Bacillus Calmette Guerin (BCG) vaccination/revaccination for prevention of Mycobacterium tuberculosis infection in healthcare students entering clinical training: A randomised placebo controlled proof of principle trial (PoP BCG trial)

INTERVENTION: BCG vaccine: a freeze‐dried vaccine, which contains live attenuated of Mycobacterium bovis. We will use BCG vaccine manufactured by PT Biofarma Indonesia derived from the Pasteur 1173P strain. Each ampoule (20 doses) of vaccine contains: Live attenuated Bacillus Calmette‐Guerin 1.5 mg semi‐dried basil (1.5‐6 million culturable particles), monosodium glutamate 7.5 mg. Each 1 mL of diluent consists of: Sodium Chloride 9 mg, Water for injection adds 1 mL. Dosing and administration BCG vaccination: 1 adult dose (0.1 mL) of vaccine (which reconstituted by 4 mL diluent) is administered intradermal with a 22‐gauge needle. CONDITION: Infection ‐ Studies of infection and infectious agents Infection;tuberculosis; ; Infection ; tuberculosis PRIMARY OUTCOME: Acceptability of the intervention: the proportion of participants who consent and accepted to be given the intervention (BCG vaccine or placebo) over the total number of eligible participants in the study.; [Baseline ‐ Randomisation day] Adverse events: the proportion of participants who experience any adverse events. Adverse event outcomes will include solicited adverse events (AEs) reported through 7 days after vaccination and unsolicited adverse events reported through one month after vaccination, injection site assessments performed at day 0 post injection, 7 days, and after one month, other AEs reported until end of study. ; ; Adverse events will be reported on the adverse event case report form (CRF) using a recognised medical term or diagnosis that accurately reflect the event. Adverse event evaluations will be reviewed by the PI or by a designated medically qualifier practitioner. Adverse event CRF pages are to be completed by designated study team. The onset and resolution dates of the event and action taken in response to the event will be documented. All adverse events will be followed until resolution is demonstrated. The resolution date will be recorded on the CRF as the last date on which the subject experienced the adverse event. If an adverse event resolution date is uncertain the PI or designee should estimate the completion date based on medical judgment and interview of the subject. [Adverse event will be assessed for each participant until 12 months post‐vaccination. ] Completeness of the study: the proportion of participants who complete follow‐up, including all tests. [12 months] ; The primary readout for immune cell function will be cytokine production of peripheral blood mononuclear cell (PBMCs) in response to BCG, M. tuberculosis and a range of unrelated microbial stimuli; the increase of ex‐vivo monocyte‐derived and lymphocyte‐derived pro‐ inflammatory cytokine production capacity following BCG vaccination/revaccination will be used as an established marker of trained immunity. ; ; [at baseline, 1 month, and 3 months ] INCLUSION CRITERIA: 1. Medical or nursing students who start their clinical training at Hasan Sadikin Hospital 2. Tested IGRA negative at screening 3. Tested HIV negative at screening 4. Completed the written informed consent SECONDARY OUTCOME: Changes in DNA methylation of monocytes associated with BCG vaccination/revaccination: DNA methylation of monocytes (using whole blood) will be measured by reduced‐representation bisulphite (RRBS) at baseline and 3 months. This will be an exploratory analysis. [baseline and 3 months] Epigenetic changes associated with BCG vaccination/revaccination and immunophenotype of innate cells. Genetic variation will be assessed by a genome‐wide SNP array from Illumina. This would be an exploratory outcome.[at baseline, 1 month, and 3 months] IGRA test conversion: the key endpoint will be cumulative IGRA test conversion (using QuantiFERON‐TB Gold Plus or QFT‐Plus), defined as IGRA test conversion at any time point during the study (at 3, 6, 9 or 12 months). IGRA test conversion will be defined as a change from a negative to a positive test plus a minimum 30% increase in TB1 minus Nil or TB2 minus Nil over the baseline value [Veerapathran et al.]. Secondarily, we will assess persistent IGRA conversion defined as at least two consecutive IGRA tests over follow‐up. Exploratory analyses will consider various combinations of IGRA test results across the four follow‐up points. A sensitivity analysis will re‐analyse the data based on a definition of IGRA test conversion that simply requires a change from a negative to a positive test.[3, 6, 9 and 12 months] Induction of trained immunity (only assessed in 100 of 150 total participants):