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. RIVASTIM

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.

研究目的：肾脏移植受者（Kidney transplant recipients, KTR）感染新型冠状病毒（SARS-CoV-2）后，住院与死亡风险显著升高，而标准两剂疫苗接种方案通常难以诱导保护性免疫。已有研究证实，肠道菌群可调控疫苗应答，产短链脂肪酸（short-chain fatty acid, SCFA）的菌群物种与膳食纤维摄入均与更强的疫苗应答水平相关。鉴于KTR群体普遍存在菌群失调，通过益生元纤维补充以增强菌群来源的短链脂肪酸，是改善疫苗诱导免疫的极具潜力的佐剂策略。
研究方法：本研究为多中心、双盲、安慰剂对照临床试验。将72名对标准两剂新冠mRNA疫苗应答不足（抗受体结合域抗体<100U/mL）的KTR受试者随机分为两组，在第3剂新冠mRNA疫苗接种前4周至接种后4周期间，分别摄入菊粉（20g/天）或安慰剂。于接种后4周检测疫苗特异性体液免疫、T细胞应答，并对粪便宏基因组进行16S核糖体RNA（16S rRNA）测序。
研究结果：受试者中男性51例（71%），年龄58±11岁（均值±标准差），肾移植术后时长为7.9[2.5–13.9]年（中位数[范围]），估算肾小球滤过率（eGFR）为56.1±25.9 ml/min，两组基线特征无显著统计学差异。益生元菊粉具备可行性、耐受性与安全性，但未显著增强疫苗特异性免疫应答（图1）。菊粉补充可显著提升产SCFA菌群的丰度（双歧杆菌属（Bifidobacterium spp.）丰度升高2.3倍，图2，p<0.001），同时可预测相关代谢通路的改变。
研究结论：益生元纤维补充是安全有效的肠道菌群调控策略，可改善KTR群体的肠道菌群组成，该策略作为佐剂以增强疫苗诱导免疫的效果值得开展进一步研究探索。