Evaluation of 20-Valent Pneumococcal Conjugate Vaccine Efficacy Against Radiologically-Confirmed Community-Acquired Pneumonia in Adults Aged 65 and Older

The primary objective of this study is to determine the effectiveness of the **20-valent pneumococcal conjugate vaccine (20vPnC)** against all radiologically-confirmed community-acquired pneumonia (RAD+CAP) due to any 20vPnC serotype plus serotypes 6C and 15C. This is clinically relevant as it aims to assess the vaccine's ability to prevent pneumonia caused by a broader range of pneumococcal serotypes, which is crucial for reducing morbidity and mortality in adults aged 65 years and older.

Secondary objectives include:

• Determining the effectiveness of 20vPnC against all (invasive and non-invasive) RAD+CAP due to the 7 additional serotypes in 20vPnC beyond 13vPnC plus 15C.
• Assessing the European/Israeli specific effectiveness of 20vPnC against all RAD+CAP due to any 20vPnC serotype plus 6C and 15C.
• Evaluating the effectiveness of 20vPnC by various participant characteristics, such as age, sex, chronic medical conditions, and immunocompromising conditions, among participants with RAD+CAP.
• Determining the effectiveness of 20vPnC against all RAD+CAP due to any 20vPnC serotype plus 6C and 15C in participants with prior influenza vaccination.
• Assessing the effectiveness of 20vPnC against all RAD+CAP by prior vaccination history.
• Evaluating the effectiveness of 20vPnC against all RAD+CAP due to individual serotypes contained in 20vPnC.
• Determining the effectiveness of 20vPnC against all RAD+CAP due to the 13 shared serotypes contained in 20vPnC and 13vPnC.

The clinical trial involves a total of **10,000 participants** who are being studied to assess the effectiveness of the 20vPnC vaccine against radiologically-confirmed community-acquired pneumonia. The study population consists of both **male and female participants** aged 65 years and older. Participants are required to have been hospitalized with a physician's clinical suspicion of community-acquired pneumonia, exhibiting at least two of ten specified clinical signs or symptoms, such as fever, chills, pleuritic chest pain, or dyspnea. Additionally, participants must have radiographic findings consistent with pneumonia. The trial does not include a vulnerable population, and all participants must be capable of providing informed consent. The selection criteria ensure that the study population is representative of the target demographic for the vaccine's intended use, focusing on older adults who are at increased risk for pneumonia. Lifestyle factors such as diet and physical activity are not specified as part of the selection criteria.

The clinical trial is designed to evaluate the effectiveness of a 20-valent pneumococcal conjugate vaccine against vaccine-type radiologically-confirmed community-acquired pneumonia in adults aged 65 years and older. This study employs a **randomized**, **double-blind**, and **controlled** methodology to ensure the reliability and validity of the results. The trial is expected to commence on March 11, 2024, and conclude by May 31, 2027, with an estimated duration of approximately three years.

Participants will undergo a series of study visits, beginning with an inclusion (screening) visit to assess eligibility based on specific criteria, such as age and clinical suspicion of community-acquired pneumonia (CAP) with radiographic findings consistent with pneumonia. The inclusion criteria require participants to exhibit at least two clinical signs or symptoms of CAP, such as fever, hypothermia, or dyspnea, among others. Following the screening, eligible participants will be enrolled and randomized to receive either the investigational vaccine or a control. Subsequent follow-up visits will be scheduled to monitor the participants' health status, vaccine effectiveness, and any adverse events. The end-of-study visit will mark the completion of the trial for each participant, during which final assessments will be conducted.

The expected length of participant involvement in the trial is approximately one year, with the possibility of early termination under certain conditions, such as withdrawal of consent or the occurrence of significant adverse events. The primary endpoint of the study is the vaccine effectiveness (VE) calculated as 1 minus the odds ratio (OR) for 20vPnC vaccination among cases and controls, adjusted for potentially confounding variables. Secondary endpoints include VE by age group, sex, and prior influenza vaccination status, among others. The trial aims to provide comprehensive data on the vaccine's efficacy across different demographics and clinical scenarios.

The clinical trial involves the administration of **Apexxnar**, a pneumococcal polysaccharide conjugate vaccine (20-valent, adsorbed), formulated as a suspension for injection in a pre-filled syringe. The vaccine is designed to target 20 different serotypes of pneumococcal polysaccharides, each conjugated to the CRM197 carrier protein and adsorbed on aluminium phosphate. The pharmaceutical form is a suspension for injection, and the vaccine is administered intramuscularly. The dosage for each administration is 0.5 ml, with a maximum treatment period of one day. The vaccine is not a paediatric formulation and is not classified as an orphan drug. The administration is conducted under the authorization of the European Union, with the marketing authorization number EU/1/21/1612/005.

In this clinical trial, no non-experimental treatments such as standard-of-care therapy, placebo, or comparator treatments are utilized. The focus is solely on evaluating the effectiveness of the **Apexxnar** vaccine. Participant compliance is monitored through adherence to the dosing schedule, which involves a single administration of the vaccine. The trial aims to assess the vaccine's effectiveness against radiologically-confirmed community-acquired pneumonia in adults aged 65 years and older. The trial is conducted under the sponsorship of Pfizer Europe MA EEIG, ensuring adherence to regulatory standards and protocols.

The efficacy of the 20-valent pneumococcal conjugate vaccine (20vPnC) will be assessed in a clinical trial involving adults aged 65 years and older. The primary endpoint for evaluating efficacy is the vaccine effectiveness (VE) calculated as 1 minus the odds ratio (OR) for 20vPnC vaccination among cases and controls, multiplied by 100, and adjusted for potentially confounding variables. Secondary endpoints include VE calculations using data from European/Israeli participants, VE by age group, sex, and ACIP-defined risk group, as well as VE by prior influenza vaccination and co-administration of influenza vaccination. Additionally, VE will be assessed against 13vPnC serotypes, the 7 additional serotypes in 20vPnC beyond 13vPnC plus 15C, and individual serotypes.