Early Versus Late BCG Vaccination in HIV-1 Exposed Infants in Uganda in Uganda

A Randomised Controlled Trial in HIV-1 Exposed Ugandan Infants to Estimate Additional Benefits (Non-specific Effects) of BCG

BCG vaccination may have non-specific effects (NSE) i.e., additional benefits on childhood morbidity and mortality that are separate the vaccine's effect on the incidence of disseminated tuberculosis. Though the available literature is mostly from observational study designs, and is fraught with controversy, BCG vaccination at birth, in a high risk population of HIV exposed children, may protect infants against serious infections other than TB. Yet, other studies indicate that giving BCG later in infancy, when the immune system is more mature, may offer even greater protection. The appropriate timing of BCG vaccination could therefore be up for revision. This study will therefore compare BCG vaccination at birth with BCG vaccination at 14 weeks of age in HIV exposed (HE) babies.

Methods: This is an individually randomized clinical trial in 4,500 HIV exposed infants. The intervention is an intra-dermal administration of 0.05 ml of BCG vaccine within 24 hours of birth while the comparator will be an intra-dermal administration of 0.05ml of BCG vaccine at 14 weeks of age.

The main study outcomes include:

1. Severe illness in the first 14 weeks of life,
2. Innate and adaptive immune responses to mycobacterial, non-mycobacterial antigens and TLR-agonists
3. Severe illness in the first 14-52 weeks and 0-52 weeks of life.

The study will be carried in two health centers and one district hospital in Uganda.

Implications: A well-timed BCG vaccination could have important additional benefits in HE infants. This trial could inform the development of programmatically appropriate timing of BCG vaccination for HE infants.

Inclusion Criteria:

A baby born at a participating study clinic will be included if s/he:

1. has a mother with a positive HIV test (ELISA or rapid test)
2. is receiving peri-exposure prophylaxis as part of the standard/national guidelines in Uganda
3. has a mother that is of legal age for participation in clinical research studies in Uganda or is an emancipated minor
4. has a mother/caregiver that resides within the study area, is not intending to move out of the area in the next 4 months and is likely to be traceable for up to 12 months
5. has a mother/caregiver that gives informed consent to random assignment to either of the two trial arms
6. has a mother that has received antiretroviral therapy (ART) for at least 4 weeks

Exclusion Criteria:

A new-born child will be excluded if she/he has:

1. an identified serious congenital malformation(s)
2. severe illness requiring hospitalization
3. a birth weight < 2.0 kg
4. a mother participating in another clinical trial on the day of enrolment or a mother who will participate in another clinical trial within the next month.
5. a mother or other household member with symptoms and signs of tuberculosis on the day of enrolment
6. a severely ill mother with (a) condition(s) requiring hospitalization
7. a baby with an Apgar score at 5 minutes <7
8. a twin or triplet