Safety and immunogenicity of the oral, inactivated, enterotoxigenic Escherichia coli vaccine ETVAX in Bangladeshi children and infants: a double-blind, randomised, placebo-controlled phase 1/2 trial

Abstract

Background Enterotoxigenic Escherichia coli causes diarrhoea, leading to substantial mortality and morbidity in children, but no specific vaccine exists. This trial tested an oral, inactivated, enterotoxigenic E coli vaccine (ETVAX), which has been previously shown to be safe and highly immuongenic in Swedish and Bangladeshi adults. We tested the safety and immunogenicity of ETVAX, consisting of four E coli strains overexpressing the most prevalent colonisation factors (CFA/I, CS3, CS5, and CS6) and a toxoid (LCTBA) administered with or without a double-mutant heat-labile enterotoxin (dmLT) as an adjuvant, in Bangladeshi children. Methods We did a randomised, double-blind, placebo-controlled, dose-escalation, age-descending, phase 1/2 trial in Dhaka, Bangladesh. Healthy children in one of three age groups (24-59 months, 12-23 months, and 6-11 months) were eligible. Children were randomly assigned with block randomisation to receive either ETVAX, with or without dmLT, or placebo. ETVAX (half [5•5 × 10¹⁰ cells], quarter [2•5 × 10¹⁰ cells], or eighth [1•25 × 10¹⁰ cells] adult dose), with or without dmLT adjuvant (2•5 µg, 5•0 µg, or 10•0 µg), or placebo were administered orally in two doses 2 weeks apart. Investigators and participants were masked to treatment allocation. The primary endpoint was safety and tolerability, assessed in all children who received at least one dose of vaccine. Antibody responses to vaccine antigens, defined as at least a two-times increase in antibody levels between baseline and post-immunisation, were assessed as secondary endpoints. This trial is registered with ClinicalTrials.gov, NCT02531802.

Colonization factor CS30 from enterotoxigenic Escherichia coli binds to sulfatide in human and porcine small intestine

“…Although ETEC is a highly heterogenous pathogen it has been shown that a mixture of prevalent antigens, such as CFs, can confer broad protection [36][37][38][39]. In addition, cross-reactive antibodies against related CFs are protective [40,41]. CS30 belongs to the Class1b CF group, also encompassing CS12, CS18, CS20, CS26, CS27, and CS28, four of which (CS26, CS27, CS28, and CS30) are relatively recently discovered.…”

Human Mucosal IgA Immune Responses against Enterotoxigenic Escherichia coli

“…Experimental infection with an ETEC strain does not seem to confer any strong protective immunity against heterologous ETEC strains [ 19 ], and efforts to develop broadly protective ETEC vaccines have recently been focused on incorporating LT- and ST-based vaccine antigens, colonization factor antigens, and nonclassical ETEC antigens in the vaccine design. Currently, trials of an oral inactivated vaccine candidate are ongoing, both in travelers and LMIC children [ 37 ]. Still lacking a reliable immune correlate of protection, ALS-based assays are usually considered to be the best proxy for measuring the intestinal SIgA antibody response that is assumed to be protective.…”

“…For these reasons, efforts have been made to identify other easily available body fluids that have an immune response that may qualitatively and quantitatively reflect the SIgA response in the gut. SIgA has, for example, been successfully measured in saliva analyzed by ELISA [ 37 ] and by whole-cell flow cytometry [ 32 ]. Aase et al found a strong correlation between anti-ETEC SIgA concentrations in lavage and submandibular/sublingual saliva, indicating that SIgA levels in saliva could reflect the gut SIgA immune response.…”

Advances in Oral Subunit Vaccine Design

“…dmLT [20][21][22][23], mmCT [24] PRR ligands β-glucans [25,26], MPL [27], Flagellin [28,29], CpG [30,31] NKT-ligands α-galactosyl ceramide [32,33]…”