Interrogation of a live-attenuated enterotoxigenic Escherichia coli vaccine highlights features unique to wild-type infection

Abstract

Enterotoxigenic Escherichia coli (ETEC) infections are a common cause of severe diarrheal illness in low- and middle-income countries. The live-attenuated ACE527 ETEC vaccine, adjuvanted with double mutant heat-labile toxin (dmLT), affords clear but partial protection against ETEC challenge in human volunteers. Comparatively, initial wild-type ETEC challenge completely protects against severe diarrhea on homologous re-challenge. To investigate determinants of protection, vaccine antigen content was compared to wild-type ETEC, and proteome microarrays were used to assess immune responses following vaccination and ETEC challenge. Although molecular interrogation of the vaccine confirmed expression of targeted canonical antigens, relative to wild-type ETEC, vaccine strains were deficient in production of flagellar antigens, immotile, and lacked production of the EtpA adhesin. Similarly, vaccination\u2009±\u2009dmLT elicited responses to targeted canonical antigens, but relative to wild-type challenge, vaccine responses to some potentially protective non-canonical antigens including EtpA and the YghJ metalloprotease were diminished or absent. These studies highlight important differences in vaccine and wild-type ETEC antigen content and call attention to distinct immunologic signatures that could inform investigation of correlates of protection, and guide vaccine antigen selection for these pathogens of global importance.Enterotoxigenic E. coli : deep dive into vaccine characteristicsAdjuvanted ACE527 is an experimental oral live-attenuated vaccine for enterotoxigenic E. coli (ETEC) but has been shown to elicit only partial protection. James M. Fleckenstein and colleagues perform a genomic and proteomic characterization of ACE527 and compare it to H10407 – a wildtype virulent strain of E. coli that can generate fully protective acquired immunity. While sharing many canonical antigens with wild-type ETEC, the attenuated E. coli strains composing ACE527 lack a number of critical characteristics, in particular they lack core components of the flagellar machinery or the adhesin EtpA and are immotile. Accordingly, and in contrast to wildtype challenge, vaccination with ACE527 fails to elicit robust antibody responses to these non-canonical antigens and this might underpin the incomplete protection afforded by this vaccine.