Vaccination Response Modulation With a Targeted Rapamycin Protocol Study

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.

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