Dose-Escalation Study to Evaluate the Safety and Immunogenicity of MTBVAC Vaccine in Comparison With BCG Vaccine.

Study Overview
=================
Brief Summary
-----------------
The purpose of this study is to test the safety and immunogenicity of MTBVAC as a potential substitute for BCG vaccination. BCG vaccination has indeed demonstrated its major limitation in inducing protection against tuberculosis (TB). Novel vaccines are essential to fight against the current world epidemics in tuberculosis and resistance to anti-TB drugs.

Detailed Description
-----------------
A randomized, double-blind, controlled Phase I study conducted at CHUV, Lausanne, Switzerland, to compare MTBVAC to licensed BCG in healthy, PPD-negative adult male and female volunteers. The study involves random allocation of up to 36 subjects (4 vaccine groups of 9 volunteers fulfilling the inclusion criteria) to MTBVAC (tested at three separate doses) or standard dose BCG (on a 3 verum : 1control basis) in a dose-escalation manner to one of three cohorts. Each cohort includes 9 subjects set to receive MTBVAC lowest dose 5x10E03, or MTBVAC intermediate dose 5x10E04, or high dose 5x10E05 colony forming units (CFU) in 0.1 mL and 3 subjects set to receive standard dose BCG (5x10E05 CFU in 0.1 mL). A single intradermal injection is given in the non-dominant arm of each volunteer starting with the lowest MTBVAC dose. Each MTBVAC vaccine dose is administered staggered by cohort, starting with the cohort with the lowest MTBVAC dose level. After at least 35 days of follow-up within each cohort a safety review and evaluation by Independent Data Safety Monitoring Board provides go/no-go for vaccination of the subsequent cohorts if no safety issues as defined by preset stopping rules.

Official Title
-----------------
Phase I Double Blind, Randomized, Controlled, Dose-Escalation Study to Evaluate the Safety and Immunogenicity of MTBVAC in Comparison With BCG in Elispot TB(ESAT-6, CFP10, PPD)- and HIV- Negative Volunteers

Conditions
-----------------
Tuberculosis, Healthy

Intervention / Treatment
-----------------
* Biological: MTBVAC live vaccine
* Biological: Commercially available BCG live vaccine


Participation Criteria
=================
Eligibility Criteria
-----------------
Inclusion Criteria: Subjects who the Investigator believes that they can and will comply with the requirements of the protocol Subjects who have no evidence of exposition to BCG as demonstrated by a ELISPOT PPD assay along with no history of BCG vaccination and no BCG scar A male or female between, and including, 18 and 45 years of age at the time of the vaccination. Written informed consent obtained from the subject prior to any study procedure. If the subject is female, she must be of non-childbearing potential, or if she is of childbearing potential, she must practice adequate contraception Clinically acceptable laboratory values for blood tests. Seronegative for human immunodeficiency virus 1 and -2 (HIV-1/2) antibodies, p24 antigen, hepatitis B surface antigen (HBsAg), and hepatitis C virus (HCV) antibodies. No evidence of pulmonary pathology as confirmed by chest X-ray. No history of extrapulmonary TB. No history of previous contact with M. tuberculosis (latent tuberculosis) as demonstrated by a negative ELISPOT Tb (ESAT-6, CFP10) assay. Exclusion Criteria: History of allergic reactions (significant IgE-mediated events) or anaphylaxis to previous immunisations (any vaccine). History of allergic disease or reactions History of previous administration of experimental Mycobacterium tuberculosis vaccines. Use of any investigational or non-registered product (drug or vaccine) in another experimental protocol other than the study vaccines within 30 days preceding the vaccination, or planned use during the study period. Any chronic drug therapy to be continued during the study period. Chronic administration of immunosuppressors or other immune-modifying drugs. Administration of any immunoglobulins, any immunotherapy and/or any blood products within the three months preceding the vaccination, or planned administrations during the study period. Any confirmed or suspected immunosuppressive or immunodeficient condition (including HIV) based on medical history and physical examination. Any condition or history of any acute or chronic illness or medication which, in the opinion of the Investigator, may interfere with the evaluation of the study objectives. A family history of congenital or hereditary immunodeficiency. A stay of more than 2 months in a highly endemic area (e.g. Eastern Europe (Romania, Bulgaria) and low-income countries) within 6 months prior to the screening visit or travel of more than 2 months foreseen in an area of high endemicity after the enrolment into the study. History of any neurologic disorders or seizures. History of chronic alcohol consumption and/or drug abuse. Major congenital defects. Pregnant or lactating female. Female planning to become pregnant or planning to discontinue contraceptive precautions.

Ages Eligible for Study
-----------------
Minimum Age: 18 Years
Maximum Age: 45 Years

Sexes Eligible for Study
-----------------
All

Accepts Healthy Volunteers
-----------------
Accepts Healthy Volunteers

Study Plan
=================
How is the study designed?
-----------------

Design Details

Primary Purpose: Prevention
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: MTBVAC group 1<br>Intervention: MTBVAC live vaccine (low dose 5 x 10E03 CFU/0.1mL) | Biological: MTBVAC live vaccine<br>* Live-attenuated Mycobacterium tuberculosis vaccine<br>|
| Experimental: MTBVAC Group 2<br>Intervention: MTBVAC live vaccine (middle dose 5 x 10E04 CFU/0.1mL) | Biological: MTBVAC live vaccine<br>* Live-attenuated Mycobacterium tuberculosis vaccine<br>|
| Experimental: MTBVAC Group 3<br>Intervention: MTBVAC live vaccine (high dose 5 x 10E05 CFU/0.1mL) | Biological: MTBVAC live vaccine<br>* Live-attenuated Mycobacterium tuberculosis vaccine<br>|
| Active Comparator: BCG Control Group<br>Intervention: Commercially available BCG live vaccine (dose 5 x 10E05 CFU/0.1mL) | Biological: Commercially available BCG live vaccine<br>* Live-attenuated Mycobacterium bovis vaccine<br>|

What is the study measuring?
-----------------
Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of Participants With Adverse Events up to 210 Days After Vaccination | Safety and reactogenicity for all subjects as determined by: Occurrence of solicited symptoms during the 7-day follow-up period following vaccination and occurrence of unsolicited symptoms during the 210-day follow-up period following vaccination. Occurrence of grade 3 vaccine related local and general symptoms during the 210-day follow-up period following vaccination and occurrence of serious adverse events throughout the entire study period. Haematological and biochemical safety test levels prior and after vaccination | 7 months follow up | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of Participants With Three-cytokine-positive CD4+ T-cell Response | Measure of the kinetics of CD4+ T-cell responses to MTBVAC or BCG vaccination by tracking the expression of IFNγ, TNFα and IL-2 upon stimulation with live MTBVAC or BCG | Day 28 |