Safety and Immunogenicity Study of BCG, H4:IC31, and H56:IC31 Revaccination in Healthy Adolescents

A Randomized, Placebo-controlled, Partially Blinded Phase 1b Clinical Trial to Evaluate the Safety and Immunogenicity of BCG Revaccination, H4:IC31, and H56:IC31 in Healthy, HIV-1-Uninfected Adolescent Participants

The aims of the phase 1b trial described here are to facilitate identification of assays and immune responses that could then be evaluated as correlates of risk and correlates of protection in efficacy studies and ultimately to provide leads for biomarkers of protection against tuberculosis. This study will complement one ongoing study (NCT02075203) evaluating the prevention of M. Tuberculosis infection using H4:IC31 (also known as AERAS-404).

This study proposes to further evaluate the safety and immunogenicity of H4:IC31, H56:IC31, and BCG revaccination. The study will be conducted in previously BCG vaccinated healthy adolescents, and will entail a thorough immunogenicity evaluation of these regimens incorporating unbiased systems vaccinology approaches and novel assessments of baseline and elicited responses that may impact vaccine responses. A major goal for this study is to generate immunological data on a wide range of immune responses using a variety of approaches including validated assessments, unbiased strategies, and novel exploratory assays to increase the likelihood of detecting responses correlating with risk or protection in the prevention of infection study. Investigators contributing to the proposed study have participated in a correlates analysis for an HIV vaccine exhibiting modest efficacy in which 2 correlates of risk were identified.

An additional aim of this study is to explore factors affecting vaccine induced responses that may also impact efficacy. For example, it is hypothesized that exposure to environmental mycobacteria may alter protection provided by BCG vaccination. Reagents for evaluating levels of exposure to environmental mycobacteria are in development as part of a concurrent collaborative study. An exploratory objective for this trial is to apply these reagents to examine whether such exposures influence immune responses elicited by the study vaccine and regimens.

Inclusion Criteria:

1. Age of 12 to ≤ 17 years at enrollment
2. Minimum weight ≥ 40 kg
3. Previous BCG vaccination at least 5 years ago documented by scarification or medical card
4. No evidence of active TB disease, as determined by history, physical examination and, if deemed appropriate, sputum investigation and / or chest x-ray.
5. Negative QFT-GIT test at screening, using the manufacturer's recommended threshold of 0.35 IU/mL
6. Assessed by the clinic staff as being at low risk for HIV infection
7. Hemoglobin ≥ 11.7 g/dL for females, ≥ 12.5 g/dL for males
8. Negative HIV-1 and -2 blood test
9. Agree to consistently use effective contraception for sexual activity that could lead to pregnancy from at least 20 days prior to enrollment through the last required protocol clinic visit.

(additional minor criteria not added due to space constraints)

Exclusion Criteria:

1. Blood products received within 120 days before first vaccination
2. Investigational research agents received within 182 days before first vaccination
3. Intent to participate in another study of an investigational research agent during the planned duration of the HVTN 602 / AERAS A-042 study
4. Pregnant or breastfeeding
5. History of alcohol or drug abuse
6. A significant contact with active TB disease: for example, shared residency with an individual receiving anti-TB treatment, or with an individual known to have incompletely treated culture or smear positive TB
7. TB prophylaxis within 90 days prior to enrollment
8. History of treatment for active TB disease or latent Mtb infection
9. Positive and indeterminate QFT-GIT result
10. Received a tuberculin skin test (TST) within 90 days prior to enrollment
11. Vaccines and other Injections
12. Immunosuppressive medications received within 168 days before first vaccination.
13. Serious adverse reactions to vaccines including history of anaphylaxis and related symptoms such as hives, respiratory difficulty, angioedema, and/or abdominal pain.
14. Immunoglobulin received within 60 days before first vaccination
15. Autoimmune disease Not excluded: mild, well-controlled psoriasis
16. Clinically significant medical condition, physical examination findings, clinically significant abnormal laboratory results, or past medical history with clinically significant implications for current health. Including but not limited to: Diabetes mellitus type 1 or type 2, Thyroidectomy, or Thyroid disease, Asthma, Asplenia, Bleeding disorders, malignancy, Seizure disorder, and Angioedema

(additional minor criteria not added due to space constraints)