Abstract
BackgroundShigella is a major diarrheal pathogen for which there is presently no vaccine. Whole genome sequencing provides the ability to predict and derive novel antigens for use as vaccines. Here, we aimed to identify novel immunogenic Shigella antigens that could serve as Shigella vaccine candidates, either alone, or when conjugated to Shigella O-antigen.MethodsUsing a reverse vaccinology approach, where genomic analysis informed the Shigella immunome via an antigen microarray, we aimed to identify novel immunogenic Shigella antigens. A core genome analysis of Shigella species, pathogenic and non-pathogenic Escherichia coli, led to the selection of 234 predicted immunogenic Shigella antigens. These antigens were expressed and probed with acute and convalescent serum from microbiologically confirmed Shigella infections.ResultsSeveral Shigella antigens displayed IgG and IgA seroconversion, with no difference in sero-reactivity across by sex or age. IgG sero-reactivity to key Shigella antigens was observed at birth, indicating transplacental antibody transfer. Six antigens (FepA, EmrK, FhuA, MdtA, NlpB, and CjrA) were identified in in vivo testing as capable of producing binding IgG and complement-mediated bactericidal antibody.ConclusionsThese findings provide six novel immunogenic Shigella proteins that could serve as candidate vaccine antigens, species-specific carrier proteins, or targeted adjuvants.
Highlights
Shigella is a major diarrheal pathogen for which there is presently no vaccine
Bioinformatic analysis identifies potential immunogenic Shigella core antigens Genomic comparison of Shigella and E. coli core genomes was conducted with the aim of selecting both species-specific and species cross-reactive Shigella proteins common to the most globally dominant species, S. flexneri and S. sonnei
Protein sequences were extracted from the annotated chromosomes of various Shigella species (n = 10), pathogenic (n = 32) and non-pathogenic (n = 15) E. coli (Table 1 and Additional File 2 Table S1), and a list of potentially immunogenic antigens was selected using bioinformatic comparison, a list of potentially immunogenic antigens was selected (Table 2 and Additional File 5 Table S3)
Summary
Shigella is a major diarrheal pathogen for which there is presently no vaccine. Whole genome sequencing provides the ability to predict and derive novel antigens for use as vaccines. Antibodies against Shigella O-antigen are highly specific for the infecting species only [11, 13], and do not provide protection against heterologous Shigella species. Since the Shigella genus consists of four species and > 50 serotypes, a lack of cross-protection against heterologous species and serotypes poses a major challenge for vaccine development [16]. This challenge may be overcome by a vaccine that elicits either a broadly reactive immune response or numerous species-specific responses against the globally dominant Shigella species (i.e., S. flexneri and S. sonnei) [17]
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