Abstract
BackgroundDiarrheal diseases are a leading cause of global morbidity and mortality affecting all ages, but especially children under the age of five in resource-limited settings. Shigella is a leading contributor to diarrheal diseases caused by bacterial pathogens and is considered a significant antimicrobial resistance threat. While improvements in hygiene, and access to clean water help as control measures, vaccination remains one of the most viable options for significantly reducing morbidity and mortality. MethodsFlexyn2a is a bioconjugate vaccine manufactured using novel conjugation methodologies enzymatically linking the O-polysaccharide of S. flexneri 2a to exotoxin A of Pseudomonas aeruginosa. The protective capacity of Flexyn2a was assessed in a controlled human infection model after two intramuscular immunizations. Immune responses pre- and post-immunization and/or infection were investigated and are described here. FindingsFlexyn2a induced lipopolysaccharide (LPS)-specific serum IgG responses post-immunization which were associated with protection against shigellosis. Additionally, several other immune parameters, including memory B cell responses, bactericidal antibodies and serum IgA, were also elevated in vaccinees protected against shigellosis. Immunization with Flexyn2a also induced gut-homing, LPS-specific IgG and IgA secreting B cells, indicating the vaccine induced immune effectors functioning at the site of intestinal infection. InterpretationCollectively, the results of these immunological investigations provide insights into protective immune mechanisms post-immunization with Flexyn2a which can be used to further guide vaccine development and may have applicability to the larger Shigella vaccine field. FundingFunding for this study was provided through a Wellcome Trust grant.
Highlights
Shigella species are one of the leading causes of diarrhea-associated morbidity and mortality across all age groups and is the second leading cause of death in children under the age of 5 years [1,2]
The current challenge study was designed to assess the efficacy of the Flexyn2a vaccine, which has an excellent safety and immunogenicity profile as previously published; this study provided the unique opportunity to thoroughly investigate the immune responses associated with protection from Shigella infection after parenteral immunization with a conjugate vaccine
Vaccinated subjects protected from shigellosis caused by S. flexneri 2a had robust increases over baseline serum IgG titres; comparable significant increases over baseline were not observed in vaccinated subjects with shigellosis
Summary
Shigella species are one of the leading causes of diarrhea-associated morbidity and mortality across all age groups and is the second leading cause of death in children under the age of 5 years [1,2]. Diarrheal diseases are a leading cause of global morbidity and mortality affecting all ages, but especially children under the age of five in resource-limited settings. Findings: Flexyn2a induced lipopolysaccharide (LPS)-specific serum IgG responses post-immunization which were associated with protection against shigellosis. Immunization with Flexyn2a induced gut-homing, LPS-specific IgG and IgA secreting B cells, indicating the vaccine induced immune effectors functioning at the site of intestinal infection. Interpretation: Collectively, the results of these immunological investigations provide insights into protective immune mechanisms post-immunization with Flexyn2a which can be used to further guide vaccine development and may have applicability to the larger Shigella vaccine field.
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