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A Study of MVA85A in Healthy Infants

Primary Purpose

Tuberculosis

Status

Completed

Phase

Phase 2

Locations

South Africa

Study Type

Interventional

Intervention

MVA85A/AERAS-485

Candida Skin Test Antigen

About this trial

This is an interventional prevention trial for Tuberculosis

Eligibility Criteria

126 Days - 182 Days (Child)All SexesAccepts Healthy Volunteers

Inclusion Criteria:

Age of 126 through 182 days on the day of randomization (Study Day 0)
Written informed consent obtained from the parents/guardian
Weight: by chart >3rd percentile on Study Day 0 or, if < 3rd percentile, infant has shown a stable growth pattern
BCG vaccination within 7 days of birth
Generally good health confirmed by medical history and physical examination within 35 days prior to Study Day 0
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
Ability to complete follow-up period as required by the protocol
Completed simultaneous enrollment in the Aeras Vaccine Development Registry protocol

Exclusion Criteria:

Acute illness on Study Day 0
Fever >=37.5 degrees Celsius on Study Day 0
Evidence of significant active infection on Study Day 0
Received a Expanded Program of Immunization (EPI) within 14 days prior to Study Day 0
Historical or virological evidence of individual or maternal human immunodeficiency virus (HIV-1) infection
History of allergic disease or reactions likely to be exacerbated by any component of the study vaccine
Previous medical history, or evidence, of an intercurrent illness that may compromise the safety of the infant in the study
Evidence of chronic hepatitis from any cause
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
History of or known tuberculosis or treatment for tuberculosis
Shared residence since birth with an individual with active tuberculosis or on anti-tuberculosis treatment for less than 2 months

Sites / Locations

South African Tuberculosis Vaccine Initiative (Satellite)
South African Tuberculosis Vaccine Initiative (Satellite)
South African Tuberculosis Vaccine Initiative (Headquarters)

Arms of the Study

Arm 1

Arm 2

Arm Type

Experimental

Placebo Comparator

Arm Label

Investigational Vaccine

Control Group

Arm Description

MVA85A/AERAS-485; subset into cohorts to explore different safety and immunogenicity tests.

Candida Skin Test Antigen control; subset into cohorts to explore different safety and immunogenicity tests.

Outcomes

Primary Outcome Measures

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.

Secondary Outcome Measures

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.

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.

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.

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.

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.

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.

Full Information

NCT ID

NCT00953927

First Posted

July 31, 2009

Last Updated

April 25, 2016

Sponsor

Aeras

Collaborators

University of Oxford, University of Cape Town

1. Study Identification

Unique Protocol Identification Number

NCT00953927

Brief Title

A Study of MVA85A in Healthy Infants

Official Title

Phase II Double-blinded Randomized Controlled Evaluation of MVA85A/AERAS-485 for Safety, Immunogenicity and Prevention of Tuberculosis in BCG-vaccinated, HIV-negative Infants

Study Type

Interventional

2. Study Status

Record Verification Date

April 2016

Overall Recruitment Status

Completed

Study Start Date

July 2009 (undefined)

Primary Completion Date

October 2012 (Actual)

Study Completion Date

undefined (undefined)

3. Sponsor/Collaborators

Responsible Party, by Official Title

Sponsor

Name of the Sponsor

Aeras

Collaborators

University of Oxford, University of Cape Town

4. Oversight

Data Monitoring Committee

Yes

5. Study Description

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.

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study

Tuberculosis

7. Study Design

Primary Purpose

Prevention

Study Phase

Phase 2

Interventional Study Model

Parallel Assignment

Masking

ParticipantCare ProviderInvestigatorOutcomes Assessor

Allocation

Randomized

Enrollment

2797 (Actual)

8. Arms, Groups, and Interventions

Arm Title

Investigational Vaccine

Arm Type

Experimental

Arm Description

MVA85A/AERAS-485; subset into cohorts to explore different safety and immunogenicity tests.

Arm Title

Control Group

Arm Type

Placebo Comparator

Arm Description

Candida Skin Test Antigen control; subset into cohorts to explore different safety and immunogenicity tests.

Intervention Type

Biological

Intervention Name(s)

MVA85A/AERAS-485

Other Intervention Name(s)

Manufactured by IDT of Germany.

Intervention Description

Attenuated virus MVA vector with insertion. Single dose vaccine, 1 x 10^8 pfu.

Intervention Type

Biological

Intervention Name(s)

Candida Skin Test Antigen

Other Intervention Name(s)

Candin(R), Manufactured by Allermed Laboratories of USA.

Intervention Description

1 test, administered once as a placebo control.

Primary Outcome Measure Information:

Title

To Evaluate the Safety Profile of MVA85A/AERAS-485 in Bacillus Calmette-Guerin (BCG) -Vaccinated, HIV-negative Infants.

Description

Time Frame

AEs recorded 28 days post-vaccination; SAEs recorded for entire study period.

Secondary Outcome Measure Information:

Title

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.

Description

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

Title

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.

Description

Time Frame

28 days post-vaccination

Title

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.

Description

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

Title

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.

Description

Time Frame

28 days post-vaccination

Title

To Discover Correlates of Protection From Tuberculosis in Infants Vaccinated With MVA85A/AERAS-485.

Description

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

Title

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.

Description

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

10. Eligibility

Sex

All

Minimum Age & Unit of Time

126 Days

Maximum Age & Unit of Time

182 Days

Accepts Healthy Volunteers

Eligibility Criteria

Inclusion Criteria: Age of 126 through 182 days on the day of randomization (Study Day 0) Written informed consent obtained from the parents/guardian Weight: by chart >3rd percentile on Study Day 0 or, if < 3rd percentile, infant has shown a stable growth pattern BCG vaccination within 7 days of birth Generally good health confirmed by medical history and physical examination within 35 days prior to Study Day 0 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 Ability to complete follow-up period as required by the protocol Completed simultaneous enrollment in the Aeras Vaccine Development Registry protocol Exclusion Criteria: Acute illness on Study Day 0 Fever >=37.5 degrees Celsius on Study Day 0 Evidence of significant active infection on Study Day 0 Received a Expanded Program of Immunization (EPI) within 14 days prior to Study Day 0 Historical or virological evidence of individual or maternal human immunodeficiency virus (HIV-1) infection History of allergic disease or reactions likely to be exacerbated by any component of the study vaccine Previous medical history, or evidence, of an intercurrent illness that may compromise the safety of the infant in the study Evidence of chronic hepatitis from any cause 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 History of or known tuberculosis or treatment for tuberculosis Shared residence since birth with an individual with active tuberculosis or on anti-tuberculosis treatment for less than 2 months

Overall Study Officials:

First Name & Middle Initial & Last Name & Degree

Michele Tameris, MD

Organizational Affiliation

South African Tuberculosis Vaccine Initiative

Official's Role

Principal Investigator

First Name & Middle Initial & Last Name & Degree

Bernard Landry, MPH

Organizational Affiliation

Aeras

Official's Role

Study Director

First Name & Middle Initial & Last Name & Degree

Helen McShane, MD

Organizational Affiliation

University of Oxford; Centre for Vaccinology & Tropical Medicine

Official's Role

Study Chair

Facility Information:

Facility Name

South African Tuberculosis Vaccine Initiative (Satellite)

City

Ceres

ZIP/Postal Code

6835

Country

South Africa

Facility Name

South African Tuberculosis Vaccine Initiative (Satellite)

City

Robertson

ZIP/Postal Code

6705

Country

South Africa

Facility Name

South African Tuberculosis Vaccine Initiative (Headquarters)

City

Worcester

ZIP/Postal Code

6850

Country

South Africa

12. IPD Sharing Statement

Citations:

PubMed Identifier

23391465

Citation

Tameris MD, Hatherill M, Landry BS, Scriba TJ, Snowden MA, Lockhart S, Shea JE, McClain JB, Hussey GD, Hanekom WA, Mahomed H, McShane H; MVA85A 020 Trial Study Team. Safety and efficacy of MVA85A, a new tuberculosis vaccine, in infants previously vaccinated with BCG: a randomised, placebo-controlled phase 2b trial. Lancet. 2013 Mar 23;381(9871):1021-8. doi: 10.1016/S0140-6736(13)60177-4.

Results Reference

background

PubMed Identifier

23410889

Citation

Tameris M, McShane H, McClain JB, Landry B, Lockhart S, Luabeya AK, Geldenhuys H, Shea J, Hussey G, van der Merwe L, de Kock M, Scriba T, Walker R, Hanekom W, Hatherill M, Mahomed H. Lessons learnt from the first efficacy trial of a new infant tuberculosis vaccine since BCG. Tuberculosis (Edinb). 2013 Mar;93(2):143-9. doi: 10.1016/j.tube.2013.01.003. Epub 2013 Feb 12.

Results Reference

background

PubMed Identifier

26226446

Citation

Mulenga H, Tameris MD, Luabeya KK, Geldenhuys H, Scriba TJ, Hussey GD, Mahomed H, Landry BS, Hanekom WA, McShane H, Hatherill M. The Role of Clinical Symptoms in the Diagnosis of Intrathoracic Tuberculosis in Young Children. Pediatr Infect Dis J. 2015 Nov;34(11):1157-62. doi: 10.1097/INF.0000000000000847.

Results Reference

background

PubMed Identifier

26252568

Citation

Luabeya KK, Tameris MD, Geldenhuys HD, Mulenga H, Van Schalkwyk A, Hughes EJ, Toefey A, Scriba TJ, Hussey G, Mahomed H, McShane H, Landry B, Hanekom WA, Hatherill M. Risk of Disease After Isoniazid Preventive Therapy for Mycobacterium tuberculosis Exposure in Young HIV-uninfected Children. Pediatr Infect Dis J. 2015 Nov;34(11):1218-22. doi: 10.1097/INF.0000000000000874.

Results Reference

background

PubMed Identifier

31697647

Citation

Muller J, Tanner R, Matsumiya M, Snowden MA, Landry B, Satti I, Harris SA, O'Shea MK, Stockdale L, Marsay L, Chomka A, Harrington-Kandt R, Thomas ZM, Naranbhai V, Stylianou E, Mbandi SK, Hatherill M, Hussey G, Mahomed H, Tameris M, McClain JB, Evans TG, Hanekom WA, Scriba TJ, McShane H, Fletcher HA. Cytomegalovirus infection is a risk factor for tuberculosis disease in infants. JCI Insight. 2019 Dec 5;4(23):e130090. doi: 10.1172/jci.insight.130090.

Results Reference

derived

PubMed Identifier

26554383

Citation

Bunyasi EW, Tameris M, Geldenhuys H, Schmidt BM, Luabeya AK, Mulenga H, Scriba TJ, Hanekom WA, Mahomed H, McShane H, Hatherill M. Evaluation of Xpert(R) MTB/RIF Assay in Induced Sputum and Gastric Lavage Samples from Young Children with Suspected Tuberculosis from the MVA85A TB Vaccine Trial. PLoS One. 2015 Nov 10;10(11):e0141623. doi: 10.1371/journal.pone.0141623. eCollection 2015.

Results Reference

derived

PubMed Identifier

24912498

Citation

Matsumiya M, Harris SA, Satti I, Stockdale L, Tanner R, O'Shea MK, Tameris M, Mahomed H, Hatherill M, Scriba TJ, Hanekom WA, McShane H, Fletcher HA. Inflammatory and myeloid-associated gene expression before and one day after infant vaccination with MVA85A correlates with induction of a T cell response. BMC Infect Dis. 2014 Jun 9;14:314. doi: 10.1186/1471-2334-14-314.

Results Reference

derived

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A Study of MVA85A in Healthy Infants

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