A randomised, placebo-controlled study to assess whether antibiotic-mediated disruption of the gut microbiota impairs BCG-induced specific and non-specific immunity in young, healthy adults: protocol for the Antibiotics and Vaccine Immune Responses Study (AVIRS)

Introduction The Bacille Calmette-Guérin (BCG) vaccine protects against severe tuberculosis in children but can also induce non-specific effects including protection against unrelated infections. For reasons that remain unclear, BCG vaccine responses vary widely between individuals, age groups and geographic regions. Emerging evidence suggests the gut microbiota influences vaccine responses but its role in modulating BCG-induced specific and non-specific immunity in humans is unknown.Methods and analysis This multiarm, randomised, placebo-controlled experimental medicine study will determine whether depletion of the gut microbiota before vaccination impairs BCG-induced specific and non-specific immunity. We plan to randomise up to 348 healthy, BCG-naïve adults (18–35 years) at a 1:1:1:1 ratio to receive 3 days of oral vancomycin and neomycin (antibiotics group) or no antibiotics (comparator group) prior to BCG (Danish strain 1331) or placebo vaccination. Participants will then undergo a challenge with either intradermal BCG vaccine 6 months postrandomisation, or live-attenuated Yellow Fever Vaccine (YFV) 3 months postrandomisation to assess BCG-induced specific and non-specific protection, respectively. Stool and blood samples will be collected longitudinally to characterise microbiota composition and immune responses. The primary endpoint in the BCG-challenge arm is BCG colony-forming units (CFU) at the dermal challenge site 14 days postchallenge in BCG-vaccinated participants in the antibiotics-treated and comparator groups. The primary outcome in the YFV-challenge arm is viraemia (viral copies/mL plasma) at 3–7 days post YFV challenge in BCG-vaccinated participants in the antibiotic-treated and comparator groups. Secondary endpoints include comparison of BCG CFU and YFV viraemia in BCG- and placebo-vaccinated participants; antimycobacterial T cell and antibody responses in all four randomisation groups in each study arm and innate immune responses to YFV challenge in the YFV-challenge arm. Exploratory analyses will assess the impact of antibiotics on stool microbiota composition, assess the transcriptome, epigenome and immune cell frequency and activation in peripheral blood and measure immune cells and spatially resolved gene expression in selected skin biopsies.Ethics and dissemination Ethical approval has been granted by the Central Adelaide Local Health Network (Adelaide, South Australia) and governance approval obtained from Royal Adelaide Hospital and South Australian Health and Medical Research Institute. Results will be published in peer-reviewed open-access journals. Deidentified data will be stored on secure institutional repositories for at least 15 years.Trial registration number NCT06148025.