Oral immunization of mice with ricin toxoid vaccine encapsulated in polymeric microspheres against aerosol challenge

Kende, Meir; Yan, Changhong; Hewetson, John F.; Frick, Matthew A.; Rill, W L; Tammariello, Ralph F.

doi:10.1016/s0264-410x(01)00484-4

Cited by 54 publications

(21 citation statements)

References 31 publications

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“…The toxoid, and to a lesser extent dgRTA, given as microencapsulated liposome formulations directly into the respiratory tract protected the lung [ 6,29 ]. The encapsulated toxoid given orally has also been shown to protect mice against oral ricin challenges [ 30 ]. However, both the toxoid and dgRTA (which still retains all of its cytotoxic activity and vascular leak site) have been determined to be too potentially toxic for general use [ 4 ].…”

Section: Discussionmentioning

confidence: 99%

RiVax, a recombinant ricin subunit vaccine, protects mice against ricin delivered by gavage or aerosol

Smallshaw

Richardson

Vitetta

2007

Vaccine

120

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Ricin is a plant toxin that is a CDC level B biothreat. Our recombinant ricin A chain vaccine (RiVax), which contains mutations in both known toxic sites, has no residual toxicity at doses at least 800 times the immunogenic dose. RiVax without adjuvant given intramuscularly (i.m.) protected mice against intraperitoneally administered ricin. Furthermore the vaccine without alum was safe and immunogenic in human volunteers. Here we describe the development of gavage and aerosol ricin challenge models in mice and demonstrate that i.m. vaccination protects mice against ricin delivered by either route. Also RiVax protects against aerosol-induced lung damage as determined by histology and lung function tests.

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Section: Discussionmentioning

confidence: 99%

RiVax, a recombinant ricin subunit vaccine, protects mice against ricin delivered by gavage or aerosol

Smallshaw

Richardson

Vitetta

2007

Vaccine

120

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“…Several studies have demonstrated a positive correlation between mucosal immunity to ricin and levels of antiricin IgA antibodies in mucosal secretions (15,16,22,46). However, discerning the role of S-IgA in protecting epithelial cells from ricin in vivo has been confounded by a number of factors, including the presence of antitoxin serum IgG antibodies and the difficulty in accurately measuring "local" IgA concentrations and specificities.…”

Section: Discussionmentioning

confidence: 99%

“…Rodents exposed to ricin (5 to 10 mg/kg) by the intragastric route develop widespread villus atrophy, mucus secretion, swelling of interepithelial spaces, separation of the epithelium from the lamina propria, and sloughing of enterocytes from the tips of villi (39; J. M. Yoder and N. Mantis, unpublished data). In both situations, it is clear that epithelial cells are a primary target for ricin.Vaccinologists have long appreciated the need to stimulate mucosal immunity against ricin in both the respiratory and gastrointestinal tracts to confer protection against a mucosal toxin challenge (19,21,22,27,34,46). This is best exemplified by the fact that mice vaccinated parenterally with ricin toxoid (RT) are immune to ricin administered systemically but are only partially protected against ricin administered as an aerosol (19,34).…”

mentioning

confidence: 99%

“…Mucosal immunity to ricin was achieved in the respiratory tract when animals were immunized intranasally or intragastrically (i.g. ), correlating with the production of secretory immunoglobulin A (S-IgA) antibodies in bronchoalveolar lavage fluids (15,16,22,46). However, direct proof that S-IgA can safeguard mucosal epithelia from ricin intoxication is lacking.…”

mentioning

confidence: 99%

“…Vaccinologists have long appreciated the need to stimulate mucosal immunity against ricin in both the respiratory and gastrointestinal tracts to confer protection against a mucosal toxin challenge (19,21,22,27,34,46). This is best exemplified by the fact that mice vaccinated parenterally with ricin toxoid (RT) are immune to ricin administered systemically but are only partially protected against ricin administered as an aerosol (19,34).…”

mentioning

confidence: 99%

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Immunoglobulin A Antibodies against Ricin A and B Subunits Protect Epithelial Cells from Ricin Intoxication

et al. 2006

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Epithelial cells of the respiratory and gastrointestinal tracts are extremely vulnerable to the cytotoxic effects of ricin, a Shiga-like toxin with ribosome-inactivating properties. While mucosal immunity to ricin correlates with secretory immunoglobulin A (IgA) antibody levels in vivo, the potential of IgA to protect epithelial cells from ricin in vitro has not been examined due to the unavailability of well-defined antitoxin IgA antibodies. Here we report the characterization of four monoclonal IgA antibodies (IgA MAbs) produced from the Peyer's patches and mesenteric lymph nodes of BALB/c mice immunized intragastrically with ricin toxoid. Two IgA MAbs (33G2 and 35H6) were active against ricin's lectin subunit (RTB), and two (23D7 and 25A4) reacted with the toxin's enzymatic subunit (RTA). All four IgA MAbs neutralized ricin in a Vero cell cytotoxicity assay, blocked toxin-induced interleukin-8 release by the human monocyte/macrophage cell line 28SC, and protected polarized epithelial cell monolayers from ricin-mediated protein synthesis inhibition. 33G2 and 35H6 reduced ricin binding to the luminal surfaces of human intestinal epithelial cells to undetectable levels in tissue section overlay assays, whereas 23D7 had no effect on toxin attachment. 23D7 and 25A4 did, however, reduce ricin transcytosis across MDCK II cell monolayers, possibly by interfering with intracellular toxin transport. We conclude that IgA antibodies against RTA and RTB can protect mucosal epithelial cells from ricin intoxication.Recent bioterrorism incidents in the United States and abroad have alerted public health officials to the need for vaccines and therapies against pathogens and toxins previously deemed to be of little concern (2, 7, 27). Ricin, for example, is an extremely potent toxin that is easily purified in high concentrations from its natural source, the castor bean (Ricinus communis). Ricin (molecular weight, 64,000) is a relatively simple toxin consisting of an enzymatic A subunit (RTA) and a binding B subunit (RTB) joined by a disulfide bond (32). Its potency is attributed in part to the fact that RTB is a bivalent lectin with specificities for ubiquitous glycoproteins and glycolipids containing ␤(1-3)-linked galactose or N-acetylgalactosamine residues (4), which enable the toxin to bind and be internalized by all known cell types. The toxic properties of ricin are further compounded by RTA, which is an extremely efficient N-glycosidase specific for a highly conserved adenine residue in the so-called sarcin/ricin loop of eukaryotic 28S rRNA (9). Due to the absence of a specific vaccine or therapy, treatment of individuals intoxicated with ricin is strictly supportive (3).As an agent of bioterrorism, it is feared that ricin will be disseminated by aerosol or food/water supplies, thereby potentially exposing humans via the respiratory or gastrointestinal tract. It is known from animal studies that both mucosal compartments are susceptible to ricin intoxication. Monkeys or rodents exposed to aerosolized ricin (ϳ20 to 40 g/k...

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Ricin Poisoning

Audi¹,

Belson²,

Patel³

et al. 2005

JAMA

567

292

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ROWING AWARENESS AND concern about ricin, a potent biologic toxin, as a possible terrorist weapon has necessitated a comprehensive review of this poison. 1 The Centers for Disease Control and Prevention (CDC) categorizes ricin as a Category B agent (second-highest priority), as it is moderately easy to disseminate, resulting in low mortality but moderate to high morbidity, and requires specific enhancement of the CDC's diagnostic and disease surveillance capacity. 2 Such agents are not routinely encountered, so heightened awareness in the health care community and a strong public health infrastructure are necessary for detection and response. We therefore have summarized the literature on ricin poisoning and provided recommendations for clinicians and public health professionals dealing with a ricin attack against a civilian population. EVIDENCE ACQUISITION Using PubMed, we searched MEDLINE and OLDMEDLINE databases from January 1950 to August 2005 using the keywords ricin, ricinus communis, ricinine, plant toxins, castor beans, castor dust, and castor oil. Keywords were used alone and with the modifiers toxicity, poisoning, diagnosis, clinical effects, treatment , warfare, chemical terrorism, and weapon. The Chemical and Biological Information Analysis Center (http: //www.cbiac.apgea.army.mil) database was searched for historical and military literature related to ricin tox-CME available online at www.jama.com Context The recent discoveries of ricin, a deadly biologic toxin, at a South Carolina postal facility, a White House mail facility, and a US senator's office has raised concerns among public health officials, physicians, and citizens. Ricin is one of the most potent and lethal substances known, particularly when inhaled. The ease with which the native plant (Ricinus communis) can be obtained and the toxin extracted makes ricin an attractive weapon. Objectives To summarize the literature on ricin poisoning and provide recommendations based on our best professional judgment for clinicians and public health officials that are faced with deliberate release of ricin into the environment. Literature Acquisition Using PubMed, we searched MEDLINE and OLDMEDLINE databases (January 1950-August 2005). The Chemical and Biological Information Analysis Center database was searched for historical and military literature related to ricin toxicity. Book chapters, unpublished reports, monographs, relevant news reports, and Web material were also reviewed to find nonindexed articles. Results Most literature on ricin poisoning involves castor bean ingestion and experimental animal research. Aerosol release of ricin into the environment or adulteration of food and beverages are pathways to exposure likely to be exploited. Symptoms after ingestion (onset within 12 hours) are nonspecific and may include nausea, vomiting, diarrhea, and abdominal pain and may progress to hypotension, liver failure, renal dysfunction, and death due to multiorgan failure or cardiovascular collapse. Inhalation (onset of symptoms is likely within 8 hou...

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Oral immunization of mice with ricin toxoid vaccine encapsulated in polymeric microspheres against aerosol challenge

Cited by 54 publications

References 31 publications

RiVax, a recombinant ricin subunit vaccine, protects mice against ricin delivered by gavage or aerosol

RiVax, a recombinant ricin subunit vaccine, protects mice against ricin delivered by gavage or aerosol

Immunoglobulin A Antibodies against Ricin A and B Subunits Protect Epithelial Cells from Ricin Intoxication

Ricin Poisoning

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