Rapamycin and inulin for third-dose vaccine response stimulation (RIVASTIM): Inulin - study protocol for a pilot, multicentre, randomised, double-blinded, controlled trial of dietary inulin to improve SARS-CoV-2 vaccine response in kidney transplant recipients

Aim: Kidney transplant recipients (KTR) are at an increased risk of hospitalisation and death from SARS-CoV-2 infection, and standard 2-dose vaccination schedules are typically inadequate to generate protective immunity. The gut microbiota has been shown to modulate vaccine responses with short-chain fatty acid (SCFA) producing species and dietary-fibre intake associated with heightened vaccine responses. With dysbiosis common in KTR, augmentation of microbiota-derived SCFAs through pre-biotic fibre supplementation is an attractive adjuvant strategy to improve vaccine-induced immunity. Methods: Multicentre, double-blinded, placebo-controlled trial. 72 KTRs with an inadequate response (anti-RBD <100U/mL) to a standard 2 dose COVID-19 mRNA vaccine schedule were randomized to dietary inulin (20g/day) or placebo 4-weeks pre- and post- 3rd mRNA COVID vaccine dose. Vaccine specific humoral and T-cell responses, and 16s-rRNA sequencing of the faecal metagenome were conducted 4-weeks post-vaccination. Results: Participants were male (51/72, 71%), age 58 ± 11 years (mean/SD), 7.9 [2.5 – 13.9] years post-transplant (median/range), with eGFR 56.1 ± 25.9 ml/min (mean/SD), with no significant differences between groups. Prebiotic inulin was feasible, tolerable, and safe, but did not significantly boost vaccine specific immune responses (Fig 1). Inulin supplementation resulted in a significant increase in SCFA-producing bacteria (2.3-fold increase in Bifidobacterium spp., Fig 2, p<0.001) and predicted metabolic pathways. Conclusion: Pre-biotic fibre supplementation is a feasible and effective strategy to enhance the gut microbiota in KTRs, and warrants further investigations as an adjuvant to enhance vaccine-induced immunity.