Clinical trial NCT00953927: 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
Overall status: COMPLETED
Phase: PHASE2
Conditions: Tuberculosis
Lead sponsor: Aeras
Sponsor class: OTHER
Collaborators: name: University of Oxford
name: University of Cape Town
First posted: 2009-08-06
Enrollment: 2797
Sex: ALL
Minimum age (years): 126
Maximum age (years): 182
Standard ages: CHILD
Accepts healthy volunteers: yes
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: PREVENTION

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.

Eligibility criteria: 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

Primary outcomes:
measure: To Evaluate the Safety Profile of MVA85A/AERAS-485 in Bacillus Calmette-Guerin (BCG) -Vaccinated, HIV-negative Infants.
timeFrame: AEs recorded 28 days post-vaccination; SAEs recorded for entire study period.
Secondary outcomes:
measure: 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.
timeFrame: 15 to 36 months post-vaccination
measure: 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.
timeFrame: 28 days post-vaccination
measure: 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.
timeFrame: 7 days post-vaccination
measure: 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.
timeFrame: 28 days post-vaccination
measure: To Discover Correlates of Protection From Tuberculosis in Infants Vaccinated With MVA85A/AERAS-485.
timeFrame: 15 to 36 months post-vaccination
measure: 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.
timeFrame: 15 to 36 months post-vaccination
Other outcomes:
Locations:
city: Ceres
country: South Africa
facility: South African Tuberculosis Vaccine Initiative (Satellite)
city: Robertson
country: South Africa
facility: South African Tuberculosis Vaccine Initiative (Satellite)
city: Worcester
country: South Africa
facility: South African Tuberculosis Vaccine Initiative (Headquarters)
Study officials:
affiliation: South African Tuberculosis Vaccine Initiative
name: Michele Tameris, MD
role: PRINCIPAL_INVESTIGATOR
affiliation: Aeras
name: Bernard Landry, MPH
role: STUDY_DIRECTOR
affiliation: University of Oxford; Centre for Vaccinology & Tropical Medicine
name: Helen McShane, MD
role: STUDY_CHAIR
References:
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.
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.
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.
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.
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.
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.
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.