Not provided
Not provided
Not provided
Not provided
Not provided
Not provided
Not provided
Not provided
Not provided
Not provided
Not provided
Not provided
Not provided
Not provided
Not provided
Not provided
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.
Not provided
Not provided
Not provided
Not provided
| Label | Type | Description | Intervention Names |
|---|---|---|---|
| Control | Active Comparator | Influenza and RSV vaccination without additional treatment |
|
| Pre-vaccine sirolimus group | Experimental | Sirolimus 2mg orally x3/week on haemodialysis for 3 weeks. Influenza and RSV vaccination 2 weeks after completing sirolimus course. |
|
| Peri-vaccine sirolimus group | Experimental | Sirolimus 2mg orally x3/week on haemodialysis for 3 weeks. Influenza and RSV vaccination 1 week after commencing sirolimus course. |
|
| Post-vaccine sirolimus group | Experimental | Sirolimus 2mg orally x3/week on haemodialysis for 3 weeks. Influenza and RSV vaccination 2 weeks prior to commencing sirolimus course. |
|
| Name | Type | Description | Arm Group Labels | Other Names |
|---|---|---|---|---|
| Sirolimus (RAPAMUNE) | Drug | All treatment groups will receive 9 doses of 2mg sirolimus over a 3 week period, at varying times relative to vaccination. |
|
| Measure | Description | Time Frame |
|---|---|---|
| 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. | Six weeks post vaccination |
| Measure | Description | Time Frame |
|---|---|---|
| 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). |
Not provided
Inclusion Criteria:
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:
Recent use of intravenous immunosuppressive medications (<6 months), including:
Has a history of problems with side-effects associated with sirolimus use including
Ongoing use of strong CYP3A4/P-gp inhibitors or inducers including
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
Not provided
Not provided
Not provided
Not provided
Not provided
| Name | Role | Phone | Extension | |
|---|---|---|---|---|
| Toby Coates, MBBS FRACP PhD | Contact | (08) 7074 0000 | Toby.Coates@sa.gov.au | |
| Griffith Perkins, BSc PhD | Contact | Griffith.Perkins@adelaide.edu.au |
Not provided
| Facility | Status | City | State | ZIP | Country | Contacts |
|---|---|---|---|---|---|---|
| Royal Prince Alfred Hospital | Camperdown | New South Wales | 2050 | Australia |
Anonymized patient-level data created for the study will be available in a persistent repository upon publication. Data will be uploaded to figshare.com.
Not provided
Anonymized IPD will be made available in a persistent repository from the date of publication of trial findings.
Anonymized IPD will be publicly accessible by download from the persistent repository.
Not provided
Not provided
Participants will be randomised to three sirolimus treatment groups and a control group (1:1:1:1). All participants will receive an RSV and seasonal influenza vaccine at week 0. All treatment groups will receive 9 doses of 2mg sirolimus over a 3 week period, at varying times relative to vaccination. The "pre-vaccine" group will receive sirolimus beginning 5 weeks before vaccination and ceasing 2 weeks before vaccination. The "peri-vaccine" group will receive sirolimus beginning 1 week prior to vaccination and ceasing 2 weeks post vaccination. The "post-vaccine" group will receive sirolimus beginning 2 weeks post vaccination and ceasing 5 weeks post vaccination.
Not provided
Not provided
Not provided
Not provided
|
| Influenza vaccine (Sequiris Fluad Quad) | Biological | All participants will receive a dose of the seasonal Influenza vaccine (Sequiris Fluad Quad) |
|
| RSV vaccine (Pfizer Abrysvo) | Biological | All participants will receive a dose of the RSV vaccine (Pfizer Abrysvo) |
|
| 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. | 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 | 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) | 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 | 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. | 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. | Three weeks after commencement of sirolimus (after administration of final dose of sirolimus) |
| Circulating IFN-α2 analysis | Pre- and post-sirolimus circulating cytokine and chemokine analysis, measured as change in concentration of serum factor IFN-α2 from baseline to the end of sirolimus administration. | Three weeks after commencement of sirolimus (after administration of final dose of sirolimus) |
| Circulating IFN-γ analysis | Pre- and post-sirolimus circulating cytokine and chemokine analysis, measured as change in concentration of serum factors IFN-γ from baseline to the end of sirolimus administration. | Three weeks after commencement of sirolimus (after administration of final dose of sirolimus) |
| Circulating TNF-α analysis | Pre- and post-sirolimus circulating cytokine and chemokine analysis, measured as change in concentration of serum factors TNF-α from baseline to the end of sirolimus administration. | Three weeks after commencement of sirolimus (after administration of final dose of sirolimus) |
| Circulating MCP-1 analysis | Pre- and post-sirolimus circulating cytokine and chemokine analysis, measured as change in concentration of serum factors MCP-1 from baseline to the end of sirolimus administration. | Three weeks after commencement of sirolimus (after administration of final dose of sirolimus) |
| Circulating IL-6 analysis | Pre- and post-sirolimus circulating cytokine and chemokine analysis, measured as change in concentration of serum factor IL-6 from baseline to the end of sirolimus administration. | Three weeks after commencement of sirolimus (after administration of final dose of sirolimus) |
| Circulating CXCL8 (IL-8) | Pre- and post-sirolimus circulating cytokine and chemokine analysis, measured as change in concentration of serum factor CXCL8 (IL-8) from baseline to the end of sirolimus administration. | Three weeks after commencement of sirolimus (after administration of final dose of sirolimus) |
| Circulating IL-10 analysis | Pre- and post-sirolimus circulating cytokine and chemokine analysis, measured as change in concentration of serum factor IL-10 from baseline to the end of sirolimus administration. | Three weeks after commencement of sirolimus (after administration of final dose of sirolimus) |
| Circulating IL-12p70 analysis | Pre- and post-sirolimus circulating cytokine and chemokine analysis, measured as change in concentration of serum factor IL-12p70 from baseline to the end of sirolimus administration. | Three weeks after commencement of sirolimus (after administration of final dose of sirolimus) |
| Circulating IL-17A analysis | Pre- and post-sirolimus circulating cytokine and chemokine analysis, measured as change in concentration of serum factors IL-17A from baseline to the end of sirolimus administration. | Three weeks after commencement of sirolimus (after administration of final dose of sirolimus) |
| Circulating IL-18 analysis | Pre- and post-sirolimus circulating cytokine and chemokine analysis, measured as change in concentration of serum factors IL-18 from baseline to the end of sirolimus administration. | Three weeks after commencement of sirolimus (after administration of final dose of sirolimus) |
| Circulating IL-23 analysis | Pre- and post-sirolimus circulating cytokine and chemokine analysis, measured as change in concentration of serum factors IL-23 from baseline to the end of sirolimus administration. | Three weeks after commencement of sirolimus (after administration of final dose of sirolimus) |
| Circulating IL-33 analysis | Pre- and post-sirolimus circulating cytokine and chemokine analysis, measured as change in concentration of serum factors IL-33 from baseline to the end of sirolimus administration. | Three weeks after commencement of sirolimus (after administration of final dose of sirolimus) |
| Circulating CRP analysis | Pre- and post-sirolimus circulating cytokine and chemokine analysis, measured as change in concentration of serum factors CRP from baseline to the end of sirolimus administration. | Three weeks after commencement of sirolimus (after administration of final dose of sirolimus) |
| Princess Alexandra Hospital | Woolloongabba | Queensland | 4102 | Australia |
|
| Royal Adelaide Hospital | Adelaide | South Australia | 5000 | Australia |
|
| ID | Term |
|---|---|
| D007251 | Influenza, Human |
| ID | Term |
|---|---|
| D012141 | Respiratory Tract Infections |
| D007239 | Infections |
| D009976 | Orthomyxoviridae Infections |
| D012327 | RNA Virus Infections |
| D014777 | Virus Diseases |
| D012140 | Respiratory Tract Diseases |
Not provided
Not provided
| ID | Term |
|---|---|
| D020123 | Sirolimus |
| D007252 | Influenza Vaccines |
| D022261 | Respiratory Syncytial Virus Vaccines |
| ID | Term |
|---|---|
| D018942 | Macrolides |
| D007783 | Lactones |
| D009930 | Organic Chemicals |
| D014765 | Viral Vaccines |
| D014612 | Vaccines |
| D001688 | Biological Products |
| D045424 | Complex Mixtures |
Not provided
Not provided