Immune response characterization in a human challenge study with a Shigella flexneri 2a bioconjugate vaccine.
Antibodies, Bacterial
/ immunology
Antibody Specificity
/ immunology
Dysentery, Bacillary
/ immunology
Humans
Immunity
Immunoglobulin A
/ blood
Immunoglobulin G
/ blood
Immunoglobulin M
/ blood
Immunologic Memory
Lipopolysaccharides
/ immunology
Lymphocytes
/ immunology
Shigella Vaccines
/ administration & dosage
Shigella flexneri
/ immunology
Vaccination
Bioconjugate vaccine
Gut-homing responses
Human challenge
Immunogenicity
Parenteral immunization
Shigella
Journal
EBioMedicine
ISSN: 2352-3964
Titre abrégé: EBioMedicine
Pays: Netherlands
ID NLM: 101647039
Informations de publication
Date de publication:
Apr 2021
Apr 2021
Historique:
received:
24
10
2020
revised:
13
02
2021
accepted:
12
03
2021
pubmed:
5
4
2021
medline:
30
11
2021
entrez:
4
4
2021
Statut:
ppublish
Résumé
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. 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. 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. 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 for this study was provided through a Wellcome Trust grant.
Sections du résumé
BACKGROUND
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
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
RESULTS
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
CONCLUSIONS
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
BACKGROUND
Funding for this study was provided through a Wellcome Trust grant.
Identifiants
pubmed: 33813141
pii: S2352-3964(21)00101-8
doi: 10.1016/j.ebiom.2021.103308
pmc: PMC8047506
pii:
doi:
Substances chimiques
Antibodies, Bacterial
0
Immunoglobulin A
0
Immunoglobulin G
0
Immunoglobulin M
0
Lipopolysaccharides
0
Shigella Vaccines
0
Types de publication
Journal Article
Langues
eng
Sous-ensembles de citation
IM
Pagination
103308Commentaires et corrections
Type : CommentIn
Informations de copyright
Published by Elsevier B.V.
Déclaration de conflit d'intérêts
Declaration of Competing Interest CA, ALB, JB, KAC, BD, AMD, DE, BF, RF, VGF, JH, RWK, PM, DS, KRT, HPW report grants from Wellcome Trust during the conduct of the study. SC, CKP, MSR report no conflicts of interest for any of the materials presented in the manuscript.