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 ± dmLT 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.

Oral delivery of Hyperimmune bovine serum antibodies against CS6-expressing enterotoxigenicEscherichia colias a prophylactic against diarrhea

“…Alternatively, there may be a role for other antigens, such as CS21 which is also expressed on B7A, in combination with CS6 which may be important and points to the potential value in immune proteomics in identifying a protective immunologic profile. 36 This may need to be explored further as multivalent vaccines and therapeutics are developed for ETEC.…”

Human Mucosal IgA Immune Responses against Enterotoxigenic Escherichia coli

“…Several of the strains used in CHIM studies produce CS6, which is the most common colonization factor produced by human ETEC. Although IgA responses to CS6 have been poor in most of these studies [ 23 , 60 , 92 , 93 ], two studies have managed to show higher levels of immunogenicity in humans after both natural infection and administration of a vaccine candidate containing CS6 [ 94 , 95 ].…”

“…Beyond the classical ETEC antigens described above, newer research has identified other virulence factors that may contribute considerably to natural protection against ETEC [ 23 , 59 ]. In recent CHIM studies, immune responses against several of these antigens have been found to be strong, supporting the notion that these could represent useful vaccine targets.…”

“…To develop protective vaccines, there is a need to identify both suitable molecular targets for the vaccines and immune responses that correlate with efficacious protection. Several promising vaccine targets have been identified, including, mainly, the ETEC colonization factors and toxins, and it is generally believed that a strong, small intestinal mucosal IgA response against these antigens is needed to protect against ETEC [ 21 , 22 , 23 ]. Being able to directly measure small intestinal IgA responses during vaccine trials would, therefore, be very valuable but this would require the use of complicated and invasive procedures.…”

Immunogenicity Evaluation of Chimeric Subunit Vaccine Comprising Adhesion Coli Surface Antigens from Enterotoxigenic <b><i>Escherichia coli</i></b>

“…Thus, the use of subunit vaccines has been more favorable [Baxter, 2007]. A study has shown the role of CooD antigen in inducing the immune system [Chakraborty et al, 2019]. In the current study, a chimeric gene composed of cooD and cotD was designed by bioinformatics tools.…”