Dose-Escalation Study on Safety and Immunogenicity of VPM1002 in Comparison to BCG in Healthy Volunteers in South Africa

Phase Ib Open Label, Randomized, Controlled, Dose-Escalation Study to Evaluate Safety and Immunogenicity of VPM1002 in Comparison With BCG in Healthy Volunteers in South Africa

Goal of VPM is the development of a recombinant urease C-deficient listeriolysin expressing BCG vaccine strain (VPM1002) as a safe, well tolerated and efficacious vaccine against tuberculosis (TB) for residents in endemic areas and persons at risk in non-endemic areas. The new vaccine should be at least as potent as the current strain and should be safer than BCG (Kaufmann, 2007a; Grode et al., 2005). The vaccine is formulated as live lyophilised bacteria to be re-suspended before intradermal injection. The preceding clinical trial in 80 volunteers in Germany indicated immunogenicity and safety being sufficient for proceeding with the clinical development. Hence, the current study is commenced in South Africa, a country highly endemic for tuberculosis.

24 volunteers were randomly allocated to 4 groups each with 6 adult healthy volunteers.

Study Overview

• Status: Completed
• Conditions: Tuberculosis
• Intervention / Treatment: Biological: VPM1002 live vaccine; Biological: commercially available live vaccine BCG

• Study Type: Interventional
• Enrollment (Actual): 24
• Phase: Phase 1

Contacts and Locations

Study Locations

• South Africa
  • Bloemfontein, South Africa, 9301
    • Farmovs-Parexel

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 45 years (ADULT)
• Accepts Healthy Volunteers: Yes
• Genders Eligible for Study: All

Description

Inclusion Criteria:

• Adult volunteers 18 to 45 years of age
• Volunteers must use acceptable contraception and avoid pregnancy for the duration of the study (6 months)
• Healthy (medical history, physical examination, vital signs, ECG and laboratory tests at screening)
• No signs of active or latent tuberculosis infection
• BMI of 19 - 33 kg/m2
• Subjects must be able and willing to comply with the study protocol, available and willing to complete all study measurements and have signed an Informed Consent form approved by the Ethics Committee.
• Reachable by phone during the whole study period (approximately 6 months).
• Negative test for HIV1 and HIV2, hepatitis B surface antigen and antibody to hepatitis C virus.
• No anamnestic evidence for a primary or secondary immunodeficiency.
• No skin eczema lesion at the intended injection site.
• No anamnestic predisposition for scarring badly or for keloid formation.
• No other vaccination during eight weeks before the current study.
• No participation in another clinical trial within 3 months before study vaccination and the 6 months of the current study.
• No prior participation in a TB vaccine trial.
• Able and willing to abstain from strenuous physical exercise 24 hours before screening examination, and 24 hours before vaccination

Exclusion Criteria:

• History of prior TB disease
• History of anaphylaxis or severe allergic reactions
• Known allergies to any component of the investigational or reference product or known history of severe skin reaction against the Tuberculin test
• Presence of any person in the household of the volunteer with active tuberculosis disease
• Tuberculin-PPD-in-vivo-test equal or more than 10 mm before baseline
• systemic disorders which could interfere with the interpretation of the study results or compromise the health of the volunteers
• BCG-vaccination during 10 years before study vaccination
• Acute fever or fever in the last 7 days before dosing
• Any malignant condition
• Concomitant treatment with medication that may affect immune function during 3 months before study vaccination and the 6 months of current study. No oral antibiotics during the 14 days before study vaccination and no injectable antibiotics during the 28 days prior to vaccination.
• Treatment with blood products in the past 6 months up to end of study.
• Any clinically significant laboratory abnormalities on screened blood samples.
• A history of drug or alcohol abuse
• Positive test for drugs of abuse on urine testing at screening
• Blood donation for non study-related purposes within 3 months before and during the entire duration of the study
• Clinically relevant result from sonographic liver imaging
• Professional or regular contact with live animals for food production

Study Plan

How is the study designed?

Design Details

• Primary Purpose: PREVENTION
• Allocation: RANDOMIZED
• Interventional Model: PARALLEL
• Masking: NONE

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
EXPERIMENTAL: VPM1002 in three dosages	Biological: VPM1002 live vaccine
ACTIVE_COMPARATOR: BCG	Biological: commercially available live vaccine BCG

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Time Frame
Safety: physical examination, vital signs, electrocardiogram, liver sonography, laboratory safety parameters, tolerability, recording of concomitant medication and adverse events	baseline, days 2, 7, 14, 28, 56, and month 6

Secondary Outcome Measures

Outcome Measure	Time Frame
Immunogenicity: Interferon-gamma-ELISA (IFN-g-ELISA) in supernatants of peripheral blood mononuclear cells (PBMC) restimulated with tuberculin (PPD from Staten Serum Institute, Denmark)	baseline, days 14, 28, 56 and month 6
Immunogenicity: ELISPOT for the number of IFN-g-secreting PBMC after restimulation with PPD	baseline, days 14, 28, 56 and month 6
Immunogenicity: Whole Blood Assays (WBA): IFN-g-ELISA of supernatants of whole blood restimulated with PPD	baseline, days 14, 28, 56 and month 6
Immunogenicity: Intracellular Cytokine Staining (ICS) for IFN-g, TNF-a and IL-2 in CD4+ and CD8+ lymphocytes upon stimulation with PPD	baseline, days 14, 28, 56 and month 6
Immunogenicity: ICS with other triple combinations of markers in CD4+ and CD8+ lymphocytes upon stimulation with PPD	baseline, days 14, 28, 56 and month 6
Immunogenicity: Antigen-85B (Ag85B) and BCG as recall antigens for ELISA, ELISPOT, WBA and ICS	baseline, days 14, 28, 56 and month 6
Immunogenicity: serum antibodies against PPD or Ag85B	baseline, days 14, 28, 56 and month 6

Collaborators and Investigators

• Sponsor: Vakzine Projekt Management GmbH
• Collaborators: University of Stellenbosch; Farmovs-Parexel Bloemfontein, Republic of South Africa (Clinical Site); Triclinium Johannesburg, RSA (Monitoring and Overall Management of the study); HJ-CTC George, RSA (Statistics & Report)
• Investigators: Principal Investigator: Mada Ferreira, MD, Farmovs-Parexel, Bloemfontein, RSA

Study record dates

Study Major Dates

• Study Start: April 1, 2010
• Primary Completion (ACTUAL): December 1, 2010
• Study Completion (ACTUAL): March 1, 2011

Study Registration Dates

• First Submitted: April 27, 2010
• First Submitted That Met QC Criteria: April 28, 2010
• First Posted (ESTIMATE): April 29, 2010

Study Record Updates

• Last Update Posted (ESTIMATE): November 21, 2011
• Last Update Submitted That Met QC Criteria: November 18, 2011
• Last Verified: November 1, 2011

More Information

Terms related to this study

• Keywords: Vaccine; Tuberculosis; rBCG; Live Vaccine
• Additional Relevant MeSH Terms: Infections; Bacterial Infections; Bacterial Infections and Mycoses; Gram-Positive Bacterial Infections; Actinomycetales Infections; Mycobacterium Infections; Tuberculosis; Physiological Effects of Drugs; Immunologic Factors; Vaccines
• Other Study ID Numbers: VPM1002-ZA-1.10TB; DOH-27-0210-3083 (OTHER: NHREC (National Health Researh Ethics Council) South Africa)