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.

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.

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.

• Exclusion criteria:

  1. Participant must not have received BCG vaccination prior to enrolment.
  2. Significant antenatal or intrapartum complications that may affect the health of the neonate.
  3. Skin condition, bruising or birth mark at the intended injection site.
  4. Maternal HIV test (rapid test, ELISA or PCR) not performed antenatally, HIV test results not available, or HIV test result known positive.
  5. Maternal history of current active TB, or other household contact with known active TB disease who has received less than 2 months of treatment.

Infants (n=66) and Adults (n=30)

14 weeks for infants, 12 weeks for adults

Infants attended study visits 4, 10, and 14 weeks after vaccination, and parents were contacted by telephone 1, 7, and 14 days after vaccination. Adults were seen 1, 2, 4, and 12 weeks after vaccination.