Tuberculosis
Conditions
Brief summary
This was a Phase II double-blinded randomized controlled evaluation of safety, immunogenicity and efficacy of MVA85A/AERAS-485 in Bacillus Calmette-Guérin (BCG) vaccinated infants without tuberculosis or HIV infection. This study planned to enroll 2784 infants (126 to 182 days of age) who received study vaccine or control and were followed for 15 - 36 months. The study was conducted at a single site in South Africa.
Detailed description
This was a Phase II double-blinded randomized controlled evaluation of safety, immunogenicity and efficacy of MVA85A/AERAS-485 in BCG vaccinated infants without tuberculosis or HIV infection. Infants (126 to 182 days) received intradermal (ID) study vaccine (MVA85A/AERAS-485 or Candida skin test antigen control). All infants were to be followed for at least 15 months after the last infant was enrolled into the study. Given completion of enrollment in 21 months, the total duration of follow-up for each infant was scheduled to be at least 15 months and up to 36 months. Infants were to be followed for the entire duration of the study both for the development of tuberculosis and serious adverse events. On enrollment to the study, eligible infants were assigned to a study group starting with Study Group 1 and were randomized in a 1:1 ratio within a study group to receive either MVA85A/AERAS-485 or Candida skin test antigen control. Infants were assigned to a safety cohort (Study Group 1), then into 1 of 3 immunological assay evaluation groups (Study Groups 2-4), and finally the remainder of infants were assigned into the correlate of protection cohort (Study Group 5). At least 330 infants were to be randomized in Study Group 1, up to 50-60 infants each in Study Groups 2-4, and the remaining infants were randomized in Study Group 5.
Interventions
BIOLOGICALMVA85A/AERAS-485
Attenuated virus MVA vector with insertion. Single dose vaccine, 1 x 10\^8 pfu.
BIOLOGICALCandida Skin Test Antigen
1 test, administered once as a placebo control.
Sponsors
University of Oxford
University of Cape Town
Aeras
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
PREVENTION
Masking
QUADRUPLE (Subject, Caregiver, Investigator, Outcomes Assessor)
Eligibility
Sex/Gender
ALL
Age
126 Days to 182 Days
Healthy volunteers
Yes
Inclusion criteria
1. Age of 126 through 182 days on the day of randomization (Study Day 0) 2. Written informed consent obtained from the parents/guardian 3. Weight: by chart \>3rd percentile on Study Day 0 or, if \< 3rd percentile, infant has shown a stable growth pattern 4. BCG vaccination within 7 days of birth 5. Generally good health confirmed by medical history and physical examination within 35 days prior to Study Day 0 6. Must have received age-appropriate doses of pneumococcal vaccine as recommended by the South African Department of Health but no injection within 14 day prior to Study Day 0 7. Ability to complete follow-up period as required by the protocol 8. Completed simultaneous enrollment in the Aeras Vaccine Development Registry protocol
Exclusion criteria
1. Acute illness on Study Day 0 2. Fever \>=37.5 degrees Celsius on Study Day 0 3. Evidence of significant active infection on Study Day 0 4. Received a Expanded Program of Immunization (EPI) within 14 days prior to Study Day 0 5. Historical or virological evidence of individual or maternal human immunodeficiency virus (HIV-1) infection 6. History of allergic disease or reactions likely to be exacerbated by any component of the study vaccine 7. Previous medical history, or evidence, of an intercurrent illness that may compromise the safety of the infant in the study 8. Evidence of chronic hepatitis from any cause 9. History or evidence of any systemic disease on physical examination or any acute, chronic or intercurrent illness that, in the opinion of the investigator, may interfere with the evaluation of the safety or immunogenicity of the vaccine 10. History of or known tuberculosis or treatment for tuberculosis 11. Shared residence since birth with an individual with active tuberculosis or on anti-tuberculosis treatment for less than 2 months
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| To Evaluate the Safety Profile of MVA85A/AERAS-485 in Bacillus Calmette-Guerin (BCG) -Vaccinated, HIV-negative Infants. | AEs recorded 28 days post-vaccination; SAEs recorded for entire study period. | Adverse events (AE) were collected for 28 days after vaccination. The subject's parent or guardian recorded information regarding occurrences of solicited adverse events in diary cards through 7 days after vaccination. Serious adverse events (SAE) were collected from the time of study vaccine dosing throughout the entire study. A safety cohort (the first 330 infants enrolled) also had serum chemistry and hematology testing up to 28 days post-vaccination. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| To Evaluate the Immunogenicity of the MVA85A/AERAS-485 Vaccine Compared to Controls as Described by Flow Cytometric Intracellular Cytokine Staining of CD4 and CD8 T Cells. | 28 days post-vaccination | Intracellular cytokine staining (ICS) assay immune response was expressed as the percentage of cluster of differentiation 4 (CD4) and cluster of differentiation 8 (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 an Ag85A peptide pool on a subset of infants. |
| To Evaluate the Immunogenicity of the MVA85A/AERAS-485 Vaccine Compared to Controls as Described by the ex Vivo Enzyme Linked Immunospot (ELISPOT) Test Used in Previous MVA85A/AERAS-485 Human Trials. | 7 days post-vaccination | An ex vivo IFN-γ ELISPOT assay was used to assess specific T cell responses to an Ag85A peptide pool for a subset of infants. |
| To Evaluate the Efficacy of the MVA85A/AERAS-485 Vaccine Compared to Controls in Prevention of Tuberculosis Using an Endpoint Derived From Epidemiological Cohort Surveys in BCG Vaccinated Infants. | 15 to 36 months post-vaccination | The number (percentage) of subjects with a diagnosis of tuberculosis based on clinically-derived tuberculosis (TB) diagnostic criteria were summarized by treatment group for all subjects. |
| To Discover Correlates of Protection From Tuberculosis in Infants Vaccinated With MVA85A/AERAS-485. | 15 to 36 months post-vaccination | Investigations for determining correlates of immune protection to TB will not be completed as planned because the study did not show TB protection in MVA85A/AERAS-485 recipients. |
| To Evaluate the QuantiFERON Conversion Rate at Final Study Assessment in MVA85A/AERAS-485 Recipients Compared to Controls in Infants Without a Diagnosis of Tuberculosis During the Trial. | 15 to 36 months post-vaccination | The number (percentage) of infants with QuantiFERON conversions at any time on the study were summarized by treatment group. |
| To Evaluate the Immunogenicity of the MVA85A/AERAS-485 Vaccine Compared to Controls as Described by the University of Capetown (UCT) Whole Blood Intracellular Cytokine Assay. | 28 days post-vaccination | Frequencies of CD4 and CD8 T cells expressing cytokines (IFN-γ, IL-2 and TNF-α) following stimulation of whole blood with an Ag85A peptide pool were also measured by flow cytometry for a subset of infants. |
Countries
South Africa
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| Investigational Vaccine MVA85A/AERAS-485; subset into cohorts to explore different safety and immunogenicity tests. | 1,399 |
| Control Group Candida Skin Test Antigen control; subset into cohorts to explore different safety and immunogenicity tests. | 1,398 |
| Total | 2,797 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | Death | 7 | 4 |
| Overall Study | Lost to Follow-up | 61 | 65 |
| Overall Study | Other study discontinuation | 1 | 1 |
| Overall Study | Withdrawal by Subject | 36 | 25 |
Baseline characteristics
| Characteristic | Control Group | Investigational Vaccine | Total |
|---|---|---|---|
| Age, Categorical <=18 years | 1398 Participants | 1399 Participants | 2797 Participants |
| Age, Categorical >=65 years | 0 Participants | 0 Participants | 0 Participants |
| Age, Categorical Between 18 and 65 years | 0 Participants | 0 Participants | 0 Participants |
| Age, Continuous | .399 years STANDARD_DEVIATION 0.037 | .401 years STANDARD_DEVIATION 0.039 | .400 years STANDARD_DEVIATION 0.038 |
| Region of Enrollment South Africa | 1398 participants | 1399 participants | 2797 participants |
| Sex: Female, Male Female | 682 Participants | 691 Participants | 1373 Participants |
| Sex: Female, Male Male | 716 Participants | 708 Participants | 1424 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — |
| other Total, other adverse events | 1,319 / 1,399 | 1,064 / 1,396 |
| serious Total, serious adverse events | 257 / 1,399 | 258 / 1,396 |
Outcome results
Primary
To Evaluate the Safety Profile of MVA85A/AERAS-485 in Bacillus Calmette-Guerin (BCG) -Vaccinated, HIV-negative Infants.
Adverse events (AE) were collected for 28 days after vaccination. The subject's parent or guardian recorded information regarding occurrences of solicited adverse events in diary cards through 7 days after vaccination. Serious adverse events (SAE) were collected from the time of study vaccine dosing throughout the entire study. A safety cohort (the first 330 infants enrolled) also had serum chemistry and hematology testing up to 28 days post-vaccination.
Time frame: AEs recorded 28 days post-vaccination; SAEs recorded for entire study period.
Population: All subjects vaccinated.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Investigational Vaccine | To Evaluate the Safety Profile of MVA85A/AERAS-485 in Bacillus Calmette-Guerin (BCG) -Vaccinated, HIV-negative Infants. | 95.9 percentage of all subjects vaccinated |
| Control Group | To Evaluate the Safety Profile of MVA85A/AERAS-485 in Bacillus Calmette-Guerin (BCG) -Vaccinated, HIV-negative Infants. | 83.7 percentage of all subjects vaccinated |
Secondary
To Discover Correlates of Protection From Tuberculosis in Infants Vaccinated With MVA85A/AERAS-485.
Investigations for determining correlates of immune protection to TB will not be completed as planned because the study did not show TB protection in MVA85A/AERAS-485 recipients.
Time frame: 15 to 36 months post-vaccination
Secondary
To Evaluate the Efficacy of the MVA85A/AERAS-485 Vaccine Compared to Controls in Prevention of Tuberculosis Using an Endpoint Derived From Epidemiological Cohort Surveys in BCG Vaccinated Infants.
The number (percentage) of subjects with a diagnosis of tuberculosis based on clinically-derived tuberculosis (TB) diagnostic criteria were summarized by treatment group for all subjects.
Time frame: 15 to 36 months post-vaccination
Population: Per protocol population
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Investigational Vaccine | To Evaluate the Efficacy of the MVA85A/AERAS-485 Vaccine Compared to Controls in Prevention of Tuberculosis Using an Endpoint Derived From Epidemiological Cohort Surveys in BCG Vaccinated Infants. | 32 participants with a diagnosis of TB |
| Control Group | To Evaluate the Efficacy of the MVA85A/AERAS-485 Vaccine Compared to Controls in Prevention of Tuberculosis Using an Endpoint Derived From Epidemiological Cohort Surveys in BCG Vaccinated Infants. | 39 participants with a diagnosis of TB |
Secondary
To Evaluate the Immunogenicity of the MVA85A/AERAS-485 Vaccine Compared to Controls as Described by Flow Cytometric Intracellular Cytokine Staining of CD4 and CD8 T Cells.
Intracellular cytokine staining (ICS) assay immune response was expressed as the percentage of cluster of differentiation 4 (CD4) and cluster of differentiation 8 (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 an Ag85A peptide pool on a subset of infants.
Time frame: 28 days post-vaccination
Population: Pre-specified population subset
| Arm | Measure | Group | Value (MEDIAN) |
|---|---|---|---|
| Investigational Vaccine | To Evaluate the Immunogenicity of the MVA85A/AERAS-485 Vaccine Compared to Controls as Described by Flow Cytometric Intracellular Cytokine Staining of CD4 and CD8 T Cells. | Percent cytokine expressing CD8 cells | 0.007 percentage of cytokine expressing cells |
| Investigational Vaccine | To Evaluate the Immunogenicity of the MVA85A/AERAS-485 Vaccine Compared to Controls as Described by Flow Cytometric Intracellular Cytokine Staining of CD4 and CD8 T Cells. | Percent cytokine expressing CD4 cells | 0.012 percentage of cytokine expressing cells |
| Control Group | To Evaluate the Immunogenicity of the MVA85A/AERAS-485 Vaccine Compared to Controls as Described by Flow Cytometric Intracellular Cytokine Staining of CD4 and CD8 T Cells. | Percent cytokine expressing CD4 cells | 0.003 percentage of cytokine expressing cells |
| Control Group | To Evaluate the Immunogenicity of the MVA85A/AERAS-485 Vaccine Compared to Controls as Described by Flow Cytometric Intracellular Cytokine Staining of CD4 and CD8 T Cells. | Percent cytokine expressing CD8 cells | 0.000 percentage of cytokine expressing cells |
Secondary
To Evaluate the Immunogenicity of the MVA85A/AERAS-485 Vaccine Compared to Controls as Described by the ex Vivo Enzyme Linked Immunospot (ELISPOT) Test Used in Previous MVA85A/AERAS-485 Human Trials.
An ex vivo IFN-γ ELISPOT assay was used to assess specific T cell responses to an Ag85A peptide pool for a subset of infants.
Time frame: 7 days post-vaccination
Population: Pre-specified population subset
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Investigational Vaccine | To Evaluate the Immunogenicity of the MVA85A/AERAS-485 Vaccine Compared to Controls as Described by the ex Vivo Enzyme Linked Immunospot (ELISPOT) Test Used in Previous MVA85A/AERAS-485 Human Trials. | 143.000 SFC per million PBMCs |
| Control Group | To Evaluate the Immunogenicity of the MVA85A/AERAS-485 Vaccine Compared to Controls as Described by the ex Vivo Enzyme Linked Immunospot (ELISPOT) Test Used in Previous MVA85A/AERAS-485 Human Trials. | 1.000 SFC per million PBMCs |
Secondary
To Evaluate the Immunogenicity of the MVA85A/AERAS-485 Vaccine Compared to Controls as Described by the University of Capetown (UCT) Whole Blood Intracellular Cytokine Assay.
Frequencies of CD4 and CD8 T cells expressing cytokines (IFN-γ, IL-2 and TNF-α) following stimulation of whole blood with an Ag85A peptide pool were also measured by flow cytometry for a subset of infants.
Time frame: 28 days post-vaccination
Population: Pre-specified population subset
| Arm | Measure | Group | Value (MEDIAN) |
|---|---|---|---|
| Investigational Vaccine | To Evaluate the Immunogenicity of the MVA85A/AERAS-485 Vaccine Compared to Controls as Described by the University of Capetown (UCT) Whole Blood Intracellular Cytokine Assay. | Percent IL2/IFN-gamma/TNF expressing CD4 cells | 0.030 percentage of cytokine expressing cells |
| Investigational Vaccine | To Evaluate the Immunogenicity of the MVA85A/AERAS-485 Vaccine Compared to Controls as Described by the University of Capetown (UCT) Whole Blood Intracellular Cytokine Assay. | Percent IL2/IFN-gamma/ TNF expressing CD8 cells | 0.000 percentage of cytokine expressing cells |
| Control Group | To Evaluate the Immunogenicity of the MVA85A/AERAS-485 Vaccine Compared to Controls as Described by the University of Capetown (UCT) Whole Blood Intracellular Cytokine Assay. | Percent IL2/IFN-gamma/TNF expressing CD4 cells | 0.001 percentage of cytokine expressing cells |
| Control Group | To Evaluate the Immunogenicity of the MVA85A/AERAS-485 Vaccine Compared to Controls as Described by the University of Capetown (UCT) Whole Blood Intracellular Cytokine Assay. | Percent IL2/IFN-gamma/ TNF expressing CD8 cells | 0.000 percentage of cytokine expressing cells |
Secondary
To Evaluate the QuantiFERON Conversion Rate at Final Study Assessment in MVA85A/AERAS-485 Recipients Compared to Controls in Infants Without a Diagnosis of Tuberculosis During the Trial.
The number (percentage) of infants with QuantiFERON conversions at any time on the study were summarized by treatment group.
Time frame: 15 to 36 months post-vaccination
Population: Per protocol population who were quantiferon negative at baseline.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Investigational Vaccine | To Evaluate the QuantiFERON Conversion Rate at Final Study Assessment in MVA85A/AERAS-485 Recipients Compared to Controls in Infants Without a Diagnosis of Tuberculosis During the Trial. | 178 participants |
| Control Group | To Evaluate the QuantiFERON Conversion Rate at Final Study Assessment in MVA85A/AERAS-485 Recipients Compared to Controls in Infants Without a Diagnosis of Tuberculosis During the Trial. | 171 participants |