Immune response characterization in a human challenge study with a Shigella flexneri 2a bioconjugate vaccine

Abstract

Background 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. 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. Methods Flexyn2a 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. Findings Flexyn2a 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. 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. Funding Funding for this study was provided through a Wellcome Trust grant.

Repertoire of naturally acquired maternal antibodies transferred to infants for protection against shigellosis

“…Mouse monoclonal antibodies specific for Shigella LPS were reported to have bactericidal activity (24). Several studies have reported increases in SBA titers in response to Shigella polysaccharide-based vaccine candidates in adult volunteers (25-27). LPS is therefore presumed to be the main antigenic target of antibody-mediated shigellacidal activity.…”

Safety and immunogenicity of intramuscularly administered CS6 subunit vaccine with a modified heat-labile enterotoxin from enterotoxigenic Escherichia coli

“…There were no significant differences in the response rates or the peak responses in subjects receiving 15 and 45 µg of CssBA (with 0.5 μg dmLT). Further analyses are being performed with faecal and saliva samples, as well as with mucosal-homing α4β7 + antibody-secreting cells, to assess whether the IM vaccination with CssBA + dmLT is able to elicit mucosal responses as has been seen with other parenterally administered vaccines [40] . These data will be important given that mucosal antibody production is thought to be required for protection against ETEC-attributable illness [17] .…”

Vaccines for Protecting Infants from Bacterial Causes of Diarrheal Disease

“…CHIMs have been established for all three target pathogens [ 52 , 143 , 144 , 145 ]. CHIM studies have the potential to play a crucial role in the testing of vaccine candidates for these three pathogens for downselection and de-risking advancement to expensive Phase 3 field studies.…”

“…The Shigella CHIM has a key role to play in the development of vaccines to prevent shigellosis. Several of the most advanced candidates have been tested in CHIM studies, including Flexyn2a [ 143 ] and GSK3536852A [ 144 ]. The results of these trials are drivers of the decisions of whether to advance one of these candidates to Phase 3 field studies.…”