Safety and Immunogenicity of MVA85A Prime and Bacille Calmette-Guerin Boost Vaccination (MVA(TB)029)
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Purpose
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.
| Condition | Intervention | Phase |
|---|---|---|
|
Tuberculosis HIV |
Biological: MVA85A Biological: Candin Biological: BCG Vaccine SSI |
Phase 2 |
| Study Type: | Interventional |
| Study Design: | Allocation: Randomized Endpoint Classification: Safety Study Intervention Model: Parallel Assignment Masking: Double Blind (Subject, Caregiver, Investigator, Outcomes Assessor) Primary Purpose: Prevention |
| Official Title: | Phase II Randomised Controlled Trial to Evaluate Safety and Immunogenicity of MVA85A and Selective, Delayed Bacille Calmette-Guerin (BCG) Vaccination in Infants of HIV Infected Mothers |
- Safety [ Time Frame: 1 year ] [ Designated as safety issue: Yes ]Local, regional, and systemic adverse events (AEs) and serious adverse events (SAEs).
- Immunogenicity [ Time Frame: 1 Year ] [ Designated as safety issue: No ]
Frequencies of CD4 and CD8 T cells producing IL-17, IFN-γ, TNF-α, or IL-2, or polyfunctional combinations of these cytokines, following stimulation with antigen Ag85A or BCG, measured by whole blood intracellular cytokine assay.
Specific proliferative capacity of CD8 and CD4 T cells that produce IFN-γ, TNF-α, or IL-2, or combinations of these cytokines, measured by whole blood 6-day lymphoproliferative flow cytometric assay.
Relative proportions and absolute numbers of peripheral blood myeloid and lymphoid cell subsets, measured directly ex vivo by flow cytometry.
| Estimated Enrollment: | 340 |
| Study Start Date: | October 2012 |
| Arms | Assigned Interventions |
|---|---|
|
Experimental: MVA85A
1 x 10(superscript'8') pfu MVA85A vaccine intradermal within 96 hours of birth
|
Biological: MVA85A
Biological: BCG Vaccine SSI
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. |
|
Active Comparator: Candin
Equal volume intradermal administration within 96 hours of birth
|
Biological: Candin
Biological: BCG Vaccine SSI
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. |
Eligibility| Ages Eligible for Study: | up to 96 Hours |
| Genders Eligible for Study: | Both |
| Accepts Healthy Volunteers: | No |
Inclusion Criteria:
- 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.
Exclusion Criteria:
- 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.
Contacts and Locations| Contact: Mark Hatherill, MD | +27214047618 | mark.hatherill@uct.ac.za |
| South Africa | |
| Desmond Tutu TB Centre (DTTC), Stellenbosch University | Recruiting |
| Khayelitsha, South Africa | |
| Contact: Claudia Francis, RN | |
| Principal Investigator: Anneke Hesseling, PhD | |
| South African Tuberculosis Vaccine Initiative (SATVI), University of Cape Town | Recruiting |
| Worcester, South Africa | |
| Contact: Danelle van As, RN | |
| Principal Investigator: Mark Hatherill, MD | |
| Principal Investigator: | Mark Hatherill, MD, FCPaed | University of Cape Town |
More Information
No publications provided
| Responsible Party: | Mark Hatherill, Associate Professor, University of Cape Town |
| ClinicalTrials.gov Identifier: | NCT01650389 History of Changes |
| Other Study ID Numbers: | G1100570/1, G1100570 |
| Study First Received: | July 23, 2012 |
| Last Updated: | January 30, 2013 |
| Health Authority: | South Africa: Medicines Control Council |
Keywords provided by University of Cape Town:
|
Tuberculosis HIV BCG Infant |
Additional relevant MeSH terms:
|
Tuberculosis Mycobacterium Infections Actinomycetales Infections Gram-Positive Bacterial Infections Bacterial Infections |
BCG Vaccine Adjuvants, Immunologic Immunologic Factors Physiological Effects of Drugs Pharmacologic Actions |
ClinicalTrials.gov processed this record on March 03, 2013
