Phase 3 Evaluation of ExPEC9V Vaccine for Preventing Invasive Extraintestinal Pathogenic Escherichia coli Disease in Adults Aged 60+ with Prior Urinary Tract Infection

The primary objective of this study is to demonstrate the efficacy of the **ExPEC9V** vaccine compared to placebo in preventing the first invasive extraintestinal pathogenic Escherichia coli disease (IED) event. This is confirmed microbiologically from blood or other sterile sites and is caused by ExPEC9V O-serotypes O1, O2, O4, O6, O15, O16, O18, O25, and O75. This objective is clinically relevant as it addresses the prevention of serious infections in adults aged 60 years and older, who have a history of urinary tract infection, thereby potentially reducing morbidity and healthcare burden associated with these infections.

The secondary objectives include demonstrating the efficacy of ExPEC9V compared to placebo in the prevention of various IED and urinary tract infection (UTI) events caused by ExPEC9V O-serotypes, such as:

• All IEDs caused by ExPEC9V O-serotypes
• The first hospitalized IED event
• The first IED event meeting criteria for sepsis
• The first bacteremic IED event
• The first pyelonephritis event
• The first UTI event
• All UTIs caused by ExPEC9V O-serotypes
• The first IED event caused by E. coli
• The first pyelonephritis event caused by E. coli
• The first UTI event caused by E. coli

Additionally, the study aims to evaluate the immunogenicity of ExPEC9V in a specific subset, as well as its safety and reactogenicity. It also seeks to assess the preservation of health status and health-related quality of life (HRQoL) compared to placebo, and the impact of IED and UTI on physical and mental health, and overall HRQoL. Furthermore, the impact of pyelonephritis caused by ExPEC9V O-serotypes on physical and mental health, and overall HRQoL, as measured by the SF-36 and the EQ-5D-5L, will be evaluated.

The clinical trial involves a total of **14,603 participants** who are being studied for the prevention of **Invasive Extraintestinal Pathogenic Escherichia coli Disease**. The study population includes both male and female subjects, aged **60 years and older**, who are medically stable and have a history of urinary tract infections within the past two years. Participants were selected based on their availability for the study duration and their ability to provide verifiable identification and complete electronic questionnaires. The trial does not include a vulnerable population. Participants are expected to have at least one additional risk factor for the disease, such as a history of urosepsis, E. coli bacteremia, or other specified medical conditions. The selection criteria ensure that participants are likely to remain in the study through the end of the protocol-specified follow-up period. The sponsor has not provided specific information regarding lifestyle considerations such as diet or physical activity.

The clinical trial is designed as a **randomized**, **double-blind**, **placebo-controlled** study to evaluate the efficacy, safety, and immunogenicity of the ExPEC9V vaccine in preventing **Invasive Extraintestinal Pathogenic Escherichia coli Disease** in adults aged 60 years and older with a history of urinary tract infection in the past two years. The trial is a Phase 3 study, with an estimated duration extending until June 2029. Participants will be randomly assigned to receive either the ExPEC9V vaccine or a placebo, specifically 0.9% Sodium Chloride, administered via **intramuscular use**. The study will involve multiple visits, starting with an inclusion (screening) visit to assess eligibility based on criteria such as age, medical stability, and history of urinary tract infections.

Following the screening, eligible participants will undergo a baseline visit where they will receive the study intervention. Subsequent follow-up visits will be scheduled to monitor the participants' health status, collect data on any adverse events, and assess the primary and secondary endpoints, including the occurrence of the first IED event with microbiological confirmation and antibody titers to vaccine O-serotype antigens. The end-of-study visit will conclude the participant's involvement, ensuring all necessary data is collected and any remaining health concerns are addressed.

The expected length of participant involvement is approximately seven years, with conditions for early termination including significant adverse events, withdrawal of consent, or any medical condition that, in the investigator's judgment, would compromise the participant's safety or the integrity of the study. The trial aims to provide comprehensive data on the vaccine's effectiveness in preventing serious infections caused by specific E. coli serotypes, contributing valuable insights into the management of this condition in the target population.

The clinical trial involves the administration of the experimental medication **JNJ-78901563**, which is a **solution for injection**. This investigational product is developed by Janssen Vaccines & Prevention B.V. and is designed as a vaccine composed of structurally diverse substances. The active substances include ECOO1A, ECOO2, ECOO4, ECOO6A, ECOO15, ECOO16, ECOO18A, ECOO25B, and ECOO75. The vaccine is administered via **intramuscular use**. The maximum daily dose is 88 micrograms, with the same amount being the maximum total dose. The treatment period is limited to a single day. The primary objective of the trial is to assess the efficacy, safety, and immunogenicity of this vaccine in preventing invasive extraintestinal pathogenic Escherichia coli disease in adults aged 60 years and older with a history of urinary tract infection in the past two years.

In addition to the experimental vaccine, the study utilizes a **placebo** control, which is **0.9% Sodium Chloride**. This placebo is used to maintain the double-blind nature of the trial, ensuring that neither the participants nor the investigators know who receives the experimental vaccine or the placebo. The placebo does not have a specific pharmaceutical form or route of administration detailed in the trial documentation, as it serves as a comparator to evaluate the true effects of the experimental vaccine.

The efficacy of the vaccine ExPEC9V in preventing invasive extraintestinal pathogenic **Escherichia coli** disease (IED) will be assessed through a series of primary and secondary endpoints. The primary endpoint is the occurrence of the first IED event with microbiological confirmation from blood or other sterile sites, excluding cases confirmed from urine only, caused by ExPEC9V O-serotypes O1, O2, O4, O6, O15, O16, O18, O25, and O75.

Secondary endpoints include the assessment of all IEDs, first hospitalized IED events, first IED events meeting criteria for sepsis, first bacteremic IED events, first pyelonephritis events, and first urinary tract infection (UTI) events, all caused by ExPEC9V O-serotypes. Additionally, antibody titers to vaccine O-serotype antigens will be measured in the Immunogenicity Subset using multiplex ECL-based immunoassay and multiplex opsonophagocytic killing assay (MOPA) at specified timepoints: Day 1 (pre-vaccination), Day 30, Day 181, Year 1, Year 2, Year 3, and Year 4.

Data collection will also include solicited local and systemic adverse events (AEs) until 14 days post-vaccination, unsolicited AEs until 29 days post-vaccination, serious adverse events (SAEs), and responses to SF-36 and EQ-5D-5L questionnaires at scheduled timepoints. The frailty index will be measured at baseline and annually up to Year 4, as well as at the time of an IED. Medical resource utilization for IED and UTI events, hospitalization details, and mortality rates will also be evaluated.