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

Abstract

The establishment of an animal model that closely approximates enterotoxigenic <i>Escherichia coli</i> (ETEC) disease in humans is critical for the development and evaluation of vaccines against this enteropathogen. Here, we evaluated the susceptibility of <i>Aotus nancymaae</i>, a New World monkey species, to ETEC infection. Animals were challenged orogastrically with 10⁹ to 10¹¹ 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 10¹¹ 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 10¹¹ 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% (<i>P</i> = 0.02), 77.7% (<i>P</i> = 0.006), and 42.9% (<i>P</i> = 0.370) to 83.3% (<i>P</i> = 0.041), respectively. In conclusion, we have shown the H10407 ETEC challenge of <i>A. nancymaae</i> 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.