Abstract
Vaccine development often encounters the challenge of virulence heterogeneity. Enterotoxigenic Escherichia coli (ETEC) bacteria producing immunologically heterogeneous virulence factors are a leading cause of children’s diarrhea and travelers’ diarrhea. Currently, we do not have licensed vaccines against ETEC bacteria. While conventional methods continue to make progress but encounter challenge, new computational and structure-based approaches are explored to accelerate ETEC vaccine development. In this study, we applied a structural vaccinology concept to construct a structure-based multiepitope fusion antigen (MEFA) to carry representing epitopes of the seven most important ETEC adhesins [CFA/I, CFA/II (CS1–CS3), CFA/IV (CS4–CS6)], simulated antigenic structure of the CFA/I/II/IV MEFA with computational atomistic modeling and simulation, characterized immunogenicity in mouse immunization, and examined the potential of structure-informed vaccine design for ETEC vaccine development. A tag-less recombinant MEFA protein (CFA/I/II/IV MEFA) was effectively expressed and extracted. Molecular dynamics simulations indicated that this MEFA immunogen maintained a stable secondary structure and presented epitopes on the protein surface. Empirical data showed that mice immunized with the tagless CFA/I/II/IV MEFA developed strong antigen-specific antibody responses, and mouse serum antibodies significantly inhibited in vitro adherence of bacteria expressing these seven adhesins. These results revealed congruence of antigen immunogenicity between computational simulation and empirical mouse immunization and indicated this tag-less CFA/I/II/IV MEFA potentially an antigen for a broadly protective ETEC vaccine, suggesting a potential application of MEFA-based structural vaccinology for vaccine design against ETEC and likely other pathogens.
Highlights
Heterogeneity of enterotoxigenic Escherichia coli (ETEC) bacterial virulence factors is a major challenge for vaccine development
ETEC bacteria that produce adhesins to attach to different host receptors and enterotoxins to disrupt fluid homeostasis in small intestinal epithelial cells, are a leading cause of diarrhea in children under the age of 5 years in developing countries and in children and adults traveling from developed countries to ETEC endemic regions [1,2,3]
Structure-based vaccine design or structural vaccinology aided by computational modeling and atomistic simulation provides a new tool to overcome antigen heterogeneity challenge in vaccine development [18,34,35,36,37,38,39,40]
Summary
Heterogeneity of enterotoxigenic Escherichia coli (ETEC) bacterial virulence factors is a major challenge for vaccine development. Because adhesin-mediated bacterial adherence to host cell receptors initiates ETEC infection, vaccines that induce antibodies preventing ETEC bacteria from adhering to host cells have been long regarded effective against ETEC infection. Developing vaccines to prevent ETEC bacteria adherence and colonization, is hampered by the heterogeneity of ETEC bacterial adhesins. Different ETEC strains produce immunologically heterogeneous adhesins [8,9,10]. Antibodies derived from one type of adhesin may not block attachment of ETEC bacteria expressing different adhesins. The conventional approach by mixing together several live or killed strains that express a few different adhesins led to vaccine candidates that induce antibodies against homologous adhesins [11,12,13,14]. A novel strategy using reverse vaccinology and computer-aided structure-based multiepitope fusion antigen (MEFA) vaccine design has been explored to develop a safer and more effective ETEC vaccine
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