Molecular aspects of creating vaccines for the prevention of poisoning ribosome-inactivating proteins of plant origin: current situation, problems of vaccine development

Abstract

This article reviews the current understanding of the mechanism of action of the toxin, the clinical effects of ricin and abrin intoxication and how these relate to current and continuing prospects for vaccine development. The threat of bioterrorism worldwide has accelerated the demand for the development of therapies and vaccines against the ribosome-inactivating proteins. The diverse and unique nature of these toxins poses a challenge to vaccinologists. This paper will review the mechanism of toxicity and vaccines development to protect against the highly toxic plant-derived ribosomal toxins. Vaccine development is further complicated by the fact that as bioterrorism agents, abrin and ricin would most likely be disseminated as aerosols supplies. Our understanding of the mechanisms by which these toxins cross mucosal surfaces, and importance of mucosal immunity in preventing toxin uptake is only rudimentary. Research is now aimed at developing recombinant, attenuated vaccines based on a detailed understanding of the molecular mechanisms by which these toxins function. The evolution of the development of specific immunoprophylaxis of acute ricin poisoning from native toxoid to genetically engineered subunit vaccines based on the method of targeted mutagenesis is traced. The past several years have seen major advances in the development of a safe and efficacious ricin toxin vaccine. These vaccines are discussed in the context of the toxicity and structure of ricin. In this review we summarize ongoing efforts to leverage recent advances in the design and use of vaccines.

Keywords

intoxication / vaccination / plant-derived lectins / recombinant subunit vaccines / ribosome-inactivating proteins of plant origin / targeted mutagenesis / immunobiological drugs

References

[1] Janik E, Cheremuga M, et al. Biological toxins as the potential tools for bioterrorism. International Journal of Molecular Sciences. 2019;20(5):1181–2019. DOI: 10.3390/ijms20051181

[2] Janik E., Cheremuga M., et al. Biological toxins as the potential tools for bioterrorism // International Journal of Molecular Sciences. 2019. Vol. 20. No. 5. P. 1181–2019. DOI: 10.3390/ijms20051181

[3] Olsnes S., Pihl A. Different biological properties of the two constituent peptide chains of ricin a toxic protein inhibiting protein synthesis. Biochemistry. 1973;12(16):3121–3126. DOI: 10.1021/bi00740a028

[4] Olsnes S., Pihl A. Different biological properties of the two constituent peptide chains of ricin a toxic protein inhibiting protein synthesis // Biochemistry. 1973. Vol. 12. No. 16. P. 3121–3126. DOI: 10.1021/bi00740a028

[5] Audi J, Belson M, Patel M, et al. Ricin poisoning. A comprehensive review. JAMA. 2005;294(18):2343–2351. DOI: 10.1001/jama.294.18.2342

[6] Audi J., Belson M., Patel M., et al. Ricin poisoning: a comprehensive review // JAMA. 2005. Vol. 294. No. 18. P. 2343–2351. DOI: 10.1001/jama.294.18.2342

[7] Konvenciya o zapreshchenii razrabotki, proizvodstva, nakopleniya i primeneniya himicheskogo oruzhiya ot 13.01.1993. Byulleten’ mezhdunarodnyh dogovorov. 1998;4:3–125. (In Russ.).

[8] Конвенция о запрещении разработки, производства, накопления и применения химического оружия от 13.01.1993 // Бюллетень международных договоров. 1998. Vol. 4. P. 3–125.

[9] Bozza WP, Tolleson WH, Rosado LAR, Zhang B. Ricin detection: Tracking active toxin. Biotechnology advances. 2015;33(1):117–123. DOI: 10.1016/j.biotechadv.2014.11.012

[10] Bozza W.P., Tolleson W.H., Rosado L.A.R., Zhang B. Ricin detection: Tracking active toxin // Biotechnology advances. 2015. Vol. 33. No. 1. P. 117–123. DOI: 10.1016/j.biotechadv.2014.11.012

[11] Mantis NJ, Morici LA, Roy CJ. Mucosal vaccines for biodefense. Curr Top Microbiol Immunol. 2011;354:181–195. DOI: 10.1007/82_2011_122

[12] Mantis N.J., Morici L.A., Roy C.J. Mucosal vaccines for biodefense // Curr. Top. Microbiol. Immunol. 2011. Vol. 354. P. 181–195. DOI: 10.1007/82_2011_122

[13] Mantis NJ. Ricin Toxin. Manual of Security Sensitive Microbes and Toxins. Boca Raton: CRC Press; 2014.

[14] Mantis N.J. Ricin Toxin. Manual of security sensitive microbes and toxins. Boca Raton: CRC Press, 2014.

[15] Pittman PR, Reisler RB, Lindsey CY, et al. Safety and immunogenicity of ricin vaccine, RVEc™, in a phase 1 clinical trial. Vaccine. 2015;33(51):7299–7306. DOI: 10.1016/j.vaccine.2015.10.094

[16] Pittman P.R., Reisler R.B., Lindsey C.Y., et al. Safety and immunogenicity of ricin vaccine, RVEc™, in a phase 1 clinical trial // Vaccine. 2015. Vol. 33. No. 51. P. 7299–7306. DOI: 10.1016/j.vaccine.2015.10.094

[17] Vitetta ES, Smallshaw JE, Schindler J. Pilot phase IB clinical trial of an alhydrogel-adsorbed recombinant ricin vaccine. Clin Vaccine Immunol. 2012;19(10):1697–1699. DOI: 10.1128/CVI.00381-12

[18] Vitetta E.S., Smallshaw J.E., Schindler J. Pilot phase IB clinical trial of an alhydrogel-adsorbed recombinant ricin vaccine // Clin. Vaccine Immunol. 2012. Vol. 19. No. 10. P. 1697–1699. DOI: 10.1128/CVI.00381-12

[19] Vance DJ, Mantis NJ. Progress and challenges associated with the development of ricin toxin subunit vaccines. Expert Rev Vaccines. 2016;15(9):1213–1222. DOI: 10.1586/14760584.2016.1168701

[20] Vance D.J., Mantis N.J. Progress and challenges associated with the development of ricin toxin subunit vaccines // Expert Rev. Vaccines. 2016. Vol. 15. No. 9. P. 1213–1222. DOI: 10.1586/14760584.2016.1168701

[21] Yan C, Rill WL, Mall LR. Intranasal stimulation of long-lasting immunity against aerosol ricin challenge with ricin toxoid vaccine encapsulated in polymeric microspheres. Vaccine. 1996;14(11):1031–1038. DOI: 10.1016/0264-410x(96)00063-1

[22] Yan C., Rill W.L., Mall L.R. Intranasal stimulation of long-lasting immunity against aerosol ricin challenge with ricin toxoid vaccine encapsulated in polymeric microspheres // Vaccine. 1996. Vol. 14. No. 11. P. 1031–1038. DOI: 10.1016/0264-410x(96)00063-1

[23] Griffiths GD, Phillips GJ, Bailey SC. Comparison of the quality of protection elicited by toxoid and peptide liposomal vaccine formulations against ricin as assessed by markers of inflammation. Vaccine. 1999;17(20–21):2562–2568. DOI: 10.1016/s0264-410x(99)00054-7

[24] Griffiths G.D., Phillips G.J., Bailey S.C. Comparison of the quality of protection elicited by toxoid and peptide liposomal vaccine formulations against ricin as assessed by markers of inflammation // Vaccine. 1999. Vol. 17. No. 20–21. P. 2562–2568. DOI: 10.1016/s0264-410x(99)00054-7

[25] Griffiths GD, Bailey SC, Hambrook JL, Keyte MP. Local and systemic responses against ricin toxin promoted by toxoid or peptide vaccines alone or in liposomal formulations. Vaccine. 1998;16(5):530–535. DOI: 10.1016/s0264-410x(97)80007-2

[26] Griffiths G.D., Bailey S.C., Hambrook J.L., Keyte M.P. Local and systemic responses against ricin toxin promoted by toxoid or peptide vaccines alone or in liposomal formulations // Vaccine. 1998. Vol. 16. No. 5. P. 530–535. DOI: 10.1016/s0264-410x(97)80007-2

[27] Mantis NJ. Vaccines against the category В toxins, staphylococcal enterotoxin B, epsilon toxin and ricin. Adv Drug Deliv Rev. 2005;57:1424–1439. DOI: 10.1016/j.addr.2005.01.017

[28] Mantis N.J. Vaccines against the category В toxins, staphylococcal enterotoxin B, epsilon toxin and ricin // Adv. Drug. Deliv. Rev. 2005. Vol. 57. P. 1424–1439. DOI: 10.1016/j.addr.2005.01.017

[29] Hewetson JF, Rivera VR, Creasia DA. Protection of mice from inhaled ricin by vaccination with ricin or by passive treatment with heterologous antibody. Vaccine. 1993;11(7):743–746. DOI: 10.1016/0264-410x(93)90259-z

[30] Hewetson J.F., Rivera V.R., Creasia D.A. Protection of mice from inhaled ricin by vaccination with ricin or by passive treatment with heterologous antibody // Vaccine. 1993. Vol. 11. No. 7. P. 743–746. DOI: 10.1016/0264-410x(93)90259-z

[31] Smallshaw JE, Firan A, Fulmer JR. A novel recombinant vaccine which protects mice against ricin intoxication. Vaccine. 2002;20(27–28):3422–3427. DOI: 10.1016/s0264-410x(02)00312-2

[32] Smallshaw J.E., Firan A., Fulmer J.R. A novel recombinant vaccine which protects mice against ricin intoxication // Vaccine. 2002. Vol. 20. No. 27–28. P. 3422–3427. DOI: 10.1016/s0264-410x(02)00312-2

[33] Smallshaw JE, Richardson JA, Pincus S. Preclinical toxicity and efficacy testing of RiVax, a recombinant protein vaccine against ricin. Vaccine. 2005;23(39):4775–4784. DOI: 10.1016/j.vaccine.2005.04.037

[34] Smallshaw J.E., Richardson J.A., Pincus S. Preclinical toxicity and efficacy testing of RiVax, a recombinant protein vaccine against ricin // Vaccine. 2005. Vol. 23. No. 39. P. 4775–4784. DOI: 10.1016/j.vaccine.2005.04.037

[35] Vitetta ES, Smallshaw JE, Coleman E. A pilot clinical trial of a recombinant ricin vaccine in normal humans. Proceedings of the National Academy of Sciences. 2006;103(7):2268–2273. DOI: 10.1073/pnas.0510893103

[36] Vitetta E.S., Smallshaw J.E., Coleman E. A pilot clinical trial of a recombinant ricin vaccine in normal humans // Proceedings of the National Academy of Sciences. 2006. Vol. 103. No. 7. P. 2268–2273. DOI: 10.1073/pnas.0510893103

[37] Smallshaw JE, Richardson JA, Vitetta ES. RiVax, a recombinant ricin subunit vaccine, protects mice against ricin delivered by gavage or aerosol. Vaccine. 2007;25(42):7459–7469. DOI: 10.1016/j.vaccine.2007.08.018

[38] Smallshaw J.E., Richardson J.A., Vitetta E.S. RiVax, a recombinant ricin subunit vaccine, protects mice against ricin delivered by gavage or aerosol // Vaccine. 2007. Vol. 25. No. 42. P. 7459–7469. DOI: 10.1016/j.vaccine.2007.08.018

[39] Vitetta ES, Smallshaw JE, Coleman E. A pilot clinical trial of a recombinant ricin vaccine in normal humans. Proceedings of the National Academy of Sciences. 2006;103(7):2268–2273. DOI: 10.1073/pnas.0510893103

[40] Vitetta E.S., Smallshaw J.E., Coleman E. A pilot clinical trial of a recombinant ricin vaccine in normal humans // Proceedings of the National Academy of Sciences. 2006. Vol. 103. No. 7. P. 2268–2273. DOI: 10.1073/pnas.0510893103

[41] McHugh CA, Tammariello RF, Millard СВ., Carra JH. Improved stability of a protein vaccine through elimination of a partially unfolded state. Protein Sci. 2004;13(10):2736–2743. DOI: 10.1110/ps.04897904

[42] McHugh C.A., Tammariello R.F., Millard СВ., Carra J.H. Improved stability of a protein vaccine through elimination of a partially unfolded state // Protein Sci. 2004. Vol. 13. No. 10. P. 2736–2743. DOI: 10.1110/ps.04897904

[43] Olson MA, Carra JH, Roxas-Duncan V. Finding a new vaccine in the ricin protein fold. Protein Engineering Design and Selection. 2004;17(4):391–397. DOI: 10.1093/protein/gzh043

[44] Olson M.A., Carra J.H., Roxas-Duncan V. Finding a new vaccine in the ricin protein fold // Protein Engineering Design and Selection. 2004. Vol. 17. No. 4. P. 391–397. DOI: 10.1093/protein/gzh043

[45] Carra JH, McHugh CA, Mulligan S, et al. Fragment-based identification of determinants of conformational and spectroscopic change at the ricin active site. BMC Structural Biology. 2007;7(1):72. DOI:10.1186/1472-6807-7-72

[46] Carra J.H., McHugh C.A., Mulligan S., et al. Fragment-based identification of determinants of conformational and spectroscopic change at the ricin active site // BMC Structural Biology. 2007. Vol. 7. No. 1. P. 72. DOI: 10.1186/1472-6807-7-72

[47] Compton JR, Legler PM, Clingan BV, et al. Introduction of a disulfide bond leads to stabilization and crystallization of a ricin immunogen. Proteins: Structure, Function, and Bioinformatics. 2011;79(4):1048–1060. DOI: 10.1002/prot.22933

[48] Compton J.R., Legler P.M., Clingan B.V., et al. Introduction of a disulfide bond leads to stabilization and crystallization of a ricin immunogen // Proteins: Structure, Function, and Bioinformatics. 2011. Vol. 79. No. 4. P. 1048–1060. DOI: 10.1002/prot.22933

[49] Smallshaw JE, Vitetta ES. Ricin vaccine development. Curr Top Microbiol Immunol. 2011;259–272. DOI: 10.1007/82_2011_156

[50] Smallshaw J.E., Vitetta E.S. Ricin vaccine development // Curr. Top. Microbiol. Immunol. 2012;357:259–272. DOI: 10.1007/82_2011_156

[51] Marconescu PS, Smallshaw JE, Pop LM, et al. Intradermal administration of RiVax protects mice from mucosal and systemic ricin intoxication. Vaccine. 2010;28(32):5315–5322. DOI: 10.1016/j.vaccine.2010.05.045

[52] Marconescu P.S., Smallshaw J.E., Pop L.M., et al. Intradermal administration of RiVax protects mice from mucosal and systemic ricin intoxication // Vaccine. 2010. Vol. 28. No. 32. P. 5315–5322. DOI: 10.1016/j.vaccine.2010.05.045

[53] McLain DE, Lewis BS, Chapman JL, et al. Protective effect of two recombinant ricin subunit vaccines in the New Zealand white rabbit subjected to a lethal aerosolized ricin challenge: survival, immunological response, and histopathological findings. Toxicological Sciences. 2011;126(1):72–83. DOI: 10.1093/toxsci/kfr274

[54] McLain D.E., Lewis B.S., Chapman J.L., et al. Protective effect of two recombinant ricin subunit vaccines in the New Zealand white rabbit subjected to a lethal aerosolized ricin challenge: survival, immunological response, and histopathological findings // Toxicological Sciences. 2011. Vol. 126. No. 1. P. 72–83. DOI: 10.1093/toxsci/kfr274

[55] McLain DE, Horn TL, Detrisac CJ, et al. Progress in biological threat agent vaccine development: A repeat-dose toxicity study of a recombinant ricin toxin A-chain (rRTA) 1-33/44-198 vaccine (RVEc) in male and female new zealand white rabbits. International journal of toxicology. 2011;30(2):143–152. DOI: 10.1177/1091581810396730

[56] McLain D.E., Horn T.L., Detrisac C.J., et al. Progress in biological threat agent vaccine development: A repeat-dose toxicity study of a recombinant ricin toxin A-chain (rRTA) 1-33/44-198 vaccine (RVEc) in male and female New Zealand white rabbits // International Journal of Toxicology. 2011. Vol. 30. No. 2. P. 143–152. DOI: 10.1177/1091581810396730

[57] O’Hara JM, Brey RN, Mantis NJ. Comparative efficacy of two leading candidate ricin toxin a subunit vaccine in mice. Clin Vaccine Immunol. 2013;20(6):789–794. DOI: 10.1128/CVI.00098-13

[58] O’Hara J.M., Brey R.N., Mantis N.J. Comparative efficacy of two leading candidate ricin toxin a subunit vaccine in mice // Clin. Vaccine Immunol. 2013. Vol. 20. No. 6. P. 89–794. DOI: 10.1128/CVI.00098-13

[59] Vance DJ, Greene CJ, Rong Y, et al. Comparative adjuvant effects of type II heat-labile enterotoxins in combination with two different candidate ricin toxin vaccine antigens. Clin Vaccine Immunol. 2015;22(12):1285–1293. DOI: 10.1128/CVI.00402-15

[60] Vance D.J., Greene C.J., Rong Y., et al. Comparative adjuvant effects of type II heat-labile enterotoxins in combination with two different candidate ricin toxin vaccine antigens // Clin. Vaccine Immunol. 2015. Vol. 22. No. 12. P. 1285–1293. DOI: 10.1128/CVI.00402-15

[61] O’Hara JM, Neal LM, McCarthy EA, et al. Folding domains within the ricin toxin A subunit as targets of protective antibodies. Vaccine. 2010;28(43):7035–7046. DOI: 10.1016/j.vaccine.2010.08.020

[62] O’Hara J.M., Neal L.M., McCarthy E.A., et al. Folding domains within the ricin toxin A subunit as targets of protective antibodies // Vaccine. 2010. Vol. 28. No. 43. P. 7035–7046. DOI: 10.1016/j.vaccine.2010.08.020

[63] Kumar MS, Karande AA. A monoclonal antibody to an abrin chimera recognizing a unique epitope on abrin A chain confers protection from abrin-induced lethality. Hum Vaccin Immunother. 2016;12:124–131. DOI: 10.1080/21645515.2015.1067741

[64] Kumar M.S., Karande A.A. A monoclonal antibody to an abrin chimera recognizing a unique epitope on abrin A chain confers protection from abrin-induced lethality // Hum. Vaccin. Immunother. 2016. Vol. 12. P. 124–131. DOI: 10.1080/21645515.2015.1067741

[65] Alcalay R. Mapping immunodominant antibody epitopes of abrin. Antibodies. 2020;9(2):11. DOI: 10.3390/antib9020011

[66] Alcalay R. Mapping immunodominant antibody epitopes of abrin // Antibodies. 2020. Vol. 9. No. 2. P. 11. DOI: 10.3390/antib9020011

[67] Han Y. A recombinant mutant abrin A chain expressed in E. coli can be used an effective vaccine candidate. Human Vaccin. 2011;7(5):838–844. DOI: 10.4161/hv.7.8.16258

[68] Han Y. A recombinant mutant abrin A chain expressed in E. coli can be used an effective vaccine candidate // Human Vaccin. 2011. Vol. 7. No. 5. P. 838–844. DOI: 10.4161/hv.7.8.16258

[69] Wang J, Gao Sh, Zhang T, et al. A recombinant chimeric protein containing B chains of ricin and abrin is an effective vaccine candidate. Hum Vaccin Immunother. 2014;10(4):938–944. DOI: 10.4161/hv.27870

[70] Wang J., Gao Sh., Zhang T., et al. A recombinant chimeric protein containing B chains of ricin and abrin is an effective vaccine candidate // Human Vaccin. Immunother. 2014. Vol. 10. No. 4. P. 938–944. DOI: 10.4161/hv.27870

[71] Wang J, Gao Sh, Xin W, et al. A novel recombinant vaccine protecting mice against abrin intoxication. Hum Vaccin Immunother. 2015;11(6):1361–1367. DOI: 10.1080/21645515.2015.1008879

[72] Wang J, Gao Sh., Xin W., et al. A novel recombinant vaccine protecting mice against abrin intoxication // Human Vaccin. Immunother. 2015. Vol. 11. No. 6. P. 1361–1367. DOI: 10.1080/21645515.2015.1008879

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