DOI QR코드

DOI QR Code

Development of Non-toxic Recombinant Ricin Vaccine and Evaluation of Vaccine Efficacy

독성을 제거한 재조합 리신 백신 개발 및 효능평가

  • Hyeongseok Yun (Defense Advanced Science and Technology Research Institute, Agency for Defense Development) ;
  • Hae-Eun Joe (Defense Advanced Science and Technology Research Institute, Agency for Defense Development) ;
  • Dong Hyun Song (Defense Advanced Science and Technology Research Institute, Agency for Defense Development) ;
  • Chi Ho Yu (Defense Advanced Science and Technology Research Institute, Agency for Defense Development) ;
  • Young-Jo Song (Defense Advanced Science and Technology Research Institute, Agency for Defense Development) ;
  • Gyeung Haeng, Hur (Defense Advanced Science and Technology Research Institute, Agency for Defense Development)
  • 윤형석 (국방과학연구소 국방첨단기술연구원) ;
  • 조혜은 (국방과학연구소 국방첨단기술연구원) ;
  • 송동현 (국방과학연구소 국방첨단기술연구원) ;
  • 유치호 (국방과학연구소 국방첨단기술연구원) ;
  • 송영조 (국방과학연구소 국방첨단기술연구원) ;
  • 허경행 (국방과학연구소 국방첨단기술연구원)
  • Received : 2023.11.24
  • Accepted : 2024.02.07
  • Published : 2024.04.05

Abstract

Ricin is a highly toxic protein which is produced in the seeds of the castor oil plant. Ricin toxin A chain has ribosomal RNA N-glycosylase activity that irreversibly hydrolyses the N-glycosidic bond of the adenine residue at position 4324 within the 28S rRNA. In this study, we developed non-toxic recombinant ricin vaccine(R51) in E. coli expression system, and evaluated efficacy of the R51 according to adjuvants. When the R51 was administered using aluminum hydroxide as an adjuvant, the vaccine efficacy was higher than that of TLR agonists or aluminum phosphate. Because it is time-consuming to administer the vaccine three times at three-week intervals, we investigated the survival rate and antibody titer of mice according to the change of time interval of vaccination. Interestingly, there was no difference in survival rate and antibody titer when R51 was administered at 0, 1, and 3 weeks or 0, 2, and 4 weeks compared to when administered at 0, 3, and 6 weeks. Therefore, the developed R51 vaccine is promising to protect soldiers from Ricin attack.

Keywords

References

  1. Vance DJ, Mantis NJ., "Progress and challenges associated with the development of ricin toxin subunit vaccines," Expert Rev Vaccines., Sep;15(9), pp. 1213-1222, 2016.  https://doi.org/10.1586/14760584.2016.1168701
  2. Endo Y, Tsurugi K., "RNA N-glycosidase activity of ricin A-chain. Mechanism of action of the toxic lectin ricin on eukaryotic ribosomes," J Biol Chem, Jun 15;262(17), pp. 8128-8130, 1987.  https://doi.org/10.1016/S0021-9258(18)47538-2
  3. Magnusson S, Kjeken R, Berg T., "Characterization of two distinct pathways of endocytosis of ricin by rat liver endothelial cells," Exp Cell Res, Mar;205(1), pp. 118-125, 1993.  https://doi.org/10.1006/excr.1993.1065
  4. Smallshaw JE, Richardson JA, Pincus S, Schindler J, Vitetta ES., "Preclinical toxicity and efficacy testing of RiVax, a recombinant protein vaccine against ricin," Vaccine, Sep 15;23(39), pp. 4775-4784, 2005.  https://doi.org/10.1016/j.vaccine.2005.04.037
  5. Griffiths GD, Phillips GJ, Holley J., "Inhalation toxicology of ricin preparations: animal models, prophylactic and therapeutic approaches to protection," Inhal Toxicol, Aug;19(10), pp. 873-887, 2007.  https://doi.org/10.1080/08958370701432124
  6. Baluna R, Rizo J, Gordon BE, Ghetie V, Vitetta ES., "Evidence for a structural motif in toxins and interleukin-2 that may be responsible for binding to endothelial cells and initiating vascular leak syndrome," Proc Natl Acad Sci U S A., Mar 30;96(7), pp. 3957-3962, 1999.  https://doi.org/10.1073/pnas.96.7.3957
  7. 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, Jun 4;17(20-21), pp. 2562-2568. 1999.  https://doi.org/10.1016/S0264-410X(99)00054-7
  8. Smallshaw JE, Firan A, Fulmer JR, Ruback SL, Ghetie V, Vitetta ES., "A novel recombinant vaccine which protects mice against ricin intoxication," Vaccine, Sep 10;20(27-28), pp. 3422-3427, 2002.  https://doi.org/10.1016/S0264-410X(02)00312-2
  9. Olson MA, Carra JH, Roxas-Duncan V, Wannemacher RW, Smith LA, Millard CB., "Finding a new vaccine in the ricin protein fold," Protein Eng Des Sel, Apr;17(4), pp. 391-397, 2004.  https://doi.org/10.1093/protein/gzh043
  10. Smallshaw JE, Richardson JA, Pincus S, Schindler J, Vitetta ES., "Preclinical toxicity and efficacy testing of RiVax, a recombinant protein vaccine against ricin," Vaccine, Sep 15;23(39), pp. 4775-4784, 2005.  https://doi.org/10.1016/j.vaccine.2005.04.037
  11. Carra JH, Wannemacher RW, Tammariello RF, Lindsey CY, Dinterman RE, Schokman RD, Smith LA., "Improved formulation of a recombinant ricin A-chain vaccine increases its stability and effective antigenicity," Vaccine, May 22;25(21), pp. 4149-4158, 2007.  https://doi.org/10.1016/j.vaccine.2007.03.011
  12. De Gregorio E, D'Oro U, Wack A., "Immunology of TLR-independent vaccine adjuvants," Curr Opin Immunol, Jun;21(3), pp. 339-345, 2009.  https://doi.org/10.1016/j.coi.2009.05.003
  13. Steinhagen F, Kinjo T, Bode C, Klinman DM., "TLR-based immune adjuvants," Vaccine, Apr 12;29(17), pp. 3341-3355, 2011.  https://doi.org/10.1016/j.vaccine.2010.08.002
  14. Apostolico Jde S, Lunardelli VA, Coirada FC, Boscardin SB, Rosa DS., "Adjuvants: Classification, Modus Operandi, and Licensing," J Immunol Res., pp. 14593-14594, 2016. 
  15. Hutchison S, Benson RA, Gibson VB, Pollock AH, Garside P, Brewer JM., "Antigen depot is not required for alum adjuvanticity," FASEB J, Mar;26(3), pp. 1272-1279, 2012.  https://doi.org/10.1096/fj.11-184556
  16. Delneste Y, Beauvillain C, Jeannin P., "Immunite naturelle: structure et fonction des Toll-like receptors [Innate immunity: structure and function of TLRs]," Med Sci (Paris), Jan;23(1), pp. 67-73, 2007.  https://doi.org/10.1051/medsci/200723167
  17. Akira S, Uematsu S, Takeuchi O., "Pathogen recognition and innate immunity," Cell, Feb 24;124(4), pp. 783-801, 2006.  https://doi.org/10.1016/j.cell.2006.02.015
  18. Qureshi N, Mascagni P, Ribi E, Takayama K., "Monophosphoryl lipid A obtained from lipopolysaccharides of Salmonella minnesota R595. Purification of the dimethyl derivative by high performance liquid chromatography and complete structural determination," J Biol Chem, May 10;260(9), pp. 5271-5278, 1985.  https://doi.org/10.1016/S0021-9258(18)89017-2
  19. Mazzeo S, Cappelli C, Caramella D, Belcari A, Forasassi F, Battaglia V, Giannini A, Pasquariello R, Pallocci S, Caproni G, Marcocci C, Pinchera A, Miccoli P, Bartolozzi C., "Multidetector CT in diagnostic work-up of patients with primary hyperparathyroidism," Radiol Med, Aug;112(5), pp. 763-775, 2007.  https://doi.org/10.1007/s11547-007-0179-8
  20. Gorden KB, Gorski KS, Gibson SJ, Kedl RM, Kieper WC, Qiu X, Tomai MA, Alkan SS, Vasilakos JP., "Synthetic TLR agonists reveal functional differences between human TLR7 and TLR8," J Immunol, Feb 1;174(3), pp. 1259-1268, 2005.  https://doi.org/10.4049/jimmunol.174.3.1259
  21. Wagner H., "Bacterial CpG DNA activates immune cells to signal infectious danger," Adv Immunol., 73, pp. 329-368, 1999.  https://doi.org/10.1016/S0065-2776(08)60790-7
  22. Olson MA., "Ricin A-chain structural determinant for binding substrate analogues: a molecular dynamics simulation analysis, Proteins, Jan;27(1), pp. 80-95, 1997.  https://doi.org/10.1002/(SICI)1097-0134(199701)27:1<80::AID-PROT9>3.0.CO;2-R
  23. Armitage P, Allen I., "Methods of estimating the LD 50 in quantal response data," J Hyg(Lond), Sep;48(3), pp. 298-322, 1950. https://doi.org/10.1017/S0022172400015084