Establishment, Validation, and Application of a New World Primate Model of Enterotoxigenic Escherichia coli Disease for Vaccine Development

• Published in: Infection and immunity 2019-02, Vol.87 (2)
• Main Authors: Rollenhagen, Julianne E, Jones, Franca, Hall, Eric, Maves, Ryan, Nunez, Gladys, Espinoza, Nereyda, O'Dowd, Aisling, Prouty, Michael G, Savarino, Stephen J
• Format: Article
• Language: English
• Subjects: Administration, Intranasal; Animals; Antibodies, Bacterial - blood; Bacterial Infections; Diarrhea - microbiology; Disease Models, Animal; Enterotoxigenic Escherichia coli - immunology; Escherichia coli Infections - immunology; Escherichia coli Infections - microbiology; Escherichia coli Infections - prevention & control; Escherichia coli Vaccines; Feces - microbiology; Humans; Immunoglobulin G - blood; Primates; Spotlight
• ISSN: 0019-9567; 1098-5522
• DOI: 10.1128/IAI.00634-18

The establishment of an animal model that closely approximates enterotoxigenic (ETEC) disease in humans is critical for the development and evaluation of vaccines against this enteropathogen. Here, we evaluated the susceptibility of , a New World monkey species, to ETEC infection. Animals were challenged orogastrically with 10 to 10 CFU of the human pathogenic CFA/I ETEC strain H10407 and examined for evidence of diarrhea and fecal shedding of bacteria. A clear dose-range effect was obtained, with diarrheal attack rates of 40% to 80%, validated in a follow-on study demonstrating an attack rate of 80% with 10 CFU of H10407 ETEC. To determine whether this model is an effective approach for assessing ETEC vaccine candidates, we used it to evaluate the ability of the donor strand-complemented CFA/I adhesin CfaE (dscCfaE) to protect against H10407 challenge. In a series of experiments, animals were intranasally vaccinated with dscCfaE alone, dscCfaE with either cholera toxin B-subunit (CTB) or heat-labile toxin (LTB), or phosphate-buffered saline (PBS) alone and then challenged with 10 CFU of H10407. Control animals vaccinated with PBS had attack rates of 70 to 90% on challenge. Vaccination with dscCfaE, or dscCfaE admixed with CTB or LTB, resulted in a reduction of attack rates, with vaccine efficacies of 66.7% (  = 0.02), 77.7% (  = 0.006), and 42.9% (  = 0.370) to 83.3% (  = 0.041), respectively. In conclusion, we have shown the H10407 ETEC challenge of to be an effective, reproducible model of ETEC disease, and importantly, we have demonstrated that in this model, vaccination with the prototype vaccine candidate dscCfaE is protective against CF-homologous disease.