Immune response characterization in a human challenge study with a Shigella flexneri 2a bioconjugate vaccine
Kristen A. Clarkson,
Kawsar R. Talaat,
Cristina Alaimo,
Patricia Martin,
A. Louis Bourgeois,
Anita Dreyer,
Chad K. Porter,
Subhra Chakraborty,
Jessica Brubaker,
Daniel Elwood,
Rahel Frölich,
Barbara DeNearing,
Hailey P. Weerts,
Brittany Feijoo,
Jane Halpern,
David Sack,
Mark S. Riddle,
Veronica Gambillara Fonck,
Robert W. Kaminski
Affiliations
Kristen A. Clarkson
Department of Enteric Infections, Bacterial Diseases Branch, Walter Reed Army Institute of Research, Silver Spring, MD, United States
Kawsar R. Talaat
Department of International Health, Johns Hopkins Bloomberg School of Public Health, Baltimore, MD, United States
Cristina Alaimo
LimmaTech Biologics AG, Schlieren, Switzerland
Patricia Martin
LimmaTech Biologics AG, Schlieren, Switzerland
A. Louis Bourgeois
PATH, Washington, DC, United States
Anita Dreyer
LimmaTech Biologics AG, Schlieren, Switzerland
Chad K. Porter
Naval Medical Research Center, Silver Spring, MD, United States
Subhra Chakraborty
Department of International Health, Johns Hopkins Bloomberg School of Public Health, Baltimore, MD, United States
Jessica Brubaker
Department of International Health, Johns Hopkins Bloomberg School of Public Health, Baltimore, MD, United States
Daniel Elwood
Department of International Health, Johns Hopkins Bloomberg School of Public Health, Baltimore, MD, United States
Rahel Frölich
LimmaTech Biologics AG, Schlieren, Switzerland
Barbara DeNearing
Department of International Health, Johns Hopkins Bloomberg School of Public Health, Baltimore, MD, United States
Hailey P. Weerts
Department of Enteric Infections, Bacterial Diseases Branch, Walter Reed Army Institute of Research, Silver Spring, MD, United States
Brittany Feijoo
Department of International Health, Johns Hopkins Bloomberg School of Public Health, Baltimore, MD, United States
Jane Halpern
Department of International Health, Johns Hopkins Bloomberg School of Public Health, Baltimore, MD, United States
David Sack
Department of International Health, Johns Hopkins Bloomberg School of Public Health, Baltimore, MD, United States
Mark S. Riddle
Naval Medical Research Center, Silver Spring, MD, United States
Veronica Gambillara Fonck
LimmaTech Biologics AG, Schlieren, Switzerland
Robert W. Kaminski
Department of Enteric Infections, Bacterial Diseases Branch, Walter Reed Army Institute of Research, Silver Spring, MD, United States; Corresponding author.
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.
