Development of effective vaccines for enterotoxigenic Escherichia coli
Authors: Hyesuk Seo, Weiping Zhang
Journal: The Lancet Infectious Diseases (2019)

Enterotoxigenic Escherichia coli (ETEC) is a leading cause of diarrhoea in children in low-income and middle-income countries (children's diarrhoea) and international travellers (travellers' diarrhoea).1Kotloff KL Platts-Mills JA Nasrin D Roose A Blackwelder WC Levine MM Global burden of diarrheal diseases among children in developing countries: incidence, etiology, and insights from new molecular diagnostic techniques.Vaccine. 2017; 35: 6783-6789Crossref PubMed Scopus (77) Google Scholar, 2Steffen R Hill DR DuPont HL Traveler's diarrhea: a clinical review.JAMA. 2015; 313: 71-80Crossref PubMed Scopus (196) Google Scholar ETEC strains produce heterogeneous fimbrial or non-fimbrial adhesins (of which there are >25), which attach bacteria to host receptors for colonisation in human small intestines and deliver heat-labile and heat-stable enterotoxins to small intestine epithelia to disrupt homoeostasis and cause fluid hypersecretion and watery diarrhoea. Vaccination is considered the most practical and effective method to prevent ETEC diarrhoea because implementation of sanitation systems and supply of safe drinking water, which can prevent diarrhoea caused by ETEC and other enteric pathogens, are not quickly achievable for many resource-limited countries. Developing effective vaccines for ETEC is a priority for many public health institutes, including WHO. However, the major challenge in developing effective ETEC vaccines is that ETEC strains are immunologically heterogeneous.3Svennerholm AM From cholera to enterotoxigenic Escherichia coli (ETEC) vaccine development.Indian J Med Res. 2011; 133: 188-196PubMed Google Scholar, 4Zhang W Sack DA Progress and hurdles in the development of vaccines against enterotoxigenic Escherichia coli in humans.Expert Rev Vaccines. 2012; 11: 677-694Crossref PubMed Scopus (83) Google Scholar An ETEC vaccine needs to induce host immunity to prevent colonisation from at least the most common strains and to neutralise enterotoxicity of both enterotoxins. No vaccines are yet licensed for ETEC. In The Lancet Infectious Diseases, Firdausi Qadri and colleagues5Qadri F Akhtar M Bhuiyan TR et al.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.Lancet Infect Dis. 2019; (published online Nov 19)https://doi.org/10.1016/S1473-3099(19)30571-7Summary Full Text Full Text PDF PubMed Scopus (40) Google Scholar report the safety and immunogenicity of a phase 1/2 trial of an oral inactivated whole-cell ETEC vaccine candidate (ETVAX)—which has already been shown to be safe and immunogenic in adults—in children and infants in Bangladesh. The vaccine combines four recombinant E coli strains that over-produce adhesins CFA/I, CS3, CS5, and CS6, mixed with a recombinant protein, LCTBA, which is a hybrid B subunit of heat-labile enterotoxin and cholera toxin.6Holmgren J Bourgeois L Carlin N et al.Development and preclinical evaluation of safety and immunogenicity of an oral ETEC vaccine containing inactivated E coli bacteria overexpressing colonization factors CFA/I, CS3, CS5 and CS6 combined with a hybrid LT/CT B subunit antigen, administered alone and together with dmLT adjuvant.Vaccine. 2013; 31: 2457-2464PubMed Google Scholar The authors concluded that ETVAX was safe and well tolerated in children aged 6–59 months when given orally at a quarter or half of an adult dose (1 × 1011 bacteria and 1 mg LCTBA), as evidenced by the absence of treatment-related serious adverse events in participants during the study period. Adverse events of greater than mild severity were vomiting and fever. Vomiting occurred exclusively in the vaccine groups, was mostly mild (moderate only when the largest dose was administered), and was inversely related to the child's age and the vaccine dose. Fever occurred in a maximum of one child per vaccine group, at a frequency not notably different from that in the placebo group. The study showed that ETVAX is immunogenic, and that immunogenicity was age-dependent. Children aged 12–59 months who received two half or quarter doses of the vaccine without, or a single half dose with, double-mutant heat-labile enterotoxin (dmLT) as an adjuvant had significant increases in IgA antibodies in lymphocyte secretions (ALS) targeting all five vaccine antigens (CFA/I, CS3, CS5, CS6, and LTB). By contrast, children aged 6–11 months had significant ALS and faecal IgA (secretory IgA) responses to only three antigens (CFA/I, CS3, and LTB). Plasma IgA and IgG responses to LTB were detected in all vaccine groups, whereas plasma IgA responses to the colonisation factors were detected only in vaccinated children older than 12 months and only for two antigens (CFA/I and CS3); no adhesin-specific plasma IgA was detected in children aged 6–11 months. The study also indicated that the adjuvant dmLT is not associated with adverse effects and it improves the kinetics of faecal IgA responses to the vaccine antigens. ETVAX appears to be an advancement of an earlier killed vaccine candidate named rCTB-CF,7Jertborn M Ahrén C Holmgren J Svennerholm AM Safety and immunogenicity of an oral inactivated enterotoxigenic Escherichia coli vaccine.Vaccine. 1998; 16: 255-260Crossref PubMed Scopus (80) Google Scholar which induced significant antigen-specific immune responses in Bangladeshi children8Qadri F Ahmed T Ahmed F Bradley Sack R Sack DA Svennerholm AM Safety and immunogenicity of an oral, inactivated enterotoxigenic Escherichia coli plus cholera toxin B subunit vaccine in Bangladeshi children 18–36 months of age.Vaccine. 2003; 21: 2394-2403Crossref PubMed Scopus (54) Google Scholar, 9Qadri F Ahmed T Ahmed F Begum YA Sack DA Svennerholm AM Reduced doses of oral killed enterotoxigenic Escherichia coli plus cholera toxin B subunit vaccine is safe and immunogenic in Bangladeshi infants 6–17 months of age: dosing studies in different age groups.Vaccine. 2006; 24: 1726-1733Crossref PubMed Scopus (48) Google Scholar but provided poor or no protection against ETEC diarrhoea in Egyptian children.10Savarino SJ Hall ER Bassily S et al.Introductory evaluation of an oral, killed whole cell enterotoxigenic Escherichia coli plus cholera toxin B subunit vaccine in Egyptian infants.Pediatr Infect Dis J. 2002; 21: 322-330Crossref PubMed Scopus (58) Google Scholar By using recombinant E coli strains that overexpress four ETEC adhesins, ETVAX does not cause the toxic effects associated with rCTB-CF and has improved antigen-specific immunogenicity. Encouraging data from this study should move ETVAX forward to efficacy trials. Although the efficacy of ETVAX against ETEC diarrhoea in children in ETEC-endemic regions is yet to be demonstrated, some concerns remain. First, ETVAX targets only four (of >25) ETEC adhesins, and the induced anti-adhesin immunity is expected to protect against homologous strains but probably not against the other prevalent and virulent ETEC strains that produce heterogeneous adhesins. Second, ETVAX induces immunity to the B subunits of heat-labile toxin, but not to the toxic heat-labile A subunit, nor to the heat-stable enterotoxin, which is more virulent than the heat-labile enterotoxin in children's diarrhoea.1Kotloff KL Platts-Mills JA Nasrin D Roose A Blackwelder WC Levine MM Global burden of diarrheal diseases among children in developing countries: incidence, etiology, and insights from new molecular diagnostic techniques.Vaccine. 2017; 35: 6783-6789Crossref PubMed Scopus (77) Google Scholar ETEC vaccines might not be truly effective if they do not also induce protective immunity against ETEC strains producing heat-stable enterotoxin and broad anti-adhesin immunity against ETEC strains expressing heterogeneous adhesins. WZ is developing an ETEC multivalent subunit vaccine, MecVax. HS declares no competing interests. 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 trialThe encouraging safety and immunogenicity of ETVAX and benefit of dmLT adjuvant in young children support its further assessment for protective efficacy in children in enterotoxigenic E coli-endemic areas. Full-Text PDF Open Access