title: Recent advances in the development of vaccines against ricin.
abstract: Several promising subunit vaccines against ricin toxin (RT) have been developed during the last decade and are now being tested for safety and immunogenicity in humans and for efficacy in nonhuman primates. The incentive to develop a preventive vaccine as a countermeasure against RT use as a bioweapon is based on the high toxicity of RT after aerosol exposure, its environmental stability, abundance, and ease of purification. RT is the second most lethal biological toxin and is considered a "universal toxin" because it can kill all eukaryotic cells through binding to ubiquitous cell surface galactosyl residues. RT has two subunits conjoined by a single disulfide linkage: RTB, which binds galactosyl residues and RTA which enzymatically inactivates ribosomes intracellularly by cleavage ribosomal RNA. Attenuation of toxicity by elimination of the active site or introduction of other structural mutations of RTA has generated two similar clinical subunit vaccine candidates which induce antibodies in both humans and nonhuman primates. In rhesus macaques, inhaled RT causes rapid lung necrosis and fibrosis followed by death. After parenteral vaccination with RTA vaccine, macaques can be protected against aerosol RT exposure, suggesting that circulating antibodies can protect lung mucosa. Vaccination induces RT-neutralizing antibodies, the most likely correlate of protection. Macaques responded to conformational determinants in an RTA vaccine formulation, indicating preservation of RTA structure during initial manufacture. Comparative mapping studies have also demonstrated that macaques and humans recognize the same epitopes, significant in the study of macaques as a model during development of vaccines which cannot be tested for efficacy in humans.
authors.affiliation: a Kinesis Vaccines, LLC , Chicago , IL , USA.
authors.forename: Robert N
authors.initials: RN
authors.lastname: Brey
authors.affiliation: b Division of Infectious Disease , Wadsworth Center, New York State Department of Health, Albany, NY, USA Department of Biomedical Sciences, University of Albany School of Public Health , Albany , NY , USA.
authors.forename: Nicholas J
authors.initials: NJ
authors.lastname: Mantis
authors.affiliation: c Departments of Pediatrics and Microbiology , Louisiana State University School of Medicine, Children's Hospital , New Orleans , LA , USA.
authors.forename: Seth H
authors.initials: SH
authors.lastname: Pincus
authors.affiliation: d Departments of Immunology and Microbiology , The University of Texas Southwestern Medical Center , Dallas , TX , USA.
authors.forename: Ellen S
authors.initials: ES
authors.lastname: Vitetta
authors.affiliation: e Medical Countermeasures Technology, US Army Medical Research Institute of Infectious Diseases , Fort Detrick , MD , USA.
authors.forename: Leonard A
authors.initials: LA
authors.lastname: Smith
authors.affiliation: f Division of Microbiology, Tulane National Primate Research Center , Covington , LA , USA.|g Department of Microbiology and Immunology , Tulane School of Medicine , New Orleans , LA , USA.
authors.forename: Chad J
authors.initials: CJ
authors.lastname: Roy
mesh_terms: D000336:Aerosols; D000818:Animals; D000911:Antibodies, Monoclonal / Q000276:immunology; D057134:Antibodies, Neutralizing / Q000276:immunology; D055808:Drug Discovery; D000939:Epitopes; D006801:Humans; D000071497:Immunogenicity, Vaccine; D008168:Lung / Q000276:immunology / Q000473:pathology; D008253:Macaca mulatta; D023421:Models, Animal; D012276:Ricin / Q000737:chemistry / Q000276:immunology*; D022223:Vaccines, Subunit / Q000276:immunology*
chemical_list: D000336:Aerosols; D000911:Antibodies, Monoclonal; D057134:Antibodies, Neutralizing; D000939:Epitopes; D022223:Vaccines, Subunit; D012276:Ricin
keywords: aerosol; antibody; epitope; immunization; non-human primate; ricin toxin
references.citation: J Mol Biol. 2014 Aug 26;426(17 ):3057-68
references.pmid: 24907552
references.citation: J Immunol Methods. 2013 Sep 30;395(1-2):71-8
references.pmid: 23774033
references.citation: Clin Vaccine Immunol. 2013 Jun;20(6):789-94
references.pmid: 23515013
references.citation: Immunol Lett. 2014 Mar-Apr;158(1-2):7-13
references.pmid: 24269767
references.citation: Toxicol Sci. 2012 Mar;126(1):72-83
references.pmid: 21987460
references.citation: Clin Vaccine Immunol. 2014 May;21(5):777-82
references.pmid: 24574537
references.citation: Clin Infect Dis. 2008 Aug 1;47(3):401-9
references.pmid: 18558875
references.citation: Toxins (Basel). 2015 Jun 09;7(6):2121-33
references.pmid: 26067369
references.citation: Vaccine. 2015 Dec 16;33(51):7299-306
references.pmid: 26546259
references.citation: J Biol Chem. 2013 Oct 18;288(42):30270-84
references.pmid: 24003229
references.citation: Toxicology. 2009 Oct 1;264(1-2):119-30
references.pmid: 19682533
references.citation: Vaccine. 2007 Oct 16;25(42):7459-69
references.pmid: 17875350
references.citation: Clin Vaccine Immunol. 2012 Oct;19(10):1697-9
references.pmid: 22914366
references.citation: Acta Crystallogr D Biol Crystallogr. 2011 Sep;67(Pt 9):826-30
references.pmid: 21904036
references.citation: J Pharm Sci. 2007 Jan;96(1):44-60
references.pmid: 16998874
references.citation: Toxicol Pathol. 2014;42(3):573-81
references.pmid: 23761937
references.citation: Am J Pathol. 2007 May;170(5):1497-510
references.pmid: 17456757
references.citation: Vaccine. 2007 May 22;25(21):4149-58
references.pmid: 17408819
references.citation: J Immunol. 2004 May 15;172(10):6221-8
references.pmid: 15128810
references.citation: J Biol Chem. 1987 Apr 15;262(11):5398-403
references.pmid: 3558397
references.citation: Eur J Pharm Biopharm. 2013 Oct;85(2):279-86
references.pmid: 23583494
references.citation: Hybridoma. 1994 Oct;13(5):417-21
references.pmid: 7860097
references.citation: Infect Immun. 2010 Jan;78(1):552-61
references.pmid: 19858297
references.citation: Int J Toxicol. 2011 Mar;30(2):143-52
references.pmid: 21378370
references.citation: Vaccine. 2002 Sep 10;20(27-28):3422-7
references.pmid: 12213413
references.citation: Vaccine. 2010 Oct 8;28(43):7035-46
references.pmid: 20727394
references.citation: Hybridoma. 1986 Spring;5(1):9-19
references.pmid: 3957360
references.citation: Clin Exp Immunol. 2004 May;136(2):365-72
references.pmid: 15086403
references.citation: Proc Natl Acad Sci U S A. 2006 Feb 14;103(7):2268-73
references.pmid: 16461456
references.citation: Toxicon. 2011 Jul;58(1):68-75
references.pmid: 21616091
references.citation: MBio. 2014 Apr 08;5(2):e00995
references.pmid: 24713323
references.citation: Clin Infect Dis. 2013 May;56(10):1458-65
references.pmid: 23386629
references.citation: Toxicology. 1985 Jan;34(1):79-88
references.pmid: 3969682
references.citation: Vaccine. 2010 Jul 19;28(32):5315-22
references.pmid: 20562013
references.citation: Toxins (Basel). 2014 May 07;6(5):1512-25
references.pmid: 24811206
references.citation: Hum Vaccin Immunother. 2013 Jul;9(7):1591-7
references.pmid: 23428906
references.citation: Int J Biol Macromol. 1999 Jan;24(1):19-26
references.pmid: 10077268
references.citation: Toxicon. 2012 Oct;60(5):874-7
references.pmid: 22750533
references.citation: PLoS One. 2013 Apr 24;8(4):e62417
references.pmid: 23638075
references.citation: Curr Top Microbiol Immunol. 2012;357:243-57
references.pmid: 21956160
references.citation: Curr Top Microbiol Immunol. 2012;357:209-41
references.pmid: 22113742
references.citation: J Immunol. 1987 May 15;138(10):3339-44
references.pmid: 2437188
references.citation: Clin Vaccine Immunol. 2015 Dec;22(12):1285-93
references.pmid: 26491037
references.citation: Proc Natl Acad Sci U S A. 2015 Mar 24;112(12):3782-7
references.pmid: 25775591