Efficacy Against TB Disease, Safety, and Immunogenicity of MVA85A/AERAS-485 in HIV-Infected Adults (C-030-485)

Study Overview
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Brief Summary
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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
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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.

Official Title
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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

Conditions
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Tuberculosis, HIV Infections

Intervention / Treatment
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* Biological: MVA85A/AERAS-485
* Biological: Placebo


Participation Criteria
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Eligibility Criteria
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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

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 50 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Prevention
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Placebo Comparator: Placebo<br>The placebo is a licensed product manufactured by Allermed, Inc. and is used for evaluation of delayed-type of hypersensitivity reactions in adults. | Biological: Placebo<br>* Subjects received an intradermal injection placebo on Study Day 0, followed 6-9 months later by a booster injection of placebo.<br>* Other names: Candin;|
| Experimental: MVA85A/AERAS-485<br>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. | Biological: MVA85A/AERAS-485<br>* 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.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| 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. | Adverse Events (AEs) are recorded for 28 days post vaccination, Serious Adverse Events (SAEs) for at least 6 months post second vaccination. | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| 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. | For at least 6 months post second vaccination up to 33 months total follow-up. | 
| 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. | 
| 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 | 
| 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). | 28 days post second vaccination. | 
| 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]). | 7 days post second vaccination. | 
| 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. | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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HIV, Tuberculosis, Vaccine