Evaluation of Live Attenuated Vaccines for Inducing Trained Immunity and Reducing Inflammation in Chronic Obstructive Pulmonary Disease Patients

The primary objective of this study is to **characterize** the changes in the **innate immune system** of patients with **chronic obstructive pulmonary disease (COPD)** following vaccination with live vaccines. The study aims to determine if such vaccination induces trained immunity, as previously reported in other populations. This is clinically relevant as enhancing the innate immune response in COPD patients could potentially reduce the frequency and severity of exacerbations, thereby improving patient outcomes and quality of life.

Secondary objectives include:

• Examining if vaccination with live vaccines causes changes in systemic inflammation, including **eosinophilic inflammation**.
• Comparing the effects of the **BCG vaccine** with the **MMR vaccine** regarding their impact on the innate immune system.

The clinical trial involves participants diagnosed with **chronic obstructive pulmonary disease** (COPD), with a focus on characterizing changes in the innate immune system following vaccination with live vaccines. The study population includes both male and female subjects, aged over 40 years, who have a specialist-verified, spirometry-confirmed diagnosis of COPD and are capable of providing informed consent. The trial does not include a vulnerable population. The sponsor has not provided information regarding the total number of participants. Participants' general health status is characterized by their COPD condition, and no specific lifestyle considerations such as diet or physical activity are highlighted. The selection criteria ensure that only individuals with confirmed COPD are included, aligning with the study's objective to assess the potential induction of trained immunity in this population.

The clinical trial is designed to evaluate the effects of live vaccines on the **innate immune system** in patients with **chronic obstructive pulmonary disease** (COPD). This is a Phase 4, randomized, double-blind, controlled trial. The study aims to determine if vaccination induces trained immunity, characterized by changes in cytokine production capacity of innate immune cells. The trial will involve the administration of live vaccines, including the M-M-RvaxPro and BCG Vaccine, as well as a saline placebo. The trial is expected to commence on January 1, 2024, and conclude by December 31, 2025.

Participants will undergo a series of study visits, beginning with an inclusion (screening) visit to confirm eligibility based on criteria such as specialist-verified, spirometry-confirmed COPD, age over 40 years, and the ability to provide informed consent. Following the inclusion visit, participants will receive the assigned intervention and attend follow-up visits to monitor immune response and health outcomes. The primary endpoint is the detection of innate immune training through fold-changes in cytokine production from inclusion to four months post-inclusion. Secondary endpoints include changes in blood levels of pro-inflammatory cytokines, epigenetic markers, and health outcomes over a 12-month period.

The expected duration of participant involvement is approximately 12 months, with regular follow-up visits to assess the primary and secondary endpoints. Conditions that may lead to early termination from the study include withdrawal of consent, adverse events, or non-compliance with study procedures. The trial will adhere to rigorous scientific and ethical standards to ensure the validity and reliability of the findings.

The clinical trial involves the administration of **M-M-RvaxPro**, a **measles, mumps, and rubella vaccine (live)**, which is provided as a **powder and solvent for suspension for injection**. The active substances include the **rubella virus Wistar RA 27/3 strain (live, attenuated)** produced in WI-38 human diploid lung fibroblasts, the **mumps virus Jeryl Lynn (Level B) strain (live, attenuated)** produced in chick embryo cells, and the **measles virus Edmonston-Enders strain (live, attenuated)** also produced in chick embryo cells. The vaccine is administered subcutaneously with a maximum daily dose of 0.5 ml and a total dose of 1.0 ml over a treatment period of 2 days. The pharmaceutical form is a suspension for injection, and the product is manufactured by Merck Sharp & Dohme BV.

Another experimental treatment in the trial is the **BCG Vaccine "AJ Vaccines"**, which is a **suspension for injection** containing the active substance **Mycobacterium bovis, Danish strain 1331**. This vaccine is administered intradermally with a maximum daily dose of 0.1 ml and a total dose of 0.2 ml over a 2-day treatment period. The vaccine is produced by AJ Vaccines A/S and is intended to induce trained immunity in the study participants.

The trial also includes a non-experimental treatment using **saline** as a placebo. The saline is provided as a **solution for injection** and is administered via injection. The maximum daily dose is 1.5 ml, with a total dose of 3.0 ml over the course of 2 days. The saline serves as an inactive comparator to evaluate the effects of the experimental vaccines. Participant compliance with the dosing schedule is monitored throughout the trial to ensure adherence to the protocol.

Efficacy in the clinical trial titled "Using live vaccines to induce beneficial innate immune training and reduce systemic inflammation in COPD patients (COPD-LIVE)" will be assessed through both primary and secondary endpoints. The primary endpoint focuses on **innate immune training**, which will be evaluated by measuring fold-changes in cytokine production capacity of innate immune cells, specifically for cytokines such as IL-1β, IL-6, IL-10, TNF-α, and IFN-γ. These measurements will be taken following pro-inflammatory stimulation from the time of inclusion to four months post-inclusion.

Secondary endpoints include further assessments of innate immune training, with cytokine production capacity measured at different intervals: from three to four months and from one to three months post-inclusion. Additional secondary endpoints involve changes in blood levels of pro-inflammatory cytokines from inclusion to three and four months post-inclusion, as well as changes in epigenetic markers of innate immune cells. The trial will also monitor the number of hospital admissions, COPD exacerbations, and mortality 12 months after inclusion. Furthermore, changes in the Medical Research Council (MRC) dyspnea scale, COPD Assessment Test (CAT), and self-reported health from baseline to 12 months post-enrolment will be evaluated.