Efficacy, safety, and immunogenicity of a nine-valent vaccine (ExPEC9V) for the prevention of invasive Escherichia coli disease in older adults: a phase 3, randomised, placebo-controlled trial (E.mbrace).

BACKGROUND

Invasive Escherichia coli disease (IED) caused by extraintestinal pathogenic Escherichia coli (ExPEC) can lead to bacteraemia and sepsis. ExPEC9V is a conjugate vaccine targeting nine E coli O-serotypes that account for most E coli bloodstream infections. We aimed to evaluate ExPEC9V for safety, immunogenicity, and prevention of IED caused by ExPEC9V O-serotypes in adults aged 60 years and older.

METHODS

In this randomised, double-blind, placebo-controlled, phase 3 study conducted at 332 clinical sites in 20 countries (E.mbrace), we enrolled participants aged 60 years and older in stable health and with a history of urinary tract infection (UTI) within the previous 2 years. Participants were randomly assigned (in blocks of no set size with the use of interactive web response system, stratified by age and presence or absence of risk factors for complicated UTI) 1:1 to receive a single dose of intramuscular ExPEC9V or placebo. Participants, study-site personnel, and investigators remained masked to group allocation throughout the study. The primary endpoint was first IED in blood or sterile sites caused by ExPEC9V O-serotypes in the per-protocol efficacy analysis set (all randomly assigned, vaccinated participants without major protocol deviations); secondary endpoints included immunogenicity assessment in a subset of participants. Safety endpoints included solicited (safety subset), unsolicited (full analysis set), and serious (full analysis set) adverse events. A prespecified futility analysis conducted when at least 40% of the expected 53 IED events had occurred indicated lack of efficacy, leading to early study termination. We present final study results (data up to the date of the futility announcement), when 17 701 of the planned 19 800 participants had been vaccinated. This trial is registered with ClinicalTrials.gov (NCT04899336).

FINDINGS: Participants were enrolled between June 30, 2021, and Feb 13, 2025. Of 18 844 individuals assessed for eligibility, 17 701 were enrolled, randomly assigned, and vaccinated (8858 with ExPEC9V and 8843 with placebo). The per-protocol efficacy included 17 637 participants (8822 for ExPEC9V and 8815 for placebo). There were 24 IED cases (11 in vaccine and 13 in placebo groups) caused by ExPEC9V O-serotypes in blood or sterile sites, yielding a vaccine efficacy of 14·63% (95% CI -106·57 to 65·38), indicating no protective effect. ExPEC9V had an acceptable safety profile, with more frequent low-grade adverse events in the ExPEC9V versus placebo group, balanced serious adverse event distribution among both groups, and no vaccine-related deaths.

INTERPRETATION: In this large phase 3 trial of older adults, ExPEC9V did not demonstrate efficacy in preventing first IED caused by ExPEC9V O-serotypes, despite generating robust and sustained antibody responses. Development of the ExPEC9V vaccine has been discontinued.

FUNDING: Johnson & Johnson and Sanofi.