Mycobacterial Antigens. | CD4+ | 0.14 Percent responding TCells |
| Placebo | Immunogenicity of MVA85A/AERAS-485 Compared to Placebo as Described by Flow Cytometric Intracellular Cytokine Staining (ICS) of CD4+ and CD8+ T Cells After Stimulation With a Peptide Pool of Mycobacterial Antigens. | CD8+ | 0.00 Percent responding TCells |
| MVA85A/AERAS-485 | Immunogenicity of MVA85A/AERAS-485 Compared to Placebo as Described by Flow Cytometric Intracellular Cytokine Staining (ICS) of CD4+ and CD8+ T Cells After Stimulation With a Peptide Pool of Mycobacterial Antigens. | CD8+ | 0.04 Percent responding TCells |
| MVA85A/AERAS-485 | Immunogenicity of MVA85A/AERAS-485 Compared to Placebo as Described by Flow Cytometric Intracellular Cytokine Staining (ICS) of CD4+ and CD8+ T Cells After Stimulation With a Peptide Pool of Mycobacterial Antigens. | CD4+ | 0.20 Percent responding TCells |
Secondary
Number of TB Cases
Efficacy of MVA85A/AERAS-485 in the prevention of TB disease compared to control subjects who received placebo in HIV-infected, African adult subjects without active TB disease.
Time frame: For at least 6 months post second vaccination up to 33 months total follow-up.
Population: Per protocol:~All randomized subjects who received a dose of study vaccine and had no major protocol deviations, were still ongoing in the study 28 days after Study Day 0, and did not have TB diagnosed within 28 days after Study Day 0.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Placebo | Number of TB Cases | 9 participants with TB |
| MVA85A/AERAS-485 | Number of TB Cases | 6 participants with TB |
Secondary
QuantiFERON (QFN) Conversion Rate in MVA85A/AERAS-485 Recipients Compared to Control Subjects Without a Diagnosis of Tuberculosis During the Trial.
Time frame: For at least 6 months post second vaccination up to 33 months total follow-up.
Population: Per protocol:~All randomized subjects who received a dose of study vaccine and had no major protocol deviations, were still ongoing in the study 28 days after Study Day 0, and did not have TB diagnosed within 28 days after Study Day 0 (QFT negative at baseline subgroup).
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Placebo | QuantiFERON (QFN) Conversion Rate in MVA85A/AERAS-485 Recipients Compared to Control Subjects Without a Diagnosis of Tuberculosis During the Trial. | 40 participants who converted |
| MVA85A/AERAS-485 | QuantiFERON (QFN) Conversion Rate in MVA85A/AERAS-485 Recipients Compared to Control Subjects Without a Diagnosis of Tuberculosis During the Trial. | 38 participants who converted |