Enterotoxigenic Escherichia coli hyperimmune bovine colostrum for preventing travellers’ diarrhoea (TD): a randomised, double-blind, placebo-controlled trial

Background Enterotoxigenic Escherichia coli (ETEC) is a leading cause of travellers' diarrhoea (TD). Hyperimmune bovine colostrum (HBC) containing ETEC specific antibodies has shown efficacy in controlled settings, but despite widespread use, real-world efficacy remains uncertain. Methods In this randomised, double-blind, placebo-controlled superiority trial, US and UK military personnel and adult civilians (aged 18–70 years) travelling to TD-risk regions were randomised (1:1) to receive ETEC HBC (600 mg twice daily) or placebo, starting 2 days before arrival and continuing for 10–20 days while in the risk area. The primary outcome was TD, defined by standardised criteria. Stool smears collected during diarrhoeal episodes and at the end-of-prophylaxis were tested by PCR for pathogen attribution. ETEC-attributable TD was assessed as a secondary outcome. This trial is registered with ClinicalTrials.gov, NCT04605783 and is complete. Findings Between June 2, 2022, and April 29, 2025, 975 participants were enrolled and 850 were randomised to ETEC HBC (n = 425) or placebo (n = 425). Of these, 317 ETEC HBC and 323 placebo recipients were included in the primary efficacy analysis. TD occurred in 22.7% of ETEC HBC and 26.3% of placebo recipients (relative protective efficacy [PE] 13.7 [95% CI −13.4 to 34.31]), below the protocol-specified efficacy threshold of ≥35%. ETEC accounted for 17% of attributable TD cases, with frequent multi-organism detections. The difference in ETEC attributable TD between the groups was not statistically significant (12.1 vs. 21.5%; PE: 43.8 [−28.5 to 75.4]). Adverse events were rare and mild (ETEC HBC 2/320 vs. placebo 2/325). Both events in the ETEC HBC group (frequent urination, hives) resolved spontaneously. Interpretation ETEC HBC did not significantly reduce overall TD risk, with interpretation of ETEC-specific efficacy constrained by limited power. Further research is warranted to determine whether broader ETEC antigenic coverage or multi-pathogen approaches can overcome the pathogen diversity and polymicrobial infections observed in field settings. Funding Defense Health Agency.