Vaccine Immune Response, Haemodialysis Patients, Older Adults
Conditions
Keywords
influenza, RSV, vaccine, haemodialysis, older adults, immunosenescence
Brief summary
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.
Detailed description
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.
Interventions
All treatment groups will receive 9 doses of 2mg sirolimus over a 3 week period, at varying times relative to vaccination.
BIOLOGICALInfluenza vaccine (Sequiris Fluad Quad)
All participants will receive a dose of the seasonal Influenza vaccine (Sequiris Fluad Quad)
BIOLOGICALRSV vaccine (Pfizer Abrysvo)
All participants will receive a dose of the RSV vaccine (Pfizer Abrysvo)
Sponsors
Central Adelaide Local Health Network Incorporated
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
PREVENTION
Masking
NONE
Intervention model description
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.
Eligibility
Sex/Gender
ALL
Age
60 Years to No maximum
Healthy volunteers
No
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
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Vaccine-specific functional T cell memory | Six weeks post vaccination | 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. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Circulating IL-1β analysis | Three weeks after commencement of sirolimus (after administration of final dose of sirolimus) | 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. |
| Circulating IFN-α2 analysis | Three weeks after commencement of sirolimus (after administration of final dose of sirolimus) | 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. |
| Circulating IFN-γ analysis | Three weeks after commencement of sirolimus (after administration of final dose of sirolimus) | 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. |
| Circulating TNF-α analysis | Three weeks after commencement of sirolimus (after administration of final dose of sirolimus) | 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. |
| Circulating MCP-1 analysis | Three weeks after commencement of sirolimus (after administration of final dose of sirolimus) | 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. |
| Circulating IL-6 analysis | Three weeks after commencement of sirolimus (after administration of final dose of sirolimus) | 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. |
| Circulating CXCL8 (IL-8) | Three weeks after commencement of sirolimus (after administration of final dose of sirolimus) | 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. |
| Circulating IL-10 analysis | Three weeks after commencement of sirolimus (after administration of final dose of sirolimus) | 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. |
| Circulating IL-12p70 analysis | Three weeks after commencement of sirolimus (after administration of final dose of sirolimus) | 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. |
| Circulating IL-17A analysis | Three weeks after commencement of sirolimus (after administration of final dose of sirolimus) | 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. |
| Circulating IL-18 analysis | Three weeks after commencement of sirolimus (after administration of final dose of sirolimus) | 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. |
| Circulating IL-23 analysis | Three weeks after commencement of sirolimus (after administration of final dose of sirolimus) | 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. |
| Circulating IL-33 analysis | Three weeks after commencement of sirolimus (after administration of final dose of sirolimus) | 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. |
| Circulating CRP analysis | Three weeks after commencement of sirolimus (after administration of final dose of sirolimus) | 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. |
| Incidence of Immunization Treatment-Emergent Adverse Events [Safety and Tolerability] | Six weeks post vaccination | 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 |
| Cellular immune response to vaccination | Six weeks post 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). |
| Vaccine-specific humoral immune response | Six week post vaccination | 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. |
| Incidence of infection post-vaccination | Twelve months post vaccination | Incidence of RSV or Influenza infection in the study cohort from 3 weeks post vaccination to 12-month follow-up |
| Quality of life questionnaire | Six weeks post-vaccination | 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. |
| Incidence of Sirolimus (Rapamycin) Treatment-Emergent Adverse Events [Safety and Tolerability] | Six week post vaccination | Safety and tolerability of 3-week course of low-dose sirolimus (rapamycin), measured as frequency of adverse events (including serious adverse events) |
Countries
Australia
Contacts
CONTACTToby Coates, MBBS FRACP PhD
CONTACTGriffith Perkins, BSc PhD
Outcome results
None listed