Production and Characterization of Chemically Inactivated Genetically Engineered Clostridium difficile Toxoids

Vidunas, Eugene; Mathews, Antony J.; Weaver, Michele; Cai, Ping; Koh, Eun Hee; Patel-Brown, Sujata; Yuan, Hailey; Zheng, Zirong; Carriere, Marjolaine; Johnson, J. Erik; Lotvin, Jason; Moran, Justin

doi:10.1016/j.xphs.2016.04.017

Cited by 17 publications

(16 citation statements)

References 24 publications

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“…Since conjugation can occur not only between separate CRM 197 molecules, but between any free amino and carboxyl groups, the number of intra-protein cross-links should also increase. Intra-protein cross-linking can change the stability and structure of a protein [18,19] and therefore could be the driving force causing the transition from the “closed” to the “open” conformation.…”

Section: Discussionmentioning

confidence: 99%

The Effect of Physicochemical Modification on the Function of Antibodies Induced by Anti-Nicotine Vaccine in Mice

et al. 2017

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Smoking remains one of the major causes of morbidity and mortality worldwide. One approach to assisting smoking cessation is via anti-nicotine vaccines, composed of nicotine-like haptens conjugated to a carrier protein plus adjuvant(s). We have previously shown that the carrier, hapten, linker, hapten load, degree of conjugate aggregation, and presence of adducts can each influence the function (nicotine-binding capacity) of the antibody (Ab) induced. Herein, we extend those findings and show that tertiary structure is also critical to the induction of functional immune responses and that this can be influenced by conjugation conditions. We evaluated immunogenicity in mice using six lots of NIC7-CRM, a conjugate of 5-aminoethoxy-nicotine (Hapten 7), and a single point (glycine 52 to glutamic acid) mutant nontoxic form of diphtheria toxin, cross-reactive material 197 (CRM197), which were synthesized under different reaction conditions resulting in conjugates with equivalent molecular characteristics (hapten load, aggregates, adducts), but a different tertiary structure. When tested in mice, better functional responses (reduced nicotine in the brain of immunized animals relative to non-immunized controls) were obtained with conjugates with a more closed structure than those with an open conformation. These studies highlight the need for a better understanding of the physicochemical properties of small molecule conjugate vaccines.

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Section: Discussionmentioning

confidence: 99%

The Effect of Physicochemical Modification on the Function of Antibodies Induced by Anti-Nicotine Vaccine in Mice

et al. 2017

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“…60 PF-06425090 is a vaccine developed by Pfizer composed of genetically modified toxins A and B from C. difficile. 61,62 The drug has completed multiple phase I and a single phase II trial so far, with another phase II trial active (NCT02561195) and a phase III trial (NCT03090191) currently recruiting. The current phase II trial has three groups: highdose (200 g) vaccine, low-dose (100 g) vaccine, and placebo.…”

Section: Prevention Of CDImentioning

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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“…Pfizer développe aussi un vaccin à base de toxines en utilisant la toxine A et B obtenues par manipulation génétique à partir d'une souche non toxinogène de C. difficile [68]. Ce vaccin a récemment été testé dans une étude de phase 1 avec et sans adjuvant et s'est avéré bien toléré avec une réponse neutralisante pour la toxine efficace [69].…”

Section: Vaccins En Développementunclassified

Les vaccins dans la prévention des infections associées aux soins

Gagneux‐Brunon

Lucht

Launay

et al. 2017

Journal des Anti-infectieux

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Production and Characterization of Chemically Inactivated Genetically Engineered Clostridium difficile Toxoids

Cited by 17 publications

References 24 publications

The Effect of Physicochemical Modification on the Function of Antibodies Induced by Anti-Nicotine Vaccine in Mice

The Effect of Physicochemical Modification on the Function of Antibodies Induced by Anti-Nicotine Vaccine in Mice

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

Les vaccins dans la prévention des infections associées aux soins

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