NCT01650389

Brief Summary

Rationale: The Bacille Calmette-Guérin (BCG) vaccine protects children against disseminated tuberculosis (TB) including TB meningitis and miliary TB, but efficacy against pulmonary TB is inconsistent among children and adults. Administration of live attenuated BCG to infants known to be HIV infected is contraindicated by the World Health Organization (WHO), due to the risk of serious vaccine adverse events (BCG disease. Developing countries, which lack capacity for integration of early infant HIV testing with infant vaccination schedules, have not fully implemented the WHO guidelines on BCG vaccination of HIV exposed infants. Newborn infants of HIV infected mothers continue to receive routine BCG before HIV infection has been excluded. Clinical trials of new viral-vectored TB vaccines, including MVA85A, a modified vaccinia virus Ankara (MVA) vaccine expressing the Mycobacterium tuberculosis antigen 85A, have to date enrolled infants who were already vaccinated with routine BCG at birth. However, TB vaccination regimens that depend on newborn BCG will remain unsafe for HIV infected infants. Infants of HIV infected mothers, who constituted 29% of babies born in South Africa in 2009, would benefit from a new TB vaccination strategy, in which BCG is delayed until after HIV infection has been excluded. These HIV exposed infants also have greater increased risk of TB disease. Testing the safety and immunogenicity of MVA85A vaccine prime, followed by selective delayed BCG boost, in HIV exposed newborns, is a critical step towards delivery of a new TB vaccine regimen that is safe and effective for all infants, regardless of HIV exposure. Study Design: Double blinded, randomised, controlled trial. HIV exposed infants will be randomised 1:1 to receive single dose, intradermal MVA85A vaccine or Candin® control at birth. The first 60 infants enrolled in the trial will form a pilot safety cohort for formal Data Monitoring \& Ethics Committee (DMEC) safety review. Thereafter, safety and immunogenicity outcomes will be measured in all infants. Study Population: Infants (n=340) born to HIV infected mothers receiving antiretroviral therapy (ART) or Prevention of Mother to Child Transmission (PMTCT) prophylaxis. Sites: Worcester (University of Cape Town) and Khayelitsha (Stellenbosch University), South Africa Study Intervention: Newborn infants will receive 1 x 108 pfu MVA85A vaccine or Candin® control by intradermal injection. Infants confirmed HIV uninfected by HIV PCR will receive BCG Vaccine SSI at 8 weeks of age. Infants confirmed HIV infected by HIV PCR will not receive BCG. Primary specific aims: To evaluate the safety of MVA85A given at birth to HIV exposed uninfected infants. To evaluate the safety of BCG given at 8 weeks of age to HIV exposed uninfected infants, using an MVA85A prime and BCG boost strategy. Secondary specific aims: To evaluate the immunogenicity of MVA85A given at birth to HIV exposed uninfected infants. To evaluate the immunogenicity of BCG given at 8 weeks of age to HIV exposed uninfected infants, using an MVA85A prime and BCG boost strategy. Safety endpoints: Local, regional, and systemic adverse events (AEs) and serious adverse events (SAEs). Immunology endpoints: Frequencies of CD4 and CD8 T cells producing any of 4 cytokines (IL-17, IFN-γ, TNF-α, or IL-2), or polyfunctional combinations of these cytokines simultaneously, following stimulation with antigen Ag85A or BCG, measured by whole blood intracellular cytokine assay (WB-ICS). Specific proliferative capacity of CD8 and CD4 T cells that produce any of the three cytokines (IFN-γ, TNF-α, and/or IL-2) or combinations of these cytokines simultaneously, measured by a novel whole blood 6-day lymphoproliferative flow cytometric assay (WB-prolif). Relative proportions and absolute numbers of peripheral blood myeloid and lymphoid cell subsets, measured directly ex vivo by flow cytometry. Study groups: The first 60 infants enrolled in Study Group 1 will undergo intensive safety evaluation, followed by DMEC review of Day-28 safety data. The DMEC will make a formal recommendation on continuation of enrollment and/or changes to the protocol, based on this safety review. Study Groups 2-5 will be evaluated for clinical safety and immunology outcomes. Statistical Analysis: Cumulative 12-month incidence of local, regional, and systemic AEs, by category, will be compared for HIV exposed uninfected subjects receiving MVA85A vaccine or Candin® control at birth. The sample size has 90% probability of detecting an SAE with a true occurrence rate of 1.5% in infants receiving MVA85A vaccine and 80% power to detect a 15% difference in the rate of non-serious AEs (20% compared to 35%) between the two study arms (p\<0.05). Multivariate models will be built to explore longitudinal immunological data and identify independent associations with MVA85A vaccination and covariates of interest.

Trial Health

87
On Track

Trial Health Score

Automated assessment based on enrollment pace, timeline, and geographic reach

Enrollment
248

participants targeted

Target at P75+ for phase_2

Timeline
Completed

Started Oct 2012

Geographic Reach
1 country

2 active sites

Status
completed

Health score is calculated from publicly available data and should be used for screening purposes only.

Trial Relationships

Click on a node to explore related trials.

Study Timeline

Key milestones and dates

First Submitted

Initial submission to the registry

July 23, 2012

Completed
3 days until next milestone

First Posted

Study publicly available on registry

July 26, 2012

Completed
2 months until next milestone

Study Start

First participant enrolled

October 1, 2012

Completed
2.6 years until next milestone

Primary Completion

Last participant's last visit for primary outcome

May 1, 2015

Completed
Same day until next milestone

Study Completion

Last participant's last visit for all outcomes

May 1, 2015

Completed
Last Updated

September 30, 2015

Status Verified

September 1, 2015

Enrollment Period

2.6 years

First QC Date

July 23, 2012

Last Update Submit

September 29, 2015

Conditions

TuberculosisHIV

Keywords

TuberculosisHIVBCGInfant

Outcome Measures

Primary Outcomes (1)

  • Safety

    Local, regional, and systemic adverse events (AEs) and serious adverse events (SAEs).

    1 year

Secondary Outcomes (1)

  • Immunogenicity

    1 Year

Study Arms (2)

MVA85A

EXPERIMENTAL

1 x 10(superscript'8') pfu MVA85A vaccine intradermal within 96 hours of birth

Biological: MVA85ABiological: BCG Vaccine SSI

Candin

ACTIVE COMPARATOR

Equal volume intradermal administration within 96 hours of birth

Biological: CandinBiological: BCG Vaccine SSI

Interventions

MVA85ABIOLOGICAL
MVA85A
CandinBIOLOGICAL
Candin
BCG Vaccine SSIBIOLOGICAL

All infants who test negative by HIV PCR will receive BCG vaccination at 8 weeks of age. Infants who test positive by HIV PCR will not receive BCG vaccination.

CandinMVA85A

Eligibility Criteria

AgeUp to 96 Hours
Sexall
Healthy VolunteersNo
Age GroupsChild (0-17)

You may qualify if:

  • HIV infected mother receiving either cART, or started on PMTCT prophylaxis
  • Maternal antenatal and post-natal written informed consent;
  • Maternal age 18 years or older at the time of informed consent;
  • Infant age \< 96 hours;
  • Infant birth and residence in the study area;
  • Mother contactable and able to attend follow-up visits.

You may not qualify if:

  • Neonatal Apgar score \< 7 at 5 minutes;
  • Infant birth weight \< 2,000g or \> 4,500g;
  • Estimated infant gestational age \< 32 weeks;
  • Neonatal respiratory distress;
  • History or evidence of infant congenital abnormality, or immunosuppressive condition, other than HIV infection;
  • Any maternal or infant condition or systemic illness that in the opinion of the investigator is likely to affect safety or immunogenicity of study vaccine;
  • Infant BCG vaccination prior to enrollment;
  • Residence in a household, or frequent close contact, with an adult diagnosed with active TB who has not yet completed TB treatment;
  • Mother with active TB who has not yet completed TB treatment;
  • Unknown or negative maternal HIV status;
  • Intention to leave the study area and/or unable to attend follow-up visits.

Contact the study team to confirm eligibility.

Sponsors & Collaborators

Study Sites (2)

Desmond Tutu TB Centre (DTTC), Stellenbosch University

Khayelitsha, South Africa

Location

South African Tuberculosis Vaccine Initiative (SATVI), University of Cape Town

Worcester, South Africa

Location

Related Publications (1)

  • Nemes E, Hesseling AC, Tameris M, Mauff K, Downing K, Mulenga H, Rose P, van der Zalm M, Mbaba S, Van As D, Hanekom WA, Walzl G, Scriba TJ, McShane H, Hatherill M; MVA029 Study Team. Safety and Immunogenicity of Newborn MVA85A Vaccination and Selective, Delayed Bacille Calmette-Guerin for Infants of Human Immunodeficiency Virus-Infected Mothers: A Phase 2 Randomized, Controlled Trial. Clin Infect Dis. 2018 Feb 1;66(4):554-563. doi: 10.1093/cid/cix834.

    PMID: 29028973DERIVED

MeSH Terms

Conditions

Tuberculosis

Interventions

MVA 85A

Condition Hierarchy (Ancestors)

Mycobacterium InfectionsActinomycetales InfectionsGram-Positive Bacterial InfectionsBacterial InfectionsBacterial Infections and MycosesInfections

Study Officials

  • Mark Hatherill, MD, FCPaed

    University of Cape Town

    PRINCIPAL INVESTIGATOR

Study Design

Study Type
interventional
Phase
phase 2
Allocation
RANDOMIZED
Masking
QUADRUPLE
Who Masked
PARTICIPANT, CARE PROVIDER, INVESTIGATOR, OUTCOMES ASSESSOR
Purpose
PREVENTION
Intervention Model
PARALLEL
Sponsor Type
OTHER
Responsible Party
SPONSOR INVESTIGATOR
PI Title
Associate Professor

Study Record Dates

First Submitted

July 23, 2012

First Posted

July 26, 2012

Study Start

October 1, 2012

Primary Completion

May 1, 2015

Study Completion

May 1, 2015

Last Updated

September 30, 2015

Record last verified: 2015-09

Locations

ZA(2)