Tuberculosis
Conditions
Keywords
disposable syringe jet injector (DSJI), DSJI, BCG, tuberculosis, intradermal delivery, South Africa
Brief summary
The study is designed to test the hypothesis that BCG administration via jet injector will produce a comparable immune response and that there will be no significant differences in safety or reactogenicity between BCG administration via jet injector and needle and syringe. The primary objectives of this study are to... 1. Compare the safety and reactogenicity of BCG administered intradermally by a jet injector device in adults and infants, to BCG administered intradermally by needle and syringe; 2. Compare the specific T cell immunity in neonates vaccinated with BCG via the jet injector device to infants vaccinated with BCG via needle and syringe.
Detailed description
A randomized, controlled, partially blinded clinical trial in 2 stages (adult stage, infant stage) will be applied at a single site. The first stage will include thirty (30) adult participants. The Data Safety Monitoring Board (DSMB) will evaluate the reactogenicity and safety data for all 30 adults up to day 28 after vaccination. Pending a favourable safety review by the DSMB, the second stage in sixty-six (66) newborn participants will commence. Potential adult and infant participants will be screened prior to enrolment to apply inclusion and exclusion criteria.Note that as the adult stage was a pilot, only results of the infant study are presented here. In each of the stages half of the study population (15 adults, 33 neonates) will receive BCG via conventional syringe and needle (standard of care administration technique), and half (15 adults, 33 neonates) will receive BCG via jet injector (investigational administration technique). A single and standard volume and dose of BCG will be administered per the package insert. Neonates will receive their BCG shortly after birth. The occurrence of injection site reactogenicity events and systemic adverse events will be compared between study groups in both adults and neonates. In the neonate stage, BCG and M.tb specific immunogenicity will also be compared between study groups. For the adult stage the vaccinator and participant will be unblinded to study arm allocation. For the infant stage, the vaccinator will be unblinded but the participant caregiver will be blinded. For both the adult and infant stages the follow-up team will be blinded to study arm allocation. The laboratory will be blinded to study arm allocation for the infant stage immunogenicity assays. The trial will be conducted at the field site of the South African Tuberculosis Vaccine Initiative (SATVI) in the Cape Winelands East district of the Western Cape of South Africa. Recruitment and vaccination of neonates will take place at 1 or more of the state public healthcare antenatal clinics and birthing units in the area. Recruitment and vaccination of adults, as well as follow-up of adults and the neonates/infants will take place on the SATVI field site premises, or on the premises of the public healthcare clinic. All study procedures, including vaccination, will be performed by SATVI study staff.
Interventions
DEVICEBioject ID Pen
Participants in this arm will receive a standard dose of BCG via the Bioject ID needle-free jet injector device (investigational administration technique).
DEVICENeedle and syringe
Participants in this arm will receive a standard dose of BCG via syringe and needle by the Mantoux technique (standard of care administration technique).
Sponsors
World Health Organization
University of Cape Town
PATH
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
PREVENTION
Masking
SINGLE (Investigator)
Eligibility
Sex/Gender
ALL
Age
No minimum to 50 Years
Healthy volunteers
Yes
Inclusion criteria
Adult stage * Inclusion criteria: 1. Male or female, age 18 to 50 years. 2. Written informed consent, including permission for access to medical records and an HIV test. 3. Available for study follow up and display a willingness and capacity to comply to study procedures. 4. In good general health, as assessed by medical history and a focused physical examination. 5. HIV test (rapid test, ELISA \[enzyme-linked immunosorbent assay\], or PCR \[polymerase chain reaction\]) negative. 6. Quantiferon®-TB Gold (Cellestis) test for latent TB infection negative within 2 weeks of enrolment. 7. BCG vaccination at birth as confirmed by history or the presence of a BCG scar. 8. In the case of female participants, a negative urine or serum pregnancy test at enrolment, and not pregnant or lactating. Evidence of contraception is not required since BCG is not contra-indicated in pregnancy. *
Exclusion criteria
1. A history or evidence of a significant or chronic medical condition or disease. 2. Skin condition, bruising or birth mark at the intended injection site. 3. History of previous active tuberculosis (TB) disease or current active TB disease. 4. History of a household contact with active TB disease who has received less than 2 months treatment. Neonate Stage * Inclusion criteria: 1. Male or female neonates within 48 hours of birth. 2. Written informed consent, including permission to access medical records and results of antenatal HIV tests. 3. Infant participants and their caregivers available for study follow-up and display the willingness and capacity to comply with study procedures. 4. Neonates must be in good general health as assessed by medical history during pregnancy and delivery, and focused physical examination. 5. Birth weight more than or equal to 2500 grams. 6. Apgar score at 5 minutes more than or equal to 7. 7. A maternal HIV test result (rapid test, ELISA or PCR) taken during pregnancy must be available, documented and negative. *
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Injection Site Adverse Events (Following Injection) | 14 weeks | Injection site adverse events including redness, swelling, induration, tenderness, ulceration, fluctuation , drainage, laceration, bruising, and scarring will be monitored for up to fourteen weeks following vaccination. |
| Systemic Adverse Events | 14 weeks | Systemic adverse events, solicited and unsolicited, including symptoms of lethargy, disrupted feeding patterns, fever, lymphadenopathy, rash, or any other physical abnormalities will be monitored for up to fourteen weeks following vaccination. |
| Short Term Whole Blood Intracellular Cytokine Staining Assay for BCG-specific CD4 (Cluster of Differentiation 4) T-cells | 10 weeks post-vaccination | BCG-specific immunogenicity was tested in infants only, since they are the target study population and BCG immunogenicity in adults is known to be different from that in infants. Utilizing a whole-blood intracellular cytokine staining (ICS) assay, we analyzed cytokine co-expression patterns by BCG-specific CD4 and CD8 T-cells. Briefly, 0.5 ml heparinized whole blood was incubated for 12 hours with BCG, no antigen or phytohemagglutinin (PHA) in the presence of anti-CD28 and anti-CD49d, with the last 5 hours including Brefeldin A prior to treating with BD FACS™ Lysing Solution and cryopreservation. Cells were batch-thawed, permeabilized with BD Perm/Wash™ buffer, and stained with fluorescent antibodies. At least 120,000 CD3+CD4+ T-cells were acquired for the no-antigen and BCG samples on a BD™ LSR II flow cytometer. |
| Short Term Whole Blood Intracellular Cytokine Staining Assay for BCG-specific CD4 T-cells | 14 weeks post-vaccination | BCG-specific immunogenicity was tested in infants only, since they are the target study population and BCG immunogenicity in adults is known to be different from that in infants. Utilizing a whole-blood intracellular cytokine staining (ICS) assay, we analyzed cytokine co-expression patterns by BCG-specific CD4 and CD8 T-cells. Briefly, 0.5 ml heparinized whole blood was incubated for 12 hours with BCG, no antigen or phytohemagglutinin (PHA) in the presence of anti-CD28 and anti-CD49d, with the last 5 hours including Brefeldin A prior to treating with BD FACS™ Lysing Solution and cryopreservation. Cells were batch-thawed, permeabilized with BD Perm/Wash™ buffer, and stained with fluorescent antibodies. At least 120,000 CD3+CD4+ T-cells were acquired for the no-antigen and BCG samples on a BD™ LSR II flow cytometer. |
Other
| Measure | Time frame |
|---|---|
| Diameter of Skin Bleb | Immediately post-vaccination |
| Fluid Leakage on Skin at Injection Site | Immediately post-vaccination |
Countries
South Africa
Participant flow
Recruitment details
Infants: 131 consents obtained; 50 screening failures, no participation refusals, and 66 enrolled at birth. 15 infants were consented, screened, and eligible for participation but were not enrolled because the enrollment target had been reached. Adults: 95 consents obtained; 63 screening failures, 2 participation refusals, and 30 enrolled.
Participants by arm
| Arm | Count |
|---|---|
| INFANTS: Bioject Intradermal (ID) Pen Intradermal administration of BCG vaccine via the Bioject ID Pen.
Bioject ID Pen | 33 |
| INFANTS: Needle and Syringe Intradermal administration of BCG vaccine via needle and syringe.
Needle and syringe | 33 |
| ADULTS: Bioject Intradermal (ID) Pen Intradermal administration of BCG vaccine via the Bioject ID Pen.
Bioject ID Pen | 15 |
| ADULTS: Needle and Syringe Intradermal administration of BCG vaccine via needle and syringe.
Needle and syringe | 15 |
| Total | 96 |
Baseline characteristics
| Characteristic | INFANTS: Bioject Intradermal (ID) Pen | INFANTS: Needle and Syringe | ADULTS: Bioject Intradermal (ID) Pen | ADULTS: Needle and Syringe | Total |
|---|---|---|---|---|---|
| Age, Categorical <=18 years | 33 Participants | 33 Participants | 0 Participants | 0 Participants | 66 Participants |
| Age, Categorical >=65 years | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Age, Categorical Between 18 and 65 years | 0 Participants | 0 Participants | 15 Participants | 15 Participants | 30 Participants |
| Gender Female | 18 Participants | 16 Participants | 13 Participants | 10 Participants | 57 Participants |
| Gender Male | 15 Participants | 17 Participants | 2 Participants | 5 Participants | 39 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk | EG003 affected / at risk |
|---|---|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — | — / — | — / — |
| other Total, other adverse events | 30 / 33 | 27 / 33 | 15 / 15 | 15 / 15 |
| serious Total, serious adverse events | 1 / 33 | 4 / 33 | 0 / 15 | 0 / 15 |
Outcome results
Primary
Injection Site Adverse Events (Following Injection)
Injection site adverse events including redness, swelling, induration, tenderness, ulceration, fluctuation , drainage, laceration, bruising, and scarring will be monitored for up to fourteen weeks following vaccination.
Time frame: 14 weeks
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| INFANTS: Bioject Intradermal (ID) Pen | Injection Site Adverse Events (Following Injection) | 138 Adverse events |
| INFANTS: Needle and Syringe | Injection Site Adverse Events (Following Injection) | 141 Adverse events |
| ADULTS: Bioject Intradermal (ID) Pen | Injection Site Adverse Events (Following Injection) | 126 Adverse events |
| ADULTS: Needle and Syringe | Injection Site Adverse Events (Following Injection) | 146 Adverse events |
Comparison: Comparison of all adverse events (both injection site and systemic AEs).p-value: 0.475Fisher Exact
Comparison: Comparison of all adverse events (both injection site and systemic AEs).p-value: 0.187Fisher Exact
Primary
Short Term Whole Blood Intracellular Cytokine Staining Assay for BCG-specific CD4 (Cluster of Differentiation 4) T-cells
BCG-specific immunogenicity was tested in infants only, since they are the target study population and BCG immunogenicity in adults is known to be different from that in infants. Utilizing a whole-blood intracellular cytokine staining (ICS) assay, we analyzed cytokine co-expression patterns by BCG-specific CD4 and CD8 T-cells. Briefly, 0.5 ml heparinized whole blood was incubated for 12 hours with BCG, no antigen or phytohemagglutinin (PHA) in the presence of anti-CD28 and anti-CD49d, with the last 5 hours including Brefeldin A prior to treating with BD FACS™ Lysing Solution and cryopreservation. Cells were batch-thawed, permeabilized with BD Perm/Wash™ buffer, and stained with fluorescent antibodies. At least 120,000 CD3+CD4+ T-cells were acquired for the no-antigen and BCG samples on a BD™ LSR II flow cytometer.
Time frame: 10 weeks post-vaccination
Population: Due to failed phlebotomy on 5 infants, results were not available for 2 participants in the Bioject ID Pen arm and for 3 participants in the Needle and syringe arm.~Immunogenicity was not measured for adults in the study.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| INFANTS: Bioject Intradermal (ID) Pen | Short Term Whole Blood Intracellular Cytokine Staining Assay for BCG-specific CD4 (Cluster of Differentiation 4) T-cells | 0.664 percentage responding to cytokines |
| INFANTS: Needle and Syringe | Short Term Whole Blood Intracellular Cytokine Staining Assay for BCG-specific CD4 (Cluster of Differentiation 4) T-cells | 0.485 percentage responding to cytokines |
p-value: 0.205Wilcoxon (Mann-Whitney)
Primary
Short Term Whole Blood Intracellular Cytokine Staining Assay for BCG-specific CD4 T-cells
BCG-specific immunogenicity was tested in infants only, since they are the target study population and BCG immunogenicity in adults is known to be different from that in infants. Utilizing a whole-blood intracellular cytokine staining (ICS) assay, we analyzed cytokine co-expression patterns by BCG-specific CD4 and CD8 T-cells. Briefly, 0.5 ml heparinized whole blood was incubated for 12 hours with BCG, no antigen or phytohemagglutinin (PHA) in the presence of anti-CD28 and anti-CD49d, with the last 5 hours including Brefeldin A prior to treating with BD FACS™ Lysing Solution and cryopreservation. Cells were batch-thawed, permeabilized with BD Perm/Wash™ buffer, and stained with fluorescent antibodies. At least 120,000 CD3+CD4+ T-cells were acquired for the no-antigen and BCG samples on a BD™ LSR II flow cytometer.
Time frame: 14 weeks post-vaccination
Population: Due to failed phlebotomy on 5 infants, results were not available for 2 participants in the Bioject ID Pen arm and for 3 participants in the Needle and syringe arm.~Immunogenicity was not measured for adults in the study.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| INFANTS: Bioject Intradermal (ID) Pen | Short Term Whole Blood Intracellular Cytokine Staining Assay for BCG-specific CD4 T-cells | 0.386 percentage responding to cytokines |
| INFANTS: Needle and Syringe | Short Term Whole Blood Intracellular Cytokine Staining Assay for BCG-specific CD4 T-cells | 0.325 percentage responding to cytokines |
p-value: 0.325Wilcoxon (Mann-Whitney)
Primary
Systemic Adverse Events
Systemic adverse events, solicited and unsolicited, including symptoms of lethargy, disrupted feeding patterns, fever, lymphadenopathy, rash, or any other physical abnormalities will be monitored for up to fourteen weeks following vaccination.
Time frame: 14 weeks
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| INFANTS: Bioject Intradermal (ID) Pen | Systemic Adverse Events | 20 Adverse events |
| INFANTS: Needle and Syringe | Systemic Adverse Events | 20 Adverse events |
| ADULTS: Bioject Intradermal (ID) Pen | Systemic Adverse Events | 18 Adverse events |
| ADULTS: Needle and Syringe | Systemic Adverse Events | 27 Adverse events |
Other Pre-specified
Diameter of Skin Bleb
Time frame: Immediately post-vaccination
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| INFANTS: Bioject Intradermal (ID) Pen | Diameter of Skin Bleb | No wheal | 0 participants |
| INFANTS: Bioject Intradermal (ID) Pen | Diameter of Skin Bleb | Wheal > 0 mm | 33 participants |
| INFANTS: Needle and Syringe | Diameter of Skin Bleb | Wheal > 0 mm | 21 participants |
| INFANTS: Needle and Syringe | Diameter of Skin Bleb | No wheal | 12 participants |
| ADULTS: Bioject Intradermal (ID) Pen | Diameter of Skin Bleb | No wheal | 0 participants |
| ADULTS: Bioject Intradermal (ID) Pen | Diameter of Skin Bleb | Wheal > 0 mm | 15 participants |
| ADULTS: Needle and Syringe | Diameter of Skin Bleb | No wheal | 0 participants |
| ADULTS: Needle and Syringe | Diameter of Skin Bleb | Wheal > 0 mm | 15 participants |
p-value: 0.001Kruskal-Wallis
p-value: 0.13Kruskal-Wallis
Other Pre-specified
Fluid Leakage on Skin at Injection Site
Time frame: Immediately post-vaccination
Population: For adults, the skin fluid deposition was estimated and categorized by the vaccinator (e.g., no wetness, damp skin, flow on skin, spray in air); for infants, volume was measured objectively and categorized by the filter paper technique (units in µl).
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| INFANTS: Bioject Intradermal (ID) Pen | Fluid Leakage on Skin at Injection Site | ≤ 2.5 µl | 5 participants |
| INFANTS: Bioject Intradermal (ID) Pen | Fluid Leakage on Skin at Injection Site | > 5 µl to ≤ 10 µl | 14 participants |
| INFANTS: Bioject Intradermal (ID) Pen | Fluid Leakage on Skin at Injection Site | Flow on skin | 0 participants |
| INFANTS: Bioject Intradermal (ID) Pen | Fluid Leakage on Skin at Injection Site | > 10 µl to ≤ 20 µl | 2 participants |
| INFANTS: Bioject Intradermal (ID) Pen | Fluid Leakage on Skin at Injection Site | > 2.5 µl to ≤ 5 µl | 12 participants |
| INFANTS: Bioject Intradermal (ID) Pen | Fluid Leakage on Skin at Injection Site | Spray in air | 0 participants |
| INFANTS: Bioject Intradermal (ID) Pen | Fluid Leakage on Skin at Injection Site | No wetness | 0 participants |
| INFANTS: Bioject Intradermal (ID) Pen | Fluid Leakage on Skin at Injection Site | Damp skin | 0 participants |
| INFANTS: Bioject Intradermal (ID) Pen | Fluid Leakage on Skin at Injection Site | > 20 µl | 0 participants |
| INFANTS: Needle and Syringe | Fluid Leakage on Skin at Injection Site | ≤ 2.5 µl | 28 participants |
| INFANTS: Needle and Syringe | Fluid Leakage on Skin at Injection Site | Flow on skin | 0 participants |
| INFANTS: Needle and Syringe | Fluid Leakage on Skin at Injection Site | > 2.5 µl to ≤ 5 µl | 2 participants |
| INFANTS: Needle and Syringe | Fluid Leakage on Skin at Injection Site | Spray in air | 0 participants |
| INFANTS: Needle and Syringe | Fluid Leakage on Skin at Injection Site | > 5 µl to ≤ 10 µl | 1 participants |
| INFANTS: Needle and Syringe | Fluid Leakage on Skin at Injection Site | > 10 µl to ≤ 20 µl | 2 participants |
| INFANTS: Needle and Syringe | Fluid Leakage on Skin at Injection Site | > 20 µl | 0 participants |
| INFANTS: Needle and Syringe | Fluid Leakage on Skin at Injection Site | No wetness | 0 participants |
| INFANTS: Needle and Syringe | Fluid Leakage on Skin at Injection Site | Damp skin | 0 participants |
| ADULTS: Bioject Intradermal (ID) Pen | Fluid Leakage on Skin at Injection Site | > 2.5 µl to ≤ 5 µl | 0 participants |
| ADULTS: Bioject Intradermal (ID) Pen | Fluid Leakage on Skin at Injection Site | No wetness | 0 participants |
| ADULTS: Bioject Intradermal (ID) Pen | Fluid Leakage on Skin at Injection Site | > 20 µl | 0 participants |
| ADULTS: Bioject Intradermal (ID) Pen | Fluid Leakage on Skin at Injection Site | Spray in air | 0 participants |
| ADULTS: Bioject Intradermal (ID) Pen | Fluid Leakage on Skin at Injection Site | Flow on skin | 0 participants |
| ADULTS: Bioject Intradermal (ID) Pen | Fluid Leakage on Skin at Injection Site | > 5 µl to ≤ 10 µl | 0 participants |
| ADULTS: Bioject Intradermal (ID) Pen | Fluid Leakage on Skin at Injection Site | Damp skin | 15 participants |
| ADULTS: Bioject Intradermal (ID) Pen | Fluid Leakage on Skin at Injection Site | > 10 µl to ≤ 20 µl | 0 participants |
| ADULTS: Bioject Intradermal (ID) Pen | Fluid Leakage on Skin at Injection Site | ≤ 2.5 µl | 0 participants |
| ADULTS: Needle and Syringe | Fluid Leakage on Skin at Injection Site | Spray in air | 0 participants |
| ADULTS: Needle and Syringe | Fluid Leakage on Skin at Injection Site | ≤ 2.5 µl | 0 participants |
| ADULTS: Needle and Syringe | Fluid Leakage on Skin at Injection Site | > 2.5 µl to ≤ 5 µl | 0 participants |
| ADULTS: Needle and Syringe | Fluid Leakage on Skin at Injection Site | > 5 µl to ≤ 10 µl | 0 participants |
| ADULTS: Needle and Syringe | Fluid Leakage on Skin at Injection Site | > 10 µl to ≤ 20 µl | 0 participants |
| ADULTS: Needle and Syringe | Fluid Leakage on Skin at Injection Site | > 20 µl | 0 participants |
| ADULTS: Needle and Syringe | Fluid Leakage on Skin at Injection Site | Damp skin | 8 participants |
| ADULTS: Needle and Syringe | Fluid Leakage on Skin at Injection Site | Flow on skin | 0 participants |
| ADULTS: Needle and Syringe | Fluid Leakage on Skin at Injection Site | No wetness | 7 participants |
p-value: 0.001Chi-squared
p-value: 0.003Chi-squared