Clinical trial NCT02378207: Safety and Immunogenicity Study of BCG, H4:IC31, and H56:IC31 Revaccination in Healthy Adolescents
Official title: 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
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE1
Conditions: Tuberculosis
Lead sponsor: Aeras
Sponsor class: OTHER
Collaborators: name: HIV Vaccine Trials Network
name: Sanofi Pasteur, a Sanofi Company
name: Statens Serum Institut
First posted: 2015-03-04
Enrollment: 84
Sex: ALL
Minimum age (years): 12
Maximum age (years): 17
Standard ages: CHILD
Accepts healthy volunteers: yes
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: PREVENTION

Brief summary: 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).

Detailed description: 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.

Eligibility criteria: 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)

Primary outcomes:
measure: Number of Participants With Adverse Events
timeFrame: Up to 8 months
measure: Percentage of Participants With Response Rates to TB Antigens as Compared to Baseline
timeFrame: Days 70 and 168
Secondary outcomes:
measure: Evaluate Humoral Responses Elicited by the Different Vaccine Regimens.
timeFrame: Up to day 168.
measure: * Evaluate Immune Response From Vaccine Regimens by Measuring Early (Innate) Vaccine-induced Peripheral Blood Transcription Profiles; Determine Which Responses Are Associated With Antigen-specific Adaptive Responses * Evaluate Adaptive Immune Response.
timeFrame: Up to day 168
measure: Evaluate Changes in Innate Cells in Response to the Vaccine Regimens
timeFrame: Up to day 168
measure: Measure Non-classical Major Histocompatibility Complex (MHC)-Restricted T-cell Vaccine-induced Responses, Such as to Mycobacterial Lipids (CD1-restricted) and Metabolites (MR1-restricted).
timeFrame: Up to day 168
measure: Evaluate QFT-GIT and ESAT-6 Free IGRA Discordance and Conversion/Reversion Rate During the Course of the Trial.
timeFrame: Up to day 168
Other outcomes:
Locations:
city: Cape Town
country: South Africa
facility: Desmond Tutu HIV Foundation
Study officials:
affiliation: Desmond Tutu HIV Centre
name: Linda-Gail Bekker, MD
role: STUDY_CHAIR
affiliation: HVTN Core, FHCRC
name: Jim Kublin, MD
role: STUDY_CHAIR
References:
citation: Bekker LG, Dintwe O, Fiore-Gartland A, Middelkoop K, Hutter J, Williams A, Randhawa AK, Ruhwald M, Kromann I, Andersen PL, DiazGranados CA, Rutkowski KT, Tait D, Miner MD, Andersen-Nissen E, De Rosa SC, Seaton KE, Tomaras GD, McElrath MJ, Ginsberg A, Kublin JG; HVTN 602/Aeras A-042 Protocol Team. A phase 1b randomized study of the safety and immunological responses to vaccination with H4:IC31, H56:IC31, and BCG revaccination in Mycobacterium tuberculosis-uninfected adolescents in Cape Town, South Africa. EClinicalMedicine. 2020 Mar 18;21:100313. doi: 10.1016/j.eclinm.2020.100313. eCollection 2020 Apr.