@article{a2e3737a796e45478e00505ff60ba22b,
title = "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.",
keywords = "Bioconjugate vaccine, Gut-homing responses, Human challenge, Immunogenicity, Parenteral immunization, Shigella",
author = "Clarkson, {Kristen A.} and Talaat, {Kawsar R.} and Cristina Alaimo and Patricia Martin and Louis Bourgeois and Anita Dreyer and Porter, {Chad K.} and Subhra Chakraborty and Jessica Brubaker and Daniel Elwood and Rahel Fr{\"o}lich and Barbara DeNearing and Weerts, {Hailey P.} and Brittany Feijoo and Jane Halpern and David Sack and Riddle, {Mark S.} and Fonck, {Veronica Gambillara} and Kaminski, {Robert W.}",
note = "Funding Information: The authors would like to acknowledge and thank the Wellcome Trust for providing funding for this study. All authors have read and approved the final version of this manuscript. KAC: Conducted laboratory immunoassays, data analysis and interpretation, drafted and edited manuscript. KRT: Helped with study design, oversaw conduct of study and care of volunteers, assisted with data analysis and interpretation, contributed to manuscript and editing. CA: Helped with study design, data analysis, interpretation, contributed to manuscript and editing. PM: Helped with data interpretation, contributed to manuscript and editing. ALB: Helped with study design, helped prepare challenge strain, significantly contributed to writing and editing of manuscript. AMD: Helped with statistical and laboratory analysis design, contributed to manuscript and editing. CKP: Helped with study design, developed statistical analysis plan, contributed to data analysis and statistical analysis, significantly contributed to writing and editing of manuscript. SC: Oversaw clinical laboratory assays and analysis, gave feedback on the manuscript. JB: Helped prepare challenge strain, conducted clinical laboratory assays and analysis, provided data for manuscript, approved manuscript. DE: Coordinated study, gave feedback on paper. RF: Helped with study coordination and documentation of clinical operations. BD: Coordinated study, gave feedback on paper. HW: Performed laboratory immunoassays for the study and provided feedback on the paper. BF: Performed clinical assessments and clinical care of volunteers, gave feedback on the manuscript. JH: Performed clinical assessments and clinical care of volunteers, gave feedback on the paper. DS: Oversaw clinical laboratories, assisted with regulatory aspects, served as study advisor. MSR: Independent medical monitor for study, helped with study design, data interpretation and gave feedback on paper. VGF: Oversaw trial from Sponsor perspective, helped with study design, analysed data and gave feedback on paper. RWK: Helped with study design, provided challenge strain, oversaw immunoassay laboratories, contributed to data analysis and interpretation, significantly contributed to writing and editing of manuscript. The data that support the findings of this study will be available on clinicaltrials.gov (NCT02646371) and from the corresponding author upon reasonable request. Material has been reviewed by the Walter Reed Army Institute of Research. There is no objection to its presentation and/or publication. The opinions or assertions contained herein are the private views of the author, and are not to be construed as official, or as reflecting true views of the Department of the Army or the Department of Defense. The investigators have adhered to the policies for protection of human subjects as prescribed in AR 70–25. Some authors (KAC, CKP, RWK) are employees of the U.S. Government. This work was prepared as part of their official duties. Title 17 U.S.C. §105 provides that “Copyright protection under this title is not available for any work of the United States Government.” Title 17 U.S.C. §101 defines a U.S. Government work as a work prepared by a military service member or employee of the U.S. Government as part of that person's official duties. Funding Information: The authors would like to acknowledge and thank the Wellcome Trust for providing funding for this study. Publisher Copyright: {\textcopyright} 2021",
year = "2021",
month = apr,
doi = "10.1016/j.ebiom.2021.103308",
language = "English (US)",
volume = "66",
journal = "EBioMedicine",
issn = "2352-3964",
publisher = "Elsevier BV",
}