Vaccination Response Modulation With a Targeted Rapamycin Protocol Study

Phase 2Not Yet RecruitingNCT07587801

Central Adelaide Local Health Network Incorporated60 enrolled

Overview

This study will investigate dialysis recipients' responses to important vaccines. Research suggests that a medication commonly used by transplant recipients may improve vaccine responses. The investigators will be conducting a clinical trial to see whether a short course of low-dose Sirolimus improves the response to vaccination against respiratory syncytial virus (RSV) and influenza (flu) in patient with kidney disease over 60 years old who receive haemodialysis.

Respiratory viruses are a significant cause of morbidity and mortality in Australia. Respiratory syncytial virus (RSV) and Influenza are major contributors to yearly respiratory virus epidemics that particularly affect older persons and persons with end-stage kidney disease. Vaccination is available for the prevention of both RSV and Influenza, but unfortunately the conditions that confer a higher risk of morbidity and mortality with infection are also key predictors of poor responses to vaccination. Effective vaccine responses require activation of both T and B cells to generate protective and long-lasting antibody and cellular immune responses. Immunosenescence from ageing and end-stage kidney disease, dampens antibody responses and impairs cellular immunity, rendering patients vulnerable to infection. Previous research suggests that sirolimus(rapamycin)-based immunosuppression regimens improve vaccine immunogenicity. Sirolimus (rapamycin) is a potent inhibitor of mTORC1 which regulates memory CD8+ T cells. Targeting mTORC1 has previous been shown to improve vaccination response in humans to influenza. More recently, small studies have suggested improved responses to COVID vaccination in kidney transplant recipients switched to sirolimus (rapamycin)-based regimens. This study will investigate a role for sirolimus (rapamycin) as a peri-vaccination immune modulation therapy. The VON TRAPP study is a phase 2a randomised clinical trial that aims to define the optimal, practical and tolerable regimen of peri-vaccination sirolimus (rapamycin) administration to positively modify vaccine responses. Haemodialysis patients over 60 years old will receive both Influenza and RSV vaccines plus either no additional treatment or a peri-vaccination regimen of sirolimus (rapamycin) to determine the most effective regimen to test further.

Study Type

INTERVENTIONAL

Allocation

RANDOMIZED

Eligibility

Sex: ALLMin age: 60 Years

Medical Language ↔ Plain English

Inclusion Criteria: * End-stage kidney disease requiring in-centre haemodialysis three times per week as kidney replacement therapy * Aged \>60 years Exclusion Criteria: * Aged \<60 years * Alternative haemodialysis regimens (e.g. twice-weekly haemodialysis, second-daily home haemodialysis) * Recent infection (\<6 months) with proven Influenza A, Influenza B, or RSV * Current use of immunosuppressive medications, including: * Oral steroid at a dose equivalent of 5 mg/day prednisolone or greater * Mycophenolate mofetil * Azathioprine * Calcineurin inhibitors * mTOR inhibitors * Recent use of intravenous immunosuppressive medications (\<6 months), including: * T-cell depleting agents (e.g. anti-thymocyte globulin) * B-cell depleting agents (e.g. rituximab) * Cyclophosphamide * Has a history of problems with side-effects associated with sirolimus use including * Angioedema * Active/recent opportunistic infection * Current or prior interstitial lung disease, non-infectious pneumonitis, organising pneumonia, or pulmonary fibrosis * Clinically significant pleural effusion or pericardial effusion * Active non-healing wounds, chronic skin ulcers, or planned major surgery/procedures * Current malignancy or recent malignancy with high recurrence risk * Severe or uncontrolled hyperlipidaemia * History of rhabdomyolysis * Severe hepatic impairment * Ongoing use of strong CYP3A4/P-gp inhibitors or inducers including * Inhibitors: Ketoconazole, Voriconazole, Itraconazole, Telithromycin, Clarithromycin * Inducers: Rifampicin, Rifabutin * Unable or unwilling to provide informed consent to participate in the trial * Known allergy to or intolerance of sirolimus (rapamycin) or the contents of the influenza or RSV vaccine

Outcomes

Primary Outcomes

Vaccine-specific functional T cell memory

The change in functional T cell memory from baseline to six weeks post vaccine dose, measured as IFN-γ spot-forming units (SFU) by ELISpot following 18-hour stimulation of PBMCs with RSV peptides.

Time frame: Six weeks post vaccination

Secondary Outcomes

Cellular immune response to vaccination

RSV vaccine-specific cellular immunity, measured as 1) change in frequency of CD8+ RSV F protein-specific T cells from baseline to six weeks post vaccine dose, identified by flow cytometry as CD8+CD134+CD69+ following 24-hour stimulation with a protein-derived peptide array (AIM, Activation-Induced Marker assay); 2) Change in frequency of RSV F protein-specific polyfunctional T cells from baseline to six weeks post vaccine dose. Polyfunctional T cells are defined as CD4+ T cells that produce more than one of IFN-γ, IL-2 and TNF identified by flow cytometry intracellular cytokine staining following 24-hour stimulation with a protein-derived peptide array (ICS, Intracellular Cytokine Staining assay).

Time frame: Six weeks post vaccination

Vaccine-specific humoral immune response

Measures of vaccine-specific humoral immunity, measured as 1) Anti-RSV F protein IgM, IgA and IgG antibody titres 6 weeks following the vaccine dose; 2) Change in haemagglutination inhibition (HAI) titre of influenza strains contained in the 2026 vaccine from baseline to six weeks post vaccination.

Time frame: Six week post vaccination

Incidence of infection post-vaccination

Incidence of RSV or Influenza infection in the study cohort from 3 weeks post vaccination to 12-month follow-up

Time frame: Twelve months post vaccination

Incidence of Sirolimus (Rapamycin) Treatment-Emergent Adverse Events [Safety and Tolerability]

Safety and tolerability of 3-week course of low-dose sirolimus (rapamycin), measured as frequency of adverse events (including serious adverse events)

Time frame: Six week post vaccination

Incidence of Immunization Treatment-Emergent Adverse Events [Safety and Tolerability]

Safety and tolerability of vaccine regimen, assessed by 1. Frequency of adverse events following immunization (AEFI), including adverse events of special interest (AESI) such as recurrence of autoimmune disease

Time frame: Six weeks post vaccination

Quality of life questionnaire

Quality of life following 3-week course of low-dose sirolimus (rapamycin) and vaccination, measured with the EQ-5D-5L quality of life questionnaire. This questionnaire reports on 5 functional domains using an ordinal scale from 1 (worst) to 5 (best) to provide a combined health state score.

Time frame: Six weeks post-vaccination

Circulating IL-1β analysis

Pre- and post-sirolimus circulating cytokine and chemokine analysis, measured as change in concentration of serum factor IL-1β from baseline to the end of sirolimus administration.