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).

Summary

In this multinational phase 3 trial of 17,701 older adults, ExPEC9V produced robust and sustained antibody responses but did not prevent invasive disease caused by vaccine-targeted ExPEC O-serotypes. Vaccine efficacy was 14.63% with a 95% confidence interval from -106.57% to 65.38%, leading to early discontinuation after a prespecified futility analysis.

Key Findings

• 17,701 participants were vaccinated: 8,858 received ExPEC9V and 8,843 received placebo.
• There were 24 vaccine-serotype invasive ExPEC disease cases: 11 in the vaccine group and 13 in the placebo group.
• Vaccine efficacy was 14.63% with a 95% confidence interval of -106.57% to 65.38%, indicating no demonstrated protective effect.
• The vaccine generated robust and sustained antibody responses but did not prevent invasive disease.

Clinical Implications

ExPEC9V should not be used for prevention of invasive ExPEC disease because efficacy was not demonstrated, and its development was discontinued. Prevention must continue to rely on established urinary-tract infection prevention, early diagnosis, antimicrobial stewardship, and management of underlying risk factors while alternative vaccine strategies are evaluated.

Limitations

• The study enrolled stable adults aged 60 years or older with a recent history of urinary tract infection, so findings may not generalize to younger adults or populations without this risk profile.
• The low number of invasive disease events produced wide confidence intervals and limited precision for estimating vaccine efficacy.

Future Directions

Future vaccine studies should investigate whether protection requires broader antigenic coverage, alternative antigen targets, improved correlates of protection, or selection of populations with higher baseline risk. Trial designs should incorporate clinically relevant invasive disease endpoints rather than relying primarily on immunogenicity.