scholarly journals Colonisation Factor CD0873, an Attractive Oral Vaccine Candidate against Clostridioides difficile

2021 ◽  
Vol 9 (2) ◽  
pp. 306
Author(s):  
Cansu Karyal ◽  
Jaime Hughes ◽  
Michelle L. Kelly ◽  
Jeni C. Luckett ◽  
Philip V. Kaye ◽  
...  
Keyword(s):  
Pseudomembranous Colitis ◽  
Vaccine Candidate ◽  
Oral Vaccine ◽  
Immunoglobulin A ◽  
Oral Route ◽  
Hamster Model ◽  
Clostridioides Difficile ◽  
Mucosal Antibody ◽  
Gut Pathogens ◽  
Secretory Immunoglobulin

Clostridioides difficile is the main cause of health-care-associated infectious diarrhoea. Toxins, TcdA and TcdB, secreted by this bacterium damage colonic epithelial cells and in severe cases this culminates in pseudomembranous colitis, toxic megacolon and death. Vaccines in human trials have focused exclusively on the parenteral administration of toxin-based formulations. These vaccines promote toxin-neutralising serum antibodies but fail to confer protection from infection in the gut. An effective route to immunise against gut pathogens and stimulate a protective mucosal antibody response (secretory immunoglobulin A, IgA) at the infection site is the oral route. Additionally, oral immunisation generates systemic antibodies (IgG). Using this route, two different antigens were tested in the hamster model: The colonisation factor CD0873 and a TcdB fragment. Animals immunised with CD0873 generated a significantly higher titre of sIgA in intestinal fluid and IgG in serum compared to naive animals, which significantly inhibited the adherence of C. difficile to Caco-2 cells. Following challenge with a hypervirulent isolate, the CD0873-immunised group showed a mean increase of 80% in time to experimental endpoint compared to naïve animals. Survival and body condition correlated with bacterial clearance and reduced pathology in the cecum. Our findings advocate CD0873 as a promising oral vaccine candidate against C. difficile.

scholarly journals Oral Immunotherapy With Human Secretory Immunoglobulin A Improves Survival in the Hamster Model of Clostridioides difficile Infection

2021 ◽  
Author(s):  
Estelle F Chiari ◽  
William Weiss ◽  
Michael R Simon ◽  
Stephan T Kiessig ◽  
Mark Pulse ◽  
...  
Keyword(s):  
Immunoglobulin A ◽  
Passive Immunization ◽  
Secretory Component ◽  
Oral Immunotherapy ◽  
Secretory Iga ◽  
Hamster Model ◽  
Clostridioides Difficile ◽  
Clostridioides Difficile Infection ◽  
Secretory Immunoglobulin ◽  
Donor Plasma

Abstract Coadministration of human secretory IgA (sIgA) together with subtherapeutic vancomycin enhanced survival in the Clostridioides difficile infection (CDI) hamster model. Vancomycin (5 or 10 mg/kg × 5 days) plus healthy donor plasma sIgA/monomeric IgA (TID × 21 days) or hyperimmune sIgA/monomeric IgA (BID × 13 days) enhanced survival. Survival was improved compared to vancomycin alone, P = .018 and .039 by log-rank Mantel-Cox, for healthy and hyperimmune sIgA, respectively. Passive immunization with sIgA (recombinant human secretory component plus IgA dimer/polymer from pooled human plasma) can be administered orally and prevents death in a partially treated CDI hamster model.

scholarly journals The immune landscape of IgA induction in the gut

2021 ◽  
Author(s):  
Claudia Seikrit ◽  
Oliver Pabst
Keyword(s):  
Protective Immunity ◽  
Immunoglobulin A ◽  
Antibody Responses ◽  
Dark Side ◽  
Secretory Immunoglobulin A ◽  
Antibody Isotype ◽  
Mucosal Antibody ◽  
Key Concepts ◽  
Basic Understanding ◽  
Secretory Immunoglobulin

AbstractAntibodies are key elements of protective immunity. In the mucosal immune system in particular, secretory immunoglobulin A (SIgA), the most abundantly produced antibody isotype, protects against infections, shields the mucosal surface from toxins and environmental factors, and regulates immune homeostasis and a peaceful coexistence with our microbiota. However, the dark side of IgA biology promotes the formation of immune complexes and provokes pathologies, e.g., IgA nephropathy (IgAN). The precise mechanisms of how IgA responses become deregulated and pathogenic in IgAN remain unresolved. Yet, as the field of microbiota research moved into the limelight, our basic understanding of IgA biology has been taking a leap forward. Here, we discuss the structure of IgA, the anatomical and cellular foundation of mucosal antibody responses, and current concepts of how we envision the interaction of SIgA and the microbiota. We center on key concepts in the field while taking account of both historic findings and exciting new observations to provide a comprehensive groundwork for the understanding of IgA biology from the perspective of a mucosal immunologist.

scholarly journals A Pathogen-specific Epitope Inserted into Recombinant Secretory Immunoglobulin A Is Immunogenic by the Oral Route

1996 ◽  
Vol 271 (52) ◽  
pp. 33670-33677 ◽  
Author(s):  
Blaise Corthésy ◽  
Muriel Kaufmann ◽  
Armelle Phalipon ◽  
Manuel Peitsch ◽  
Marian R. Neutra ◽  
...  
Keyword(s):  
Immunoglobulin A ◽  
Oral Route ◽  
Secretory Immunoglobulin A ◽  
Specific Epitope ◽  
Secretory Immunoglobulin

scholarly journals Oral Immunization with NontoxigenicClostridium difficileStrains Expressing Chimeric Fragments of TcdA and TcdB Elicits Protective Immunity againstC. difficileInfection in Both Mice and Hamsters

2018 ◽  
Vol 86 (11) ◽  
Author(s):  
Yuanguo Wang ◽  
Shaohui Wang ◽  
Laurent Bouillaut ◽  
Chunhui Li ◽  
Zhibian Duan ◽  
...  
Keyword(s):  
Vaccine Candidate ◽  
Cysteine Proteinase ◽  
Oral Vaccine ◽  
Lethal Dose ◽  
Disease Onset ◽  
Oral Immunization ◽  
Mucosal Vaccine ◽  
Hamster Model ◽  
Content Type ◽  
Protection Against Infection

ABSTRACTThe symptoms ofClostridium difficileinfection (CDI) are attributed largely to twoC. difficiletoxins, TcdA and TcdB. Significant efforts have been devoted to developing vaccines targeting both toxins through parenteral immunization routes. However,C. difficileis an enteric pathogen, and mucosal/oral immunization would be particularly useful to protect the host against CDI, considering that the gut is the main site of disease onset and progression. Moreover, vaccines directed only against toxins do not target the cells and spores that transmit the disease. Previously, we constructed a chimeric vaccine candidate, mTcd138, comprised of the glucosyltransferase and cysteine proteinase domains of TcdB and the receptor binding domain of TcdA. In this study, to develop an oral vaccine that can target bothC. difficiletoxins and colonization/adhesion factors, we expressed mTcd138 in a nontoxigenicC. difficile(NTCD) strain, resulting in strain NTCD_mTcd138. Oral immunization with spores of NTCD_mTcd138 provided mice full protection against infection with a hypervirulentC. difficilestrain, UK6 (ribotype 027). The protective strength and efficacy of NTCD_mTcd138 were further evaluated in the acute CDI hamster model. Oral immunization with spores of NTCD_mTcd138 also provided hamsters significant protection against infection with 2 × 104UK6 spores, a dose 200-fold higher than the lethal dose of UK6 in hamsters. These results imply that the genetically modified, nontoxigenicC. difficilestrain expressing mTcd138 may represent a novel mucosal vaccine candidate against CDI.

scholarly journals Phylogenomic analysis of Clostridioides difficile ribotype 106 strains reveals novel genetic islands and emergent phenotypes

2020 ◽  
Vol 10 (1) ◽  
Author(s):  
Bryan Angelo P. Roxas ◽  
Jennifer Lising Roxas ◽  
Rachel Claus-Walker ◽  
Anusha Harishankar ◽  
Asad Mansoor ◽  
...  
Keyword(s):  
Biofilm Formation ◽  
Diarrheal Disease ◽  
The United States ◽  
Genomic Islands ◽  
Rapid Expansion ◽  
Phylogenomic Analysis ◽  
Community Settings ◽  
Hamster Model ◽  
Clostridioides Difficile ◽  
Healthcare Associated

AbstractClostridioides difficile infection (CDI) is a major healthcare-associated diarrheal disease. Consistent with trends across the United States, C. difficile RT106 was the second-most prevalent molecular type in our surveillance in Arizona from 2015 to 2018. A representative RT106 strain displayed robust virulence and 100% lethality in the hamster model of acute CDI. We identified a unique 46 KB genomic island (GI1) in all RT106 strains sequenced to date, including those in public databases. GI1 was not found in its entirety in any other C. difficile clade, or indeed, in any other microbial genome; however, smaller segments were detected in Enterococcus faecium strains. Molecular clock analyses suggested that GI1 was horizontally acquired and sequentially assembled over time. GI1 encodes homologs of VanZ and a SrtB-anchored collagen-binding adhesin, and correspondingly, all tested RT106 strains had increased teicoplanin resistance, and a majority displayed collagen-dependent biofilm formation. Two additional genomic islands (GI2 and GI3) were also present in a subset of RT106 strains. All three islands are predicted to encode mobile genetic elements as well as virulence factors. Emergent phenotypes associated with these genetic islands may have contributed to the relatively rapid expansion of RT106 in US healthcare and community settings.

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