Please select the eligibility criteria that correspond to the clinical trial below.
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
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.


Options:
A: 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.
B: Inclusion Criteria

Participants must meet all of the following criteria to enter the trial:

* Healthy adolescents aged 12-17 years (both male and female)
* Resident in the study area for the duration of the study period
* Confirmation of prior vaccination with BCG not less than 6 months prior to projected study vaccination date (by visible BCG scar on examination or written documentation)
* No relevant findings in medical history or on physical examination
* Written informed consent by parent or guardian
* Written informed assent by subject
* Refrain from blood donation during the trial
* Agree to avoid pregnancy for the duration of the trial (female only)
* Able and willing (in the Investigator's opinion) to comply with all the study requirements
* Stool sample negative for S. mansoni (group 1) or positive for S. mansoni infection (group 2), based on the results of the Kato Katz stool analysis
* Willing to delay treatment for schistosomiasis for at least one month (group 2)

Exclusion Criteria

Participants may not enter the trial if ANY of the following apply:

* Clinical, radiological, or laboratory evidence of current active TB disease
* Laboratory evidence at screening of latent M. tb infection as indicated by a positive ELISPOT response to ESAT6 or CFP10 antigens
* Previous treatment for active or latent tuberculosis infection
* Shared a residence within one year prior to day 0 with an individual on anti-tuberculosis treatment or with culture or smear-positive pulmonary tuberculosis
* Received a TST within 90 days prior to day 0
* Clinically significant history of skin disorder, allergy, immunodeficiency (including HIV), cancer (except BCC or CIS), cardiovascular disease, gastrointestinal disease, liver disease, renal disease, endocrine disorder and neurological illness, drug or alcohol abuse
* History of serious psychiatric condition or disorder
* Concurrent oral or systemic steroid medication or the concurrent use of other immunosuppressive agents within 2 months prior to enrolment
* History of anaphylaxis to vaccination or any allergy likely to be exacerbated by any component of the study vaccine, including eggs
* Any abnormality of screening blood or urine tests that is deemed to be clinically significant or that may compromise the safety of the volunteer in the study
* Positive HBsAg, HCV or HIV antibodies
* Use of an investigational medicinal product or non-registered drug, live vaccine, or medical device other than the study vaccine for 30 days prior to dosing with the study vaccine, or planned use during the study period
* Administration of immunoglobulins and/or any blood products within the three months preceding the planned trial vaccination date
* Female currently lactating, confirmed pregnancy or intention to become pregnant during the trial period
* Screening blood sample positive for malaria or Mansonella perstans by microscopy
* Schistosoma mansoni infection intensity greater than 2000 eggs per gram of stool
* Any of the three screening stool samples positive for any helminths on Kato Katz examinations or for S. mansoni or Strongyloides stercoralis by PCR (group 1); or any of the three screening stool samples positive for helminths other than S. mansoni on Kato Katz examinations or for Strongyloides stercoralis by PCR (group 2)
* Screening urine sample positive for S. mansoni infection (group 1)
* Any other significant disease, disorder, or finding, which, in the opinion of the Investigator, may either put the subject at risk or may influence the result of the trial or may affect the subject's ability to participate in the trial
C: 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
D: Inclusion Criteria:

* Healthy adult male aged 18-45 years.
* Normal medical history and physical examination. Minor physical ailments e.g. Fungal skin infections, will not be sufficient to define a physical examination as abnormal.
* Normal urine dipstick, blood count, liver enzymes, and creatinine
* Frequency \<4 SFU per/well/3x105 PBMC as determined by ELISPOT with ESAT6/CFP-10 antigens and less than 100 SFU per/well/1x106 PBMC as determined by ELISPOT with PPD.
* Mantoux negative (0.0 mm induration).
* Normal Chest X-ray.
* Willing to donate blood samples as required by the protocol

Exclusion Criteria:

* Clinically significant history of skin disorder (eczema, psoriasis, etc.), allergy, immunodeficiency, cardiovascular disease, respiratory disease, endocrine disorder, liver disease, renal disease, gastrointestinal disease or neurological illness.
* Any clinical evidence of immunosuppression such as oral candida, stomatitis, aphthous or septic ulceration, septic skin lesions or any clinical or laboratory evidence of infection or immunocompromise.
* History of splenectomy
* Haematocrit of less than 30%
* Serum creatinine concentration \>130mmol
* Serum ALT concentration \>80IU/L
* Blood transfusion within one month of the beginning of the study
* History of vaccination with any previous experimental poxvirus vaccine
* Administration of any other vaccine or immunoglobulin within two weeks before or two weeks after vaccination.
* Positive HIV antibody test, evidence of HBV (Hepatitis B vaccination is not an exclusion criteria)..
* Current participation in another clinical trial, or within 12 weeks of this study
* Any other finding which in the opinion of the investigators would increase the risk of an adverse outcome from participation in the trial.
* Likelihood of travel away from the study area for the duration of the study
* Untreated malaria infection

Answer: A