COPD-2VAX: Enhancing Protection Against Respiratory Infections Through AS01-Mediated Innate Immune Activation in High-Risk Patients

This study evaluates the specific and non-specific effects of innate immune activation induced by the AS01-adjuvanted RSV vaccine in individuals at high risk for severe respiratory disease and insufficient vaccine response. The primary objective encompasses three specific aims: to investigate whether the AS01-adjuvanted RSV vaccine induces potent mucosal and systemic innate responses in COPD patients aged 60 years and older; to evaluate whether ipsilateral and/or contralateral co-administration with PCV20 enhances the vaccine-specific adaptive immune response to pneumococcal antigens; and to assess non-specific effects of the AS01-adjuvanted RSV vaccine regarding the duration of innate enhancement that affects adaptive responses using a controlled delayed vaccine co-administration model, mucosal protection against viral and bacterial respiratory pathogens, and sustained systemic control of viral replication in chronic or latent infections. These objectives are clinically relevant as COPD patients represent a vulnerable population with impaired immune responses and increased susceptibility to respiratory infections, making optimization of vaccination strategies critical for reducing morbidity and mortality in this high-risk group.

The sponsor did not provide information regarding the total number of participants enrolled in this clinical trial. The study population consists of individuals diagnosed with **Chronic Obstructive Pulmonary Disease (COPD)** who are aged 60 years or older. Both male and female subjects are included in the trial. Participants must have a confirmed COPD diagnosis by a **respiratory medicine specialist** and require ongoing attention at a hospital's outpatient clinic. Eligible individuals must have received **PPV23 vaccination** more than one year prior to enrollment. The trial does not involve vulnerable populations. No specific information regarding lifestyle considerations such as diet, physical activity, or habits was provided by the sponsor.

This clinical trial evaluates the specific and non-specific effects of innate immune activation induced by an **AS01-adjuvanted** **respiratory syncytial virus vaccine** in individuals at high risk for severe respiratory disease. The study is designed as a **randomized**, **controlled** trial classified as a **low intervention** clinical investigation, as both vaccines utilized are already approved and marketed products administered according to their marketing authorization. The trial is categorized as **Phase IV** and will be conducted in patients diagnosed with **Chronic Obstructive Pulmonary Disease**.

The investigational medicinal products include **Arexvy** powder and suspension for suspension for injection, a recombinant adjuvanted RSV vaccine containing respiratory syncytial virus glycoprotein F stabilized in the pre-fusion conformation and adjuvanted with AS01E, and **Prevenar 20** suspension for injection in pre-filled syringe, a 20-valent **pneumococcal polysaccharide conjugate vaccine** adsorbed. A **saline** solution for injection serves as the **placebo** comparator. All products are administered via the **intramuscular** route at a dose of 0.5 ml, with a maximum treatment period of one day or one dose depending on the study arm.

The primary objective is to investigate whether the AS01-adjuvanted RSV vaccine induces potent mucosal and systemic **innate immune responses** in COPD patients aged 60 years or older. Secondary objectives include evaluating whether ipsilateral or contralateral co-administration with PCV20 enhances the vaccine-specific **adaptive immune response** to pneumococcal antigens, assessing non-specific effects regarding the duration of innate enhancement that affects adaptive responses using a controlled delayed vaccine co-administration model, examining mucosal protection against viral and bacterial respiratory pathogens, and evaluating sustained systemic control of viral replication in chronic or latent infections.

The **primary endpoint** is the **interferon-gamma** response, measured as the increase in systemic IFN-γ levels at 24 hours post-vaccination compared to baseline. **Secondary endpoints** include **Natural Killer cell** activation assessed by changes in activation markers such as CD69 expression at 24 hours post-vaccination, gene signature of innate activation measured through expression levels of interferon response-associated genes via transcriptomic analysis of **peripheral blood mononuclear cells**, pneumococcal-specific **IgG antibody titers** and functional activity including increase in IgG geometric mean concentrations for 12 pneumococcal serotypes at 30 and 180 days post-vaccination, assessment of functional pneumococcal antibodies through **opsonophagocytic assay** for key serotypes including serotype 3, antibody glycosylation analysis, **CD4+ T-cell responses** quantified by polyfunctional Th1-biased responses assessed through cytokine production following ex vivo stimulation with RSV and pneumococcal antigens, RSV pre-F-binding antibody titers quantified at days 0, 30, and 180, and CD4 responses directed against RSV and the conjugate protein of the pneumococcal vaccine.

Principal inclusion criteria require participants to have a confirmed COPD diagnosis by a respiratory medicine specialist requiring attention at the hospital's outpatient clinic, be aged 60 years or older, have received previous **PPV23 vaccination** more than one year before inclusion, and agree to participate in all aspects of the trial with signed informed consent. The estimated recruitment start date is September 1, 2025, with an estimated trial end date of December 31, 2027. The expected duration of participant involvement extends to 180 days post-vaccination based on the timing of final immunological assessments. Conditions that may lead to early termination from the study are not explicitly specified in the available protocol information.

The experimental vaccine **Prevenar 20** is administered as a **suspension for injection** in a **pre-filled syringe**. This **pneumococcal polysaccharide conjugate vaccine** is **20-valent** and **adsorbed**. The vaccine contains 20 different **pneumococcal polysaccharide serotypes** (1, 3, 4, 5, 6A, 6B, 7F, 8, 9V, 10A, 11A, 12F, 14, 15B, 18C, 19A, 19F, 22F, 23F, and 33F), each **conjugated to CRM197** and **adsorbed on aluminium phosphate**. The vaccine is administered via the **intramuscular route**. The maximum daily dose is **0.5 ml**, with a maximum total dose of **0.5 ml** administered over a treatment period of 1 day.

The experimental vaccine **Arexvy** is supplied as a **powder and suspension** for reconstitution into a **suspension for injection**. This **recombinant respiratory syncytial virus vaccine** is **adjuvanted** with **AS01E**. The active substance is **respiratory syncytial virus glycoprotein F**, which is produced by **recombinant technology** and **stabilised in the pre-fusion conformation**. The vaccine is administered via the **intramuscular route**. The maximum daily dose is **0.5 ml**, with a maximum total dose of **0.5 ml** administered over a treatment period of 1 week.

**Saline** is used as a **placebo** comparator in this clinical trial. It is administered as a **solution for injection** via the **intramuscular route**. The maximum daily dose is **0.5 ml**, with a maximum total dose of **0.5 ml** administered over a treatment period of 1 week. The placebo is used to maintain blinding and to control for non-specific effects of injection.

The primary efficacy endpoint is the interferon-gamma response, measured as the increase in systemic interferon-gamma levels at 24 hours post-vaccination compared to baseline. Secondary efficacy endpoints include Natural Killer cell activation, assessed by changes in activation markers such as CD69 expression at 24 hours post-vaccination compared to baseline. Gene signature of innate activation will be evaluated through the expression levels of a predefined set of genes associated with the interferon response, including IRF7 and IFIT1, measured via transcriptomic analysis of peripheral blood mononuclear cells pre- and post-vaccination. Pneumococcal-specific IgG antibody titers and functional activity will be assessed through the increase in IgG geometric mean concentrations for 12 pneumococcal serotypes included in PCV20, measured at 30 days and 180 days post-vaccination. Functional pneumococcal antibodies will be evaluated through opsonophagocytic assay for key serotypes, including serotype 3, at 30 and 180 days post-vaccination. Antibody glycosylation analysis, specifically sialylation and desialylation, will be performed at 30 and 180 days post-vaccination. CD4+ T-cell responses will be quantified by assessing polyfunctional CD4+ T-cell responses with a Th1-biased profile, measured through cytokine production including interferon-gamma, tumor necrosis factor-alpha, and interleukin-2 following ex vivo stimulation with RSV and pneumococcal antigens. RSV pre-F-binding antibody titers will be quantified on samples obtained on days 0, 30, and 180. CD4 responses directed against RSV and the conjugate protein of the pneumococcal vaccine will also be evaluated.