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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
  • Singer J
  • Tunbridge M
  • Perkins GB
  • Salehi T
  • Ying T
  • et al.
BMJ Open. 2022 Dec 1;12(12):e062747 doi: 10.1136/bmjopen-2022-062747.
CET Conclusion
Reviewer: Mr John Fallon, Centre for Evidence in Transplantation, Nuffield Department of Surgical Sciences University of Oxford
Conclusion: This manuscript describes the protocol of an upcoming multi-centre, double blinded RCT of a size larger than many previous RCTs, attempting to assess gut biome effects on vaccine responses. Of the 26 previously conducted RCTs around 50% have demonstrated some beneficial effects of probiotics on vaccine response. It has been commented that the response may be reduced as none of these trials contained patients who had a disrupted microbiome, including immunosuppressed renal recipients. The intervention has been previously demonstrated to improve the gut biome and increase reactivity to parenteral vaccines. The authors propose a well-designed study with sound methodology, containing a clearly defined primary outcome which can be unambiguously tested. The proposed intervention is unlikely to have any serious adverse events and is inexpensive. Based on previous literature it is a study that has good potential.
Aims: This study aims to examine whether dietary fibre supplementation will lead to attenuation of gut dysbiosis and promote vaccine responsiveness in renal transplant patients.
Interventions: Patients will be randomly assigned to receive either inulin (active) or maltodextrin (placebo).
Participants: Kidney transplant recipients (age ≥ 18 years).
Outcomes: The primary endpoint is the proportion of participants to achieve in vitro neutralisation of live SARS-CoV-2 virus four weeks after the third dose of the COVID-19 vaccine. Secondary endpoints are safety and tolerability of dietary inulin, vaccine-specific immune cell populations and responses, and the diversity and differential abundance of gut microbiota.
Follow Up: 4- 6 weeks following vaccination.
INTRODUCTION:

Kidney transplant recipients (KTRs) are at an increased risk of hospitalisation and death from COVID-19. Vaccination against SARS-CoV-2 is our primary risk mitigation strategy, yet vaccine effectiveness in KTRs is suboptimal. Strategies to enhance vaccine efficacy are therefore required. Current evidence supports the role of the gut microbiota in shaping the immune response to vaccination. Gut dysbiosis is common in KTRs and is a potential contributor to impaired COVID-19 vaccine responses. We hypothesise that dietary fibre supplementation will attenuate gut dysbiosis and promote vaccine responsiveness in KTRs.

METHODS AND ANALYSIS:

Rapamycin and inulin for third-dose vaccine response stimulation-inulin is a multicentre, randomised, prospective, double-blinded, placebo-controlled pilot trial examining the effect of dietary inulin supplementation prior to a third dose of COVID-19 vaccine in KTRs who have failed to develop protective immunity following a 2-dose COVID-19 vaccine schedule. Participants will be randomised 1:1 to inulin (active) or maltodextrin (placebo control), administered as 20 g/day of powdered supplement dissolved in water, for 4 weeks prior to and following vaccination. The primary outcome is the proportion of participants in each trial arm that achieve in vitro neutralisation of live SARS-CoV-2 virus at 4 weeks following a third dose of COVID-19 vaccine. Secondary outcomes include the safety and tolerability of dietary inulin, the diversity and differential abundance of gut microbiota, and vaccine-specific immune cell populations and responses.

ETHICS AND DISSEMINATION:

Ethics approval was obtained from the Central Adelaide Local Health Network (CALHN) Human Research Ethics Committee (HREC) (approval number: 2021/HRE00354) and the Sydney Local Health District (SHLD) HREC (approval numbers: X21-0411 and 2021/STE04280). Results of this trial will be published following peer-review and presented at scientific meetings and congresses.

TRIAL REGISTRATION NUMBER:

ACTRN12621001465842.
Rapamycin and inulin for booster vaccine response stimulation (RIVASTIM)-rapamycin: study protocol for a randomised, controlled trial of immunosuppression modification with rapamycin to improve SARS-CoV-2 vaccine response in kidney transplant recipients
  • Tunbridge M
  • Perkins GB
  • Singer J
  • Salehi T
  • Ying T
  • et al.
Trials. 2022 Sep 15;23(1):780 doi: 10.1186/s13063-022-06634-w.
UNLABELLED:

Kidney transplant recipients are at an increased risk of severe COVID-19-associated hospitalisation and death. Vaccination has been a key public health strategy to reduce disease severity and infectivity, but the effectiveness of COVID vaccines is markedly reduced in kidney transplant recipients. Urgent strategies to enhance vaccine efficacy are needed.

METHODS:

RIVASTIM-rapamycin is a multicentre, randomised, controlled trial examining the effect of immunosuppression modification prior to a third dose of COVID-19 vaccine in kidney transplant recipients who have failed to develop protective immunity to a 2-dose COVID-19 vaccine schedule. Participants will be randomised 1:1 to either remain on standard of care immunosuppression with tacrolimus, mycophenolate, and prednisolone (control) or cease mycophenolate and commence sirolimus (intervention) for 4 weeks prior to and following vaccination. The primary outcome is the proportion of participants in each trial arm who develop protective serological neutralisation of live SARS-CoV-2 virus at 4-6 weeks following a third COVID-19 vaccination. Secondary outcomes include SARS-CoV-receptor binding domain IgG, vaccine-specific immune cell populations and responses, and the safety and tolerability of sirolimus switch.

DISCUSSION:

Immunosuppression modification strategies may improve immunological vaccine response. We hypothesise that substituting the mTOR inhibitor sirolimus for mycophenolate in a triple drug regimen will enhance humoral and cell-mediated responses to COVID vaccination for kidney transplant recipients.

TRIAL REGISTRATION:

Australia New Zealand Clinical Trials Registry ACTRN12621001412820. Registered on 20 October 2021; https://www.anzctr.org.au/Trial/Registration/TrialReview.aspx?id=382891&isReview=true.