Clinical and Experimental Vaccine Research

The Korean Vaccine Society (대한백신학회)
권호 표지
DOI QR코드

DOI QR Code

Safety assessments of recombinant DTaP vaccines developed in South Korea

  • Gi-Sub Choi (CLIPS BnC, Research Center) ;
  • Kyu-Ri Kang (The Vaccine Bio Research Institute, Seoul St. Mary's Hospital, College of Medicine, The Catholic University of Korea) ;
  • Seung-Bum Kim (CLIPS BnC, Research Center) ;
  • Joon-Hwan Ji (CLIPS BnC, Research Center) ;
  • Gyu-Won Cho (The Vaccine Bio Research Institute, Seoul St. Mary's Hospital, College of Medicine, The Catholic University of Korea) ;
  • Hyun-Mi Kang (The Vaccine Bio Research Institute, Seoul St. Mary's Hospital, College of Medicine, The Catholic University of Korea) ;
  • Jin-Han Kang (The Vaccine Bio Research Institute, Seoul St. Mary's Hospital, College of Medicine, The Catholic University of Korea)
  • Received : 2024.03.06
  • Accepted : 2024.03.26
  • Published : 2024.04.30
Download PDF
⟨ Previous Next ⟩

Abstract

Purpose: Pertussis bacteria have many pathogenic and virulent antigens and severe adverse reactions have occurred when using inactivated whole-cell pertussis vaccines. Therefore, inactivated acellular pertussis (aP) vaccines and genetically detoxified recombinant pertussis (rP) vaccines are being developed. The aim of this study was to assess the safety profile of a novel rP vaccine under development in comparison to commercial diphtheria-tetanus-acellular pertussis (DTaP) vaccines. Materials and Methods: The two positive control DTaP vaccines (two- and tri-components aP vaccines) and two experimental recombinant DTaP (rDTaP) vaccine (two- and tri-components aP vaccines adsorbed to either aluminum hydroxide or purified oat beta-glucan) were used. Temperature histamine sensitization test (HIST), indirect Chinese hamster ovary (CHO) cell cluster assay, mouse-weight-gain (MWG) test, leukocytosis promoting (LP) test, and intramuscular inflammatory cytokine assay of the injection site performed for safety assessments. Results: HIST results showed absence of residual pertussis toxin (PTx) in both control and experimental DTaP vaccine groups, whereas in groups immunized with tri-components vaccines, the experimental tri-components rDTaP absorbed to alum showed an ultra-small amount of 0.0066 IU/mL. CHO cell clustering was observed from 4 IU/mL in all groups. LP tests showed that neutrophils and lymphocytes were in the normal range in all groups immunized with the two components vaccine. However, in the tri-components control DTaP vaccine group, as well as two- and tri-components rDTaP with beta-glucan group, a higher monocyte count was observed 3 days after vaccination, although less than 2 times the normal range. In the MWG test, both groups showed changes less than 20% in body temperature and body weight before the after the final immunizations. Inflammatory cytokines within the muscle at the injection site on day 3 after intramuscular injection revealed no significant response in all groups. Conclusion: There were no findings associated with residual PTx, and no significant differences in both local and systemic adverse reactions in the novel rDTaP vaccine compared to existing available DTaP vaccines. The results suggest that the novel rDTaP vaccine is safe.

Keywords

Acknowledgement

This research was supported by grant from Ministry of Food and Drug Safety in 2023 (22183MFDS448).

References

  1. Melvin JA, Scheller EV, Miller JF, Cotter PA. Bordetella pertussis pathogenesis: current and future challenges. Nat Rev Microbiol 2014;12:274-88. https://doi.org/10.1038/nrmicro3235
  2. Dorji D, Mooi F, Yantorno O, Deora R, Graham RM, Mukkur TK. Bordetella pertussis virulence factors in the continuing evolution of whooping cough vaccines for improved performance. Med Microbiol Immunol 2018;207:3-26. https://doi.org/10.1007/s00430-017-0524-z
  3. Corbel MJ, Xing DK. Toxicity and potency evaluation of pertussis vaccines. Expert Rev Vaccines 2004;3:89-101. https://doi.org/10.1586/14760584.3.1.89
  4. Higgs R, Higgins SC, Ross PJ, Mills KH. Immunity to the respiratory pathogen Bordetella pertussis. Mucosal Immunol 2012;5:485-500. https://doi.org/10.1038/mi.2012.54
  5. Gustafsson L, Hallander HO, Olin P, Reizenstein E, Storsaeter J. A controlled trial of a two-component acellular, a five-component acellular, and a whole-cell pertussis vaccine. N Engl J Med 1996;334:349-55. https://doi.org/10.1056/NEJM199602083340602
  6. Sekura RD, Fish F, Manclark CR, Meade B, Zhang YL. Pertussis toxin: affinity purification of a new ADP-ribosyltransferase. J Biol Chem 1983;258:14647-51. https://doi.org/10.1016/S0021-9258(17)43911-1
  7. Tamura M, Nogimori K, Yajima M, Ase K, Ui M. A role of the B-oligomer moiety of islet-activating protein, pertussis toxin, in development of the biological effects on intact cells. J Biol Chem 1983;258:6756-61. https://doi.org/10.1016/S0021-9258(18)32285-3
  8. Bokoch GM, Katada T, Northup JK, Hewlett EL, Gilman AG. Identification of the predominant substrate for ADP-ribosylation by islet activating protein. J Biol Chem 1983;258:2072-5. https://doi.org/10.1016/S0021-9258(18)32881-3
  9. Katada T, Ui M. ADP ribosylation of the specific membrane protein of C6 cells by islet-activating protein associated with modification of adenylate cyclase activity. J Biol Chem 1982;257:7210-6. https://doi.org/10.1016/S0021-9258(18)34558-7
  10. Title 21: pertussis vaccine 620.1. In: US Code of Federal Regulations. Washington (DC): Government Printing Office; 1983. p. 58-61.
  11. Munoz J. Biological activities of pertussigen (pertussis toxin). In: Sekura RD, Moss J, Vaughan M, editors. Pertussis toxin. London: Academic Press Inc.; 1985. p. 1-18.
  12. Markey K, Asokanathan C, Feavers I. Assays for determining pertussis toxin activity in acellular pertussis vaccines. Toxins (Basel) 2019;11:417.
  13. Hoonakker ME. In vivo models and in vitro assays for the assessment of pertussis toxin activity. Toxins (Basel) 2021;13:565.
  14. Kang KR, Kim JA, Cho GW, et al. Comparative evaluation of recombinant and acellular pertussis vaccines in a murine model. Vaccines (Basel) 2024;12:108.
  15. World Health Organization. WHO Expert Committee on Biological Standardization. World Health Organ Tech Rep Ser 2013;(979):1-366.
  16. Isbrucker R, Daas A, Wagner L, Costanzo A. Transferability study of CHO cell clustering assays for monitoring of pertussis toxin activity in acellular pertussis vaccines. Pharmeur Bio Sci Notes 2016;2015:97-114.
  17. Gray MC, Guerrant RL, Hewlett EL. The CHO cell clustering response to pertussis toxin: history of its discovery and recent developments in its use. Toxins (Basel) 2021;13:815.
  18. Carbonetti NH. Pertussis toxin and adenylate cyclase toxin: key virulence factors of Bordetella pertussis and cell biology tools. Future Microbiol 2010;5:455-69. https://doi.org/10.2217/fmb.09.133
  19. Tamura M, Nogimori K, Murai S, et al. Subunit structure of islet-activating protein, pertussis toxin, in conformity with the A-B model. Biochemistry 1982;21:5516-22. https://doi.org/10.1021/bi00265a021
  20. Sato Y, Sato H. Development of acellular pertussis vaccines. Biologicals 1999;27:61-9. https://doi.org/10.1006/biol.1999.0181
  21. Kind LS. The altered reactivity of mice after inoculation with Bordetella pertussis vaccine. Bacteriol Rev 1958;22:173-82. https://doi.org/10.1128/br.22.3.173-182.1958
  22. Hoonakker M, Arciniega J, Hendriksen C. Safety testing of acellular pertussis vaccines: use of animals and 3Rs alternatives. Hum Vaccin Immunother 2017;13:2522-30. https://doi.org/10.1080/21645515.2017.1349585
  23. Wagner LD, Corvette LJ, Ngundi MM, Burns DL. Towards replacement of the acellular pertussis vaccine safety test: comparison of in vitro cytotoxic activity and in vivo activity in mice. Vaccine 2017;35:7160-5. https://doi.org/10.1016/j.vaccine.2017.10.082
  24. Parfentjev IA, Goodline MA. Histamine shock in mice sensitized with Hemophilus pertussis vaccine. J Pharmacol Exp Ther 1948;92:411-3.
  25. Carbonetti NH. Pertussis leukocytosis: mechanisms, clinical relevance and treatment. Pathog Dis 2016;74:ftw087.
  26. WHO Expert Committee on Biological Standardization. Recommendations to assure the quality, safety and efficacy of acellular pertussis vaccines. In: WHO Expert Committee on Biological Standardization, editor. WHO Expert Committee on Biological Standardization: sixty-second report. Geneva: WHO Press; 2013. p. 187-260 (WHO technical report series; no. 979).
  27. Jensen SE, Illigen KE, Badsberg JH, Haslov KR. Specificity and detection limit of a dermal temperature histamine sensitization test for absence of residual pertussis toxin in vaccines. Biologicals 2012;40:36-40. https://doi.org/10.1016/j.biologicals.2011.09.015
  28. Gaines-Das R, Ochiai M, Douglas-Bardsley A, et al. Transferability of dermal temperature histamine sensitization test for estimation of pertussis toxin activity in vaccines. Hum Vaccin 2009;5:166-71. https://doi.org/10.4161/hv.5.3.6615
  29. Ochiai M, Yamamoto A, Kataoka M, Toyoizumi H, Arakawa Y, Horiuchi Y. Highly sensitive histamine-sensitization test for residual activity of pertussis toxin in acellular pertussis vaccine. Biologicals 2007;35:259-64. https://doi.org/10.1016/j.biologicals.2007.01.004
  30. Morse SI, Morse JH. Isolation and properties of the leukocytosis- and lymphocytosis-promoting factor of Bordetella pertussis. J Exp Med 1976;143:1483-502. https://doi.org/10.1084/jem.143.6.1483
  31. Gupta RK, Saxena SN, Sharma SB, Ahuja S. The effects of purified pertussis components and lipopolysaccharide on the results of the mouse weight gain test. J Biol Stand 1988;16:321-31. https://doi.org/10.1016/0092-1157(88)90020-0
  32. Hewlett EL, Sauer KT, Myers GA, Cowell JL, Guerrant RL. Induction of a novel morphological response in Chinese hamster ovary cells by pertussis toxin. Infect Immun 1983;40:1198-203. https://doi.org/10.1128/iai.40.3.1198-1203.1983
  33. Pertussis vaccines: WHO position paper. Wkly Epidemiol Rec 2010;85:385-400.
  34. Sato Y, Kimura M, Fukumi H. Development of a pertussis component vaccine in Japan. Lancet 1984;1:122-6. https://doi.org/10.1016/S0140-6736(84)90061-8
  35. Pierce VM, Vazquez M. New combination vaccines: integration into pediatric practice. Pediatr Infect Dis J 2007;26:1149-50. https://doi.org/10.1097/INF.0b013e31815dd80f
  36. Hoonakker ME, Ruiterkamp N, Hendriksen CF. The cAMP assay: a functional in vitro alternative to the in vivo Histamine Sensitization test. Vaccine 2010;28:1347-52. https://doi.org/10.1016/j.vaccine.2009.11.009
  37. Markey K, Asokanathan C, Tierney S, Hockley J, Douglas-Bardsley A. Collaborative study: evaluation of proposed second international standard for pertussis toxin code: 15/126. Geneva: WHO Press; 2017.
  38. Markey K, Douglas-Bardsley A, Hockley J, Le Tallec D, Costanzo A. Calibration of pertussis toxin BRP batch 1 in a standardised CHO cell-based clustering assay. Pharmeur Bio Sci Notes 2018;2018:112-23.
  39. Wagner L, Isbrucker R, Locht C, et al. In search of acceptable alternatives to the murine histamine sensitisation test (HIST): what is possible and practical? Pharmeur Bio Sci Notes 2016;2016:151-70.
  40. Yuen CT, Horiuchi Y, Asokanathan C, et al. An in vitro assay system as a potential replacement for the histamine sensitisation test for acellular pertussis based combination vaccines. Vaccine 2010;28:3714-21. https://doi.org/10.1016/j.vaccine.2010.03.009
  41. Pittman M, Cox CB. Pertussis vaccine testing for freedom-from-toxicity. Appl Microbiol 1965;13:447-56. https://doi.org/10.1128/am.13.3.447-456.1965
  42. Kashiwagi Y, Maeda M, Kawashima H, Nakayama T. Inflammatory responses following intramuscular and subcutaneous immunization with aluminum-adjuvanted or non-adjuvanted vaccines. Vaccine 2014;32:3393-401. https://doi.org/10.1016/j.vaccine.2014.04.018