The Prospect for Vaccines to Prevent Clostridium difficile Infection

Ghose, Chandrabali; Kelly, Ciarán P.

doi:10.1016/j.idc.2014.11.013

Cited by 43 publications

(38 citation statements)

References 94 publications

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“…Current vaccine approaches have focused on humoral immunity and neutralization of toxins A and B, which are considered the primary virulence factors (8,9). Thus, vaccines currently in clinical evaluation use parenteral administration of toxoids (A and B) or defined segments of them (10). These vaccines generate antitoxin IgG, and preclinical studies show protection (11).…”

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confidence: 99%

Mucosal Antibodies to the C Terminus of Toxin A Prevent Colonization of Clostridium difficile

et al. 2017

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Mucosal immunity is considered important for protection against Clostridium difficile infection (CDI). We show that in hamsters immunized with Bacillus subtilis spores expressing a carboxy-terminal segment (TcdA 26 -39 ) of C. difficile toxin A, no colonization occurs in protected animals when challenged with C. difficile strain 630. In contrast, animals immunized with toxoids showed no protection and remained fully colonized. Along with neutralizing toxins, antibodies to TcdA 26 -39 (but not to toxoids), whether raised to the recombinant protein or to TcdA 26 -39 expressed on the B. subtilis spore surface, cross-react with a number of seemingly unrelated proteins expressed on the vegetative cell surface or spore coat of C. difficile. These include two dehydrogenases, AdhE1 and LdhA, as well as the CdeC protein that is present on the spore. Anti-TcdA 26 -39 mucosal antibodies obtained following immunization with recombinant B. subtilis spores were able to reduce the adhesion of C. difficile to mucus-producing intestinal cells. This cross-reaction is intriguing yet important since it illustrates the importance of mucosal immunity for complete protection against CDI.

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confidence: 99%

Mucosal Antibodies to the C Terminus of Toxin A Prevent Colonization of Clostridium difficile

et al. 2017

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“…Indeed, early preclinical efforts to develop a vaccine against CDI focused on toxoid preparations of toxin A and toxin B formulated with alum, and were designed to elicit systemic antibody responses against both toxins. A number of C. difficile toxin-based vaccines are currently in human clinical trials [19,20].…”

Section: Clostridium Difficilementioning

confidence: 99%

Vaccines for Healthcare-associated Infections: Promise and Challenge

et al. 2016

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As antibiotic resistance increases and the rate of antibiotic development slows, it is becoming more urgent to develop novel approaches to prevent and mitigate serious bacterial and fungal infections. Healthcare-associated infections (HAIs), including those caused by Clostridium difficile, Staphylococcus aureus, Pseudomonas aeruginosa, Acinetobacter baumannii, carbapenem-resistant Enterobacteriaceae, and Candida species, are a major cause of morbidity, mortality, and healthcare costs. HAIs are also a key driver of antibiotic use. Vaccines directed toward these pathogens could help prevent a large number of HAIs and associated antibiotic use if administered to targeted populations. Despite numerous scientific and operational challenges, there are vaccine candidates in late-stage clinical development for C. difficile, S. aureus, and P. aeruginosa. Basic, preclinical, and early clinical research to develop vaccines for other types of HAIs is also under way. In addition, other prophylactic immune interventions, such as monoclonal antibodies, for several of these pathogens are in advanced development. Here we describe the promise, challenges, and current pipeline of vaccines to prevent HAIs.

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“…These conflicting reports may be attributed to heterogeneity in study design and subject populations. Although the role of humoral immunity remains incompletely understood, vaccination strategies using inactivated toxins or recombinant toxin fragments are currently the subject of intense investigation (22,23). More recently, the possibility of adding other vaccine targets, such as surface-associated proteins and polysaccharides, to toxin combinations is gaining traction and could be of added value in the prevention of C. difficile colonization and disease transmission (22,23).…”

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confidence: 99%

“…Although the role of humoral immunity remains incompletely understood, vaccination strategies using inactivated toxins or recombinant toxin fragments are currently the subject of intense investigation (22,23). More recently, the possibility of adding other vaccine targets, such as surface-associated proteins and polysaccharides, to toxin combinations is gaining traction and could be of added value in the prevention of C. difficile colonization and disease transmission (22,23). It is likely that the design of these next-generation multicomponent vaccines targeting colonization, persistence, and toxin production will stimulate the requirement for evaluating humoral immune responses to multiple antigens.…”

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confidence: 99%

“…We and other groups (13,15,(18)(19)(20) have independently developed and used a traditional standardized ELISA format for the purposes of determining human specific IgG responses against C. difficile antigens (toxins). However, ELISAbased tests can be time consuming and require large quantities of both sample and reagents, thus limiting their potential for highthroughput use (23,24). ELISA offers only monoplex data, or results of a single protein per assay (typically TcdA, TcdB, or SLPs) and from a single C. difficile strain.…”

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confidence: 99%

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Profiling Humoral Immune Responses to Clostridium difficile-Specific Antigens by Protein Microarray Analysis

Negm

Hamed

Dilnot

et al. 2015

Clin Vaccine Immunol

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g Clostridium difficile is an anaerobic, Gram-positive, and spore-forming bacterium that is the leading worldwide infective cause of hospital-acquired and antibiotic-associated diarrhea. Several studies have reported associations between humoral immunity and the clinical course of C. difficile infection (CDI). Host humoral immune responses are determined using conventional enzyme-linked immunosorbent assay (ELISA) techniques. Herein, we report the first use of a novel protein microarray assay to determine systemic IgG antibody responses against a panel of highly purified C. difficile-specific antigens, including native toxins A and B (TcdA and TcdB, respectively), recombinant fragments of toxins A and B (TxA4 and TxB4, respectively), ribotypespecific surface layer proteins (SLPs; 001, 002, 027), and control proteins (tetanus toxoid and Candida albicans). Microarrays were probed with sera from a total of 327 individuals with CDI, cystic fibrosis without diarrhea, and healthy controls. For all antigens, precision profiles demonstrated <10% coefficient of variation (CV). Significant correlation was observed between microarray and ELISA in the quantification of antitoxin A and antitoxin B IgG. These results indicate that microarray is a suitable assay for defining humoral immune responses to C. difficile protein antigens and may have potential advantages in throughput, convenience, and cost. C lostridium difficile is the leading worldwide infective cause of hospital-acquired and antibiotic-associated diarrhea, imposing a considerable financial burden on health service providers in both Europe and the United States (1-3). Infection causes a spectrum of clinical presentations ranging from an asymptomatic carrier state to severe fulminant colitis and death (4). Following successful treatment, an estimated 20% to 30% of patients with primary C. difficile infection (CDI) develop recurrence of symptoms, caused by either relapse of the original infection or reinfection with a new strain (5).This anaerobic and spore-forming bacterium exerts its major pathological effects through two proinflammatory and cytotoxic protein exotoxins, TcdA (toxin A) and TcdB (toxin B) (6). Nontoxin virulence factors, such as surface layer proteins (SLPs) and cell wall proteins, have also been described and may play a role in disease expression (7-9).The majority of healthy adults have detectable antibodies to C. difficile TcdA and TcdB in their sera that are thought to arise from colonization in infancy or from repeated exposure to C. difficile in adulthood from the environment (10, 11). Several clinical studies suggest that adaptive humoral immune responses, in particular to TcdA and TcdB, may influence clinical outcomes of CDI (12). Most notably, a landmark study in 2000 reported that a low IgG titer to TcdA, but not TcdB, at the time of infection is associated with development of symptomatic disease (13). More recently, the same group demonstrated an association between median IgG titers to TcdA and 30-day all-cause mortality (14). Several r...

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The Prospect for Vaccines to Prevent Clostridium difficile Infection

Cited by 43 publications

References 94 publications

Mucosal Antibodies to the C Terminus of Toxin A Prevent Colonization of Clostridium difficile

Mucosal Antibodies to the C Terminus of Toxin A Prevent Colonization of Clostridium difficile

Vaccines for Healthcare-associated Infections: Promise and Challenge

Profiling Humoral Immune Responses to Clostridium difficile-Specific Antigens by Protein Microarray Analysis

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