Intradermal administration of RiVax protects mice from mucosal and systemic ricin intoxication

Marconescu, Praveena S.; Smallshaw, Joan E.; Pop, Laurentiu M.; Ruback, Stephen; Vitetta, Ellen S.

doi:10.1016/j.vaccine.2010.05.045

Cited by 31 publications

(29 citation statements)

References 35 publications

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“…), subcutaneous (s.c.), or intradermal (i.d.) route elicits toxin-specific serum IgG antibodies (Abs) that are sufficient to confer protection against a lethal dose of ricin (8)(9)(10)(15)(16)(17). Phase I clinical trials have demonstrated that RiVax is safe and immunogenic in healthy human volunteers (18,19).…”

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confidence: 99%

Comparative Efficacy of Two Leading Candidate Ricin Toxin A Subunit Vaccines in Mice

O’Hara

Brey

Mantis

2013

Clin Vaccine Immunol

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The two leading ricin toxin vaccine candidates, RVEc and RiVax, are recombinant derivatives of the toxin's 267-amino-acid enzymatic A chain (RTA). RVEc is truncated at the C terminus (residues 199 to 267) to improve protein thermostability, while RiVax has two point mutations (V76M and Y80A) that eliminate the RNA N-glycosidase activity of RTA, as well as its ability to induce vascular leak syndrome. The two vaccines have never been directly compared in terms of their ability to stimulate RTAspecific antibodies (Abs), toxin-neutralizing activity (TNA), or protective immunity. To address this issue, groups of female BALB/c mice were immunized two or three times with Alhydrogel-adsorbed RiVax or RVEc at a range of doses (0.3 to 20 g) and then challenged with 10 50% lethal doses (LD 50 s) of ricin. We found that the vaccines were equally effective at eliciting protective immunity at the doses tested. There were, however, quantitative differences in the antibody responses. RVEc tended to elicit higher levels of ricin-specific RTA IgG and TNA than did RiVax. Pepscan analysis revealed that serum Abs elicited by RVEc were skewed toward a solvent-exposed immunodominant ␣-helix known to be the target of potent toxin-neutralizing Abs. Finally, immunodepletion experiments suggest that the majority of toxin-neutralizing Abs elicited by RiVax were confined to residues 1 to 198, possibly explaining the equal effectiveness of RVEc as a vaccine. R icin, one of the most potent biological toxins known, consists of two subunits, RTA and RTB. RTA is a 267-amino-acid RNA N-glycosidase that selectively and irreversibly inactivates eukaryotic ribosomes (1). RTB is a galactose/N-acetylgalactosamine-specific lectin that facilitates the delivery of RTA into the cytoplasm of eukaryotic cells in general (2). Once in the cytoplasm, it is estimated that a single molecule of RTA can inactivate Ͼ1,000 ribosomes per minute.Despite the history of ricin as an agent of biological warfare and bioterrorism, there is currently no available ricin toxin vaccine (3, 4). As early as the 1940s, the United States military focused on the development of a simple formalin-treated holotoxin toxoid vaccine. Although ricin toxoid is highly efficacious in rodents and nonhuman primates, its use in humans was abandoned because of manufacturing problems and safety concerns (5). For those reasons, current efforts are aimed at the development of a recombinant subunit vaccine. While RTB is an obvious candidate, RTB immunization confers only partial protection against ricin challenge (6, 7). In contrast, immunization of mice with RTA or nontoxic derivatives of RTA is sufficient to protect mice against a 10 50% lethal dose (LD 50 ) ricin challenge (8).There are currently two RTA-based vaccines under development: RiVax and RVEc. RiVax is a recombinant derivative of RTA with two point mutations at residues Y80 and V76. The Y80A mutation abolishes the RNA N-glycosidase activity of the toxin, while the V76M mutation eliminates the ability of RTA to elicit vascular leak syndr...

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confidence: 99%

Comparative Efficacy of Two Leading Candidate Ricin Toxin A Subunit Vaccines in Mice

O’Hara

Brey

Mantis

2013

Clin Vaccine Immunol

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“…or intradermally (i.d.) with three doses of as little as 1 g each were uniformly protected from a subsequent ricin challenge (10 50% lethal doses [LD 50 s]) administered by injection, aerosol, or intragastric gavage (10,15,16).…”

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Pilot Phase IB Clinical Trial of an Alhydrogel-Adsorbed Recombinant Ricin Vaccine

Vitetta

Smallshaw

Schindler

2012

Clin. Vaccine Immunol.

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“…However, while such results were encouraging, vaccine formulation and stability remain problematic. Hence, a lyophilized formulation that retained immunogenicity when stored at 4ºC was developed (Smallshaw & Vitetta, 2010;Marconescu et al, 2010).…”

Section: Vaccination and Passive Protectionmentioning

confidence: 99%

Ricin Perspective in Bioterrorism

Roxas-Duncan¹,

Smith²

2012

Bioterrorism

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Intradermal administration of RiVax protects mice from mucosal and systemic ricin intoxication

Cited by 31 publications

References 35 publications

Comparative Efficacy of Two Leading Candidate Ricin Toxin A Subunit Vaccines in Mice

Comparative Efficacy of Two Leading Candidate Ricin Toxin A Subunit Vaccines in Mice

Pilot Phase IB Clinical Trial of an Alhydrogel-Adsorbed Recombinant Ricin Vaccine

Ricin Perspective in Bioterrorism

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