Dietary Inulin to Improve SARS-CoV-2 Vaccine Response in Kidney Transplant Recipients: The RIVASTIM-Inulin Randomised Controlled Trial

Abstract

Kidney transplant recipients are at an increased risk of hospitalisation and death from SARS-CoV-2 infection, and standard two-dose vaccination schedules are typically inadequate to generate protective immunity. Gut dysbiosis, which is common among kidney transplant recipients and known to effect systemic immunity, may be a contributing factor to a lack of vaccine immunogenicity in this at-risk cohort. The gut microbiota modulates vaccine responses, with the production of immunomodulatory short-chain fatty acids by bacteria such as Bifidobacterium associated with heightened vaccine responses in both observational and experimental studies. As SCFA-producing populations in the gut microbiota are enhanced by diets rich in non-digestible fibre, dietary supplementation with prebiotic fibre emerges as a potential adjuvant strategy to correct dysbiosis and improve vaccine-induced immunity. In a randomised, double-bind, placebo-controlled trial of 72 kidney transplant recipients, we found dietary supplementation with prebiotic inulin for 4 weeks before and after a third SARS-CoV2 mRNA vaccine to be feasible, tolerable, and safe. Inulin supplementation resulted in an increase in gut Bifidobacterium, as determined by 16S RNA sequencing, but did not increase in vitro neutralisation of live SARS-CoV-2 virus at 4 weeks following a third vaccination. Dietary fibre supplementation is a feasible strategy with the potential to enhance vaccine-induced immunity and warrants further investigation.

Keywords: COVID-19; SARS-CoV-2; dysbiosis; immunisation; immunity; kidney transplantation; microbiota; prebiotics.

Figure 1

RIVASTIM-Inulin trial design.

Figure 2

CONSORT flow diagram of the RIAVSTIM-inulin trial. KTRs were screened for inadequate immunity following two doses of SARS-CoV-2 vaccination and randomly allocated to receive dietary supplementation with inulin (n = 37) or placebo (n = 35). Following 4 weeks of supplementation, participants received a third SARS-CoV-2 vaccine and the subsequent immune response was assessed in 65 participants at 4–6 weeks post-vaccination. A total of 39 participants in the RIVSTIM-inulin trial provided faecal samples for microbiota analysis at baseline and after 4 weeks of dietary supplementation with either inulin or placebo.

Figure 3

Immunological results of the RIVASTIM-Inulin trial. KTRs with an unsatisfactory response to a primary two-dose COVID-19 vaccination schedule (anti-RBD Ig < 100 U/mL) were randomised to supplementation with dietary inulin or placebo 4 weeks prior to a third dose of mRNA COVID-19 vaccine. At 4 weeks following vaccination, serum neutralisation against live SARS-CoV-2 was assessed for both the ancestral A.2.2 strain (A) and the BA.5 strain (B), with results expressed as log IC50 values. (C) A comparison was made between pre- and post-vaccination anti-RBD Ig titres (U/mL) in both the inulin and placebo groups, with no significant distinction observed in the proportion of patients achieving the predefined target threshold of 100 U/mL between the two groups (p = 0.96). (D) Compared to non-responders, patients with an initial low response to a primary vaccination course were significantly more likely to develop protective neutralisation following a third vaccination (RR 2.71, 95% CI: 1.37–5.37, p = 0.004). (E) Inulin supplementation increased Spike-specific T-cell responses as measured by IFN-γ ELISpot (SFU/106 cells), following a third vaccination (Wilcoxon signed-rank test); however, there was no significant difference in the median change in Spike-specific T-cell response between treatment groups by quantile regression (F) (n = 56, p = 0.74).

Figure 4

Inulin supplementation in KTRs results in select changes to the gut microbiota. (A) The microbiota of KTRs at baseline demonstrates marked heterogeneity although is dominated by the phylum Firmicutes in the majority of KTRs. (B) The alpha-diversity of the gut microbiota, as assessed by richness, Shannon diversity index, Inverse Simpson, and evenness, did not differ significantly between groups. Beta diversity, as assessed by principal coordinate analysis (PCA) of Aitchison distances, in individuals at baseline and after 4 weeks of treatment did not differ significantly following placebo (C) or inulin (D) supplementation. (E) At the time of a third SARS-CoV-2 vaccination, there was no significant difference in the microbial community composition between treatment groups. (F) The relative abundance of the gut microbiota at the family level is demonstrated at baseline and following 4 weeks of dietary supplementation. (G) Inulin supplementation increased the relative abundance of key SCFA-producing bacteria at the genus level by Mann–Whitney U-test and by ALDEx2 (H) following correction for multiple comparisons.

Figure 5

Dietary inulin supplementation alters the metagenomic function of the gut microbiota. KEGG orthologue (KO) genes were predicted using PiCRUST2 and mapped to KEGG pathways. (A) The differential abundance of KEGG pathways between the inulin and placebo groups show an increase in the expression of pathways involved in microbial SCFA production following inulin supplementation (ALDEx2 Benjamini–Hochberg-corrected expected p-value < 0.05). (B) Chord diagram depicting microbial associations with the differentially abundant KEGG pathways. (Spearman’s correlation, Benjamini–Hochberg-corrected expected p-value < 0.05).