Safety, immunogenicity and dose response of VLA84, a new vaccine candidate against Clostridium difficile, in healthy volunteers

Bézay, Nicole; Ayad, Andrea; Dubischar, Katrin; Firbas, Christa; Hochreiter, Romana; Kiermayr, Sigrid; Kiss, István; Pinl, Fritz; Jilma, Bernd; Westritschnig, Kerstin

doi:10.1016/j.vaccine.2016.03.098

Cited by 69 publications

(58 citation statements)

References 15 publications

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“…A vaccine developed by Pfizer using genetically modified full length TcdA and TcdB have completed phase II testing and phase III begun this year (Tian et al, 2012). VLA84, a recombinant vaccine consisting of truncated TcdA fused to TcdB has completed phase I study (Bezay et al, 2016). Although results from these clinical trials have generally been positive, but the long term protection afforded by these vaccine remains unknown.…”

Section: Discussionmentioning

confidence: 99%

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Immunization with Recombinant TcdB-Encapsulated Nanocomplex Induces Protection against Clostridium difficile Challenge in a Mouse Model

Liu

Chen

et al. 2017

Front. Microbiol.

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Clostridium difficile is considered to be one of the major cause of infectious diarrhea in healthcare systems worldwide. Symptoms of C. difficile infection are caused largely by the production of two cytotoxins: toxin A (TcdA) and toxin B (TcdB). Vaccine development is considered desirable as it would decrease the mounting medical costs and mortality associated with C. difficile infections. Biodegradable nanoparticles composed of poly-γ-glutamic acid (γ-PGA) and chitosan have proven to be a safe and effective antigen delivery system for many viral vaccines. However, few studies have used this efficient antigen carrier for bacterial vaccine development. In this study, we eliminated the toxin activity domain of toxin B by constructing a recombinant protein rTcdB consists of residues 1852-2363 of TcdB receptor binding domain. The rTcdB was encapsulated in nanoparticles composed of γ-PGA and chitosan. Three rounds of intraperitoneal vaccination led to high anti-TcdB antibody responses and afforded mice full protection mice from lethal dose of C. difficile spore challenge. Protection was associated with high levels of toxin-neutralizing antibodies, and the rTcdB-encapsulated NPs elicited a longer-lasting antibody titers than antigen with the conventional adjuvant, aluminum hydroxide. Significant reductions in the level of proinflammatory cytokines and chemokines were observed in vaccinated mouse. These results suggested that polymeric nanocomplex-based vaccine design can be useful in developing vaccine against C. difficile infections.

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Section: Discussionmentioning

confidence: 99%

“…Past immunization studies using the RBDs of C. difficile toxins have been shown to induce antibody responses with toxin-neutralizing activity in mice or hamsters challenged with either toxins or live bacteria (Baliban et al, 2014; Maynard-Smith et al, 2014; Guo et al, 2015; Huang et al, 2015; Wang et al, 2015; Bezay et al, 2016). …”

Section: Introductionmentioning

confidence: 99%

Immunization with Recombinant TcdB-Encapsulated Nanocomplex Induces Protection against Clostridium difficile Challenge in a Mouse Model

Liu

Chen

et al. 2017

Front. Microbiol.

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“…VLA84 (IC84) is a recombinant vaccine developed by Valneva™ that is composed of truncated portions of C. difficile toxins A and B. In a phase I trial of 51 adult and 50 elderly patients, VLA84 was well tolerated and induced high levels of antibodies against C. difficile toxins A and B . A phase II trial (NCT02316470) was completed in 2015, in which patients were divided into four groups receiving either VLA84 75 μg without Alum (150 patients), VLA84 200 μg without Alum (150 patients), VLA84 200 μg with Alum (150 patients), or placebo (50 patients).…”

Section: Areas For Improvement and Targets For Emerging Therapiesmentioning

confidence: 99%

Novel therapies and preventative strategies for primary and recurrent Clostridium difficile infections

Dieterle

Rao

Young

2018

Annals of the New York Academy of Sciences

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Clostridium difficile is the leading infectious cause of antibiotic-associated diarrhea and colitis. Clostridium difficile infection (CDI) places a heavy burden on the health care system, with nearly half a million infections yearly and an approximate 20% recurrence risk after successful initial therapy. The high incidence has driven new research on improved prevention such as the emerging use of probiotics, intestinal microbiome manipulation during antibiotic therapies, vaccinations, and newer antibiotics that reduce the disruption of the intestinal microbiome. While the treatment of acute C. difficile is effective in most patients, it can be further optimized by adjuvant therapies that improve the initial treatment success and decrease the risk of subsequent recurrence. Lastly, the high risk of recurrence has led to multiple emerging therapies that target toxin activity, recovery of the intestinal microbial community, and elimination of latent C. difficile in the intestine. In summary, CDIs illustrate the complex interaction among host physiology, microbial community, and pathogen that requires specific therapies to address each of the factors leading to primary infection and recurrence.

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“…Alum is heavily used in the US and results in reasonably good humoral immunity, but stimulates poor cellular immunity [15]. However, Alum formulations substantially enhance the anti-TcdB IgG response in mouse models [10], but the benefit of adjuvant inclusion is less clear in human volunteers [16]. Another major challenge is the inherent variation in human immune responses.…”

Section: Vaccine Candidates and Constraints On Adaptive Immunity To Themmentioning

confidence: 99%

Adaptive immune constraints on C. difficile vaccination

Lang

Shrestha

2017

Expert Review of Vaccines

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Safety, immunogenicity and dose response of VLA84, a new vaccine candidate against Clostridium difficile, in healthy volunteers

Cited by 69 publications

References 15 publications

Immunization with Recombinant TcdB-Encapsulated Nanocomplex Induces Protection against Clostridium difficile Challenge in a Mouse Model

Immunization with Recombinant TcdB-Encapsulated Nanocomplex Induces Protection against Clostridium difficile Challenge in a Mouse Model

Novel therapies and preventative strategies for primary and recurrent Clostridium difficile infections

Adaptive immune constraints on C. difficile vaccination

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