ETVAX shows 48.2% efficacy against moderate-to-severe ETEC diarrhoea in Gambian children despite missing primary endpoint

BACKGROUND: Enterotoxigenic Escherichia coli (ETEC) causes 75 million diarrhoea episodes with up to 42 000 deaths annually in children. To prevent ETEC in children, we aimed to evaluate the safety, immunogenicity, and efficacy of ETVAX, an oral, inactivated, whole-cell ETEC vaccine with toxoid and double-mutant heat-labile toxin adjuvant. METHODS: In this phase 2b, double-blind, placebo-controlled trial, Gambian children aged 6-18 months were recruited from four enrolment centres and block-randomised (1:1) via a computer-generated sequence, stratified by enrolment centres, to receive ETVAX or placebo on days 1, 15, and 90. Parents, staff, investigators assessing outcomes, and investigators analysing the data were masked to group assignment. An immunogenicity subset was assessed for serum antibody responses to ETEC colonisation factors and heat-labile toxin. The primary safety endpoint was serious adverse events, assessed in all children who received at least one intervention dose. The primary efficacy endpoint was vaccine efficacy against moderate-to-severe ETEC-positive diarrhoea (MSD-ETEC), excluding co-infections with Cryptosporidium spp, norovirus genogroup II, rotavirus, or Shigella spp, assessed in the per-protocol population. Secondary endpoints included vaccine efficacy against MSD-ETEC regardless of copathogens and against moderate-to-severe diarrhoea (MSD) regardless of cause. Exploratory vaccine efficacy analyses were against MSD-ETEC excluding only enteroparasitic copathogens (Giardia lamblia and Cryptosporidium) and against MSD-ETEC regardless of copathogens when first dose was given before age 9 months. This trial was registered with the Pan African Clinical Trials Registry (PACTR20201081921856). FINDINGS: Between Feb 22, 2021, and June 24, 2022, 5253 children were screened and 4936 (2499 [51%] girls, 2437 [49%] boys) were randomly assigned (2468 to ETVAX, 2468 to placebo). Serious adverse events occurred in 24 (1·0%) of 2474 in the vaccine group and 32 (1·3%) of 2462 in the placebo group, with none related to the investigational product. Immunogenicity was assessed in 122 children. ETVAX increased antibodies to colonisation factors (CFA/I, CS3) and heat-labile toxins. Vaccine efficacy was 26·6% (95% CI -58·3 to 66·0; p=0·43) for the primary endpoint, 48·2% (p=0·053) against MSD-ETEC regardless of copathogens, and 80·6% (p=0·0092) when excluding enteroparasitic copathogens. Vaccine efficacy against all MSD-ETEC reached 67·8% (p=0·026) when dosing started before age 9 months. Vaccine efficacy against MSD regardless of cause was 21·4% (p=0·032). INTERPRETATION: ETVAX was safe and immunogenic. Although the primary endpoint was not met, the secondary and exploratory findings suggest ETVAX protects Gambian children against ETEC-positive MSD particularly when administered before age 9 months and when children were not co-infected with enteroparasites. ETVAX also showed a reduction in all-cause MSD. These results support advancing ETVAX to a pivotal phase 3 trial. FUNDING: European & Developing Countries Clinical Trials Partnership.