Enhancement of intranasal vaccination in mice with deglycosylated chain A ricin by LTR72, a novel mucosal adjuvant

Kende, Meir; Giudice, Giuseppe Del; Rivera, Noelia; Hewetson, John F.

doi:10.1016/j.vaccine.2004.12.034

Cited by 24 publications

(10 citation statements)

References 22 publications

(15 reference statements)

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“…It can increase reversibly the intestinal mucosa permeability by affecting the structure of tight junctions. Several mutant heat-labile enterotoxins were found to be effective as adjuvants for nasal administration of pneumococcal vaccine [277], deglycosylated chain A ricin (DGCA) [278], or influenza vaccine [279], and for vaginal administration of inactivated caprine herpes virus 1 vaccine [280].…”

Section: Toxinsmentioning

confidence: 99%

Selection of Adjuvants for Enhanced Vaccine Potency

Wang¹,

Singh²

2011

WJV

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Section: Toxinsmentioning

confidence: 99%

Selection of Adjuvants for Enhanced Vaccine Potency

Wang¹,

Singh²

2011

WJV

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“…There is accumulating evidence that SIgA may be necessary to confer complete protection against ricin intoxication in mucosal compartments (15,19,20,33,44). This is best exemplified by the fact that serum IgG antibodies elicited by parental vaccination with RT provide only partial protection against an aerosol challenge (i.e., mice demonstrated widespread inflammation and necrotic lesions within the upper and lower respiratory tracts and remained debilitated for 10 to 14 days following challenge (15,33).…”

Section: Fig 4 Antiricin Igg Andmentioning

confidence: 99%

Evidence for Widespread Epithelial Damage and Coincident Production of Monocyte Chemotactic Protein 1 in a Murine Model of Intestinal Ricin Intoxication

2007

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The development of small-animal models is necessary to understand host responses and immunity to emerging infectious diseases and potential bioterrorism agents. In this report we have characterized a murine model of intestinal ricin intoxication. Ricin administered intragastrically (i.g.) to BALB/c mice at doses ranging from 1 to 10 mg/kg of body weight induced dose-dependent morphological changes in the proximal small intestine (i.e., duodenum), including widespread villus atrophy and epithelial damage. Coincident with epithelial damage was a localized increase in monocyte chemotactic protein 1, a chemokine known to be associated with inflammation of the intestinal mucosa. Immunity to intestinal ricin intoxication was achieved by immunizing mice i.g. with ricin toxoid and correlated with elevated levels of antitoxin mucosal immunoglobulin A (IgA) and serum IgG antibodies. We expect that this model will serve as a valuable tool in identifying the inflammatory pathways and protective immune responses that are elicited in the intestinal mucosa following ricin exposure and will prove useful in the evaluation of antitoxin vaccines and therapeutics.The development and testing of effective vaccines and therapeutics against potential bioterrorism agents pose major challenges to the biomedical scientific community (2). Foremost is the fact that human exposure to these so-called select agents is rare and often is poorly documented in the clinic. Consequently, an understanding of the molecular basis of both pathophysiology of and protective immunity to this diverse collection of viruses, microbial pathogens, and toxins must rely on the use of well-established animal models. This is especially true in the case of ricin toxin, a potent ribosome-inactivating protein from the castor bean (Ricinus communis) that has already proven to be an effective murder weapon and bioterrorism agent (25).While ricin (ϳ64 kDa) is one of the simplest members of the A-B family of toxins, it is also one of the most promiscuous (32, 37). The toxin's single A subunit (RTA) is an N-glycosidase that selectively depurinates a conserved adenine residue within 28S rRNA and in this respect is indistinguishable from shiga toxin (11). The toxin's B subunit (RTB) is a bivalent lectin that mediates toxin attachment to terminal galactose residues on glycoproteins and glycolipids (4). The ubiquitous nature of ricin's receptors, combined with its universally conserved enzymatic substrate, enables ricin to intoxicate virtually all known cell types. Not surprisingly, ricin can be lethal to humans following injection, inhalation, or ingestion (3,6,26).Although a recent expert panel workshop sponsored by the National Institutes of Health deemed the adulteration of food and water supplies to be the most likely mechanism by which ricin would be disseminated as a bioterrorism agent, very little is known about the effects of ricin on the gastrointestinal mucosa (1). Ingestion of whole castor beans results in severe abdominal pain, vomiting, diarrhea, and (depending o...

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“…Although formaldehyde-treated ricin toxoid (RT) preparations are effective at eliciting protective immunity in rodents, they are not being considered for use in humans, because of concerns about residual toxicity (11). Therefore, the current emphasis is on the development of attenuated subunit vaccines (6,16,32,45,52). One of the most promising candidates is a recombinant derivative of RTA containing two point mutations: one in the enzymatic active site (Y80A) and the other in a residue (V76M) involved in eliciting vascular leak syndrome (42)(43)(44)(45)52).…”

mentioning

confidence: 99%

A Monoclonal Immunoglobulin G Antibody Directed against an Immunodominant Linear Epitope on the Ricin A Chain Confers Systemic and Mucosal Immunity to Ricin

et al. 2010

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Due to the potential use of ricin and other fast-acting toxins as agents of bioterrorism, there is an urgent need for the development of safe and effective antitoxin vaccines. A candidate ricin subunit vaccine (RiVax) consisting of a recombinant attenuated enzymatic A chain (RTA) has been shown to elicit protective antitoxin antibodies in mice and rabbits and is currently being tested in phase I human clinical trials. However, evaluation of the efficacy of this vaccine for humans is difficult for a number of reasons, including the fact that the key neutralizing B-cell epitopes on RTA have not been fully defined. Castelletti and colleagues (Clin. Exp. Immunol. 136:365-372, 2004) recently identified a linear epitope on RTA, spanning residues L161 to I175, as a primary target of serum antibodies derived from humans who had been treated with ricin immunotoxin. While affinity-purified polyclonal IgG antibodies against this region of RTA were capable of neutralizing ricin in vitro, their capacity to confer protection against ricin challenge in vivo was not determined. In this report, we describe the production and characterization of GD12, a murine monoclonal IgG1 antibody specifically directed against residues 163 to 174 (TLARSFIICIQM) of RTA. GD12 bound ricin holotoxin with high affinity (K D [dissociation constant], 2.9 ؋ 10 ؊9 M) and neutralized it with a 50% inhibitory concentration of ϳ0.25 g/ml, as determined by a Vero cell-based cytotoxicity assay. Passive administration of GD12 was sufficient to protect BALB/c mice against intraperitoneal and intragastric ricin challenges. These data are important in terms of vaccine development, since they firmly establish that preexisting serum antibodies directed against residues 161 to 175 on RTA are sufficient to confer both systemic and mucosal immunity to ricin. The potential of GD12 to serve as a therapeutic following ricin challenge was not explored in this study.

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Enhancement of intranasal vaccination in mice with deglycosylated chain A ricin by LTR72, a novel mucosal adjuvant

Cited by 24 publications

References 22 publications

Selection of Adjuvants for Enhanced Vaccine Potency

Selection of Adjuvants for Enhanced Vaccine Potency

Evidence for Widespread Epithelial Damage and Coincident Production of Monocyte Chemotactic Protein 1 in a Murine Model of Intestinal Ricin Intoxication

A Monoclonal Immunoglobulin G Antibody Directed against an Immunodominant Linear Epitope on the Ricin A Chain Confers Systemic and Mucosal Immunity to Ricin

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