Clinical and Experimental Vaccine Research

The Korean Vaccine Society (대한백신학회)
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Immunogenicity of a bivalent killed thimerosal-free oral cholera vaccine, Euvichol, in an animal model

  • Lee, Eun Young (Clinical Research Laboratory, Sciences Unit, International Vaccine Institute) ;
  • Lee, Sena (Clinical Research Laboratory, Sciences Unit, International Vaccine Institute) ;
  • Rho, Semi (Clinical Research Laboratory, Sciences Unit, International Vaccine Institute) ;
  • Kim, Jae-Ouk (Clinical Research Laboratory, Sciences Unit, International Vaccine Institute) ;
  • Choi, Seuk Keun (EuBiologics Co. Ltd.) ;
  • Lee, Young Jin (EuBiologics Co. Ltd.) ;
  • Park, Joo Young (EuBiologics Co. Ltd.) ;
  • Song, Manki (Clinical Research Laboratory, Sciences Unit, International Vaccine Institute) ;
  • Yang, Jae Seung (Clinical Research Laboratory, Sciences Unit, International Vaccine Institute)
  • Received : 2018.07.17
  • Accepted : 2018.07.30
  • Published : 2018.07.31
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Abstract

Purpose: An oral cholera vaccine (OCV), Euvichol, with thimerosal (TM) as preservative, was prequalified by the World Health Organization (WHO) in 2015. In recent years, public health services and regulatory bodies recommended to eliminate TM in vaccines due to theoretical safety concerns. In this study, we examined whether TM-free Euvichol induces comparable immunogenicity to its TM-containing formulation in animal model. Materials and Methods: To evaluate and compare the immunogenicity of the two variations of OCV, mice were immunized with TM-free or TM-containing Euvichol twice at 2-week interval by intranasal or oral route. One week after the last immunization, mice were challenged with Vibrio cholerae O1 and daily monitored to examine the protective immunity against cholera infection. In addition, serum samples were obtained from mice to measure vibriocidal activity and vaccine-specific IgG, IgM, and IgA antibodies using vibriocidal assay and enzyme-linked immunosorbent assay, respectively. Results: No significant difference in immunogenicity, including vibriocidal activity and vaccine-specific IgG, IgM, and IgA in serum, was observed between mice groups administered with TM-free and -containing Euvichol, regardless of immunization route. However, intranasally immunized mice elicited higher levels of serum antibodies than those immunized via oral route. Moreover, intranasal immunization completely protected mice against V. cholerae challenge but not oral immunization. There was no significant difference in protection between two Euvichol variations. Conclusion: These results suggested that TM-free Euvichol could provide comparable immunogenicity to the WHO prequalified Euvichol containing TM as it was later confirmed in a clinical study. The pulmonary mouse cholera model can be considered useful to examine in vivo the potency of OCVs.

Keywords

Acknowledgement

Supported by : National Research Foundation of Korea

References

  1. Ali M, Nelson AR, Lopez AL, Sack DA. Updated global burden of cholera in endemic countries. PLoS Negl Trop Dis 2015;9:e0003832. https://doi.org/10.1371/journal.pntd.0003832
  2. Clemens JD, Nair GB, Ahmed T, Qadri F, Holmgren J. Cholera. Lancet 2017;390:1539-49. https://doi.org/10.1016/S0140-6736(17)30559-7
  3. Deen J, von Seidlein L, Luquero FJ, et al. The scenario approach for countries considering the addition of oral cholera vaccination in cholera preparedness and control plans. Lancet Infect Dis 2016;16:125-9. https://doi.org/10.1016/S1473-3099(15)00298-4
  4. Baker JP. Mercury, vaccines, and autism: one controversy, three histories. Am J Public Health 2008;98:244-53. https://doi.org/10.2105/AJPH.2007.113159
  5. Geier MR, Geier DA. Neurodevelopmental disorders after thimerosal-containing vaccines: a brief communication. Exp Biol Med (Maywood) 2003;228:660-4. https://doi.org/10.1177/153537020322800603
  6. Parker SK, Schwartz B, Todd J, Pickering LK. Thimerosal-containing vaccines and autistic spectrum disorder: a critical review of published original data. Pediatrics 2004;114: 793-804. https://doi.org/10.1542/peds.2004-0434
  7. Ball LK, Ball R, Pratt RD. An assessment of thimerosal use in childhood vaccines. Pediatrics 2001;107:1147-54. https://doi.org/10.1542/peds.107.5.1147
  8. World Health Organization. Guidelines on regulatory expectations related to the elimination, reduction or replacement of thiomersal in vaccines. WHO Technical Report Series, No. 926. Annex 4. Geneva: World Health Organization; 2004.
  9. World Health Organization. Vaccines and biologicals: recommendations from the strategic advisory group of experts, weekly epidemiologic record. WHO Weekly Epidemiological Record. Vol. 37. Geneva: World Health Organization; 2002.
  10. Kang SS, Yang JS, Kim KW, et al. Anti-bacterial and anti-toxic immunity induced by a killed whole-cell-cholera toxin B subunit cholera vaccine is essential for protection against lethal bacterial infection in mouse pulmonary cholera model. Mucosal Immunol 2013;6:826-37. https://doi.org/10.1038/mi.2012.121
  11. Yang JS, Kang SS, Yun CH, Han SH. Evaluation of anticoagulants for serologic assays of cholera vaccination. Clin Vaccine Immunol 2014;21:854-8. https://doi.org/10.1128/CVI.00012-14
  12. Yang JS, Kim HJ, Yun CH, et al. A semi-automated vibriocidal assay for improved measurement of cholera vaccine-induced immune responses. J Microbiol Methods 2007; 71:141-6. https://doi.org/10.1016/j.mimet.2007.08.009
  13. Clemens JD, Stanton BF, Chakraborty J, et al. B subunit-whole cell and whole cell-only oral vaccines against cholera: studies on reactogenicity and immunogenicity. J Infect Dis 1987;155:79-85. https://doi.org/10.1093/infdis/155.1.79
  14. Clemens JD, van Loon F, Sack DA, et al. Field trial of oral cholera vaccines in Bangladesh: serum vibriocidal and antitoxic antibodies as markers of the risk of cholera. J Infect Dis 1991;163:1235-42. https://doi.org/10.1093/infdis/163.6.1235
  15. Mosley WH, Ahmad S, Benenson AS, Ahmed A. The relationship of vibriocidal antibody titre to susceptibility to cholera in family contacts of cholera patients. Bull World Health Organ 1968;38:777-85.
  16. Nygren E, Li BL, Holmgren J, Attridge SR. Establishment of an adult mouse model for direct evaluation of the efficacy of vaccines against Vibrio cholerae. Infect Immun 2009;77:3475-84. https://doi.org/10.1128/IAI.01197-08
  17. Villeneuve S, Boutonnier A, Mulard LA, Fournier JM. Immunochemical characterization of an Ogawa-Inaba common antigenic determinant of Vibrio cholerae O1. Microbiology 1999;145(Pt 9):2477-84. https://doi.org/10.1099/00221287-145-9-2477
  18. Baik YO, Choi SK, Olveda RM, et al. A randomized, non-inferiority trial comparing two bivalent killed, whole cell, oral cholera vaccines (Euvichol vs Shanchol) in the Philippines. Vaccine 2015;33:6360-5. https://doi.org/10.1016/j.vaccine.2015.08.075
  19. Saha A, Chowdhury MI, Khanam F, et al. Safety and immunogenicity study of a killed bivalent (O1 and O139) whole-cell oral cholera vaccine Shanchol, in Bangladeshi adults and children as young as 1 year of age. Vaccine 2011; 29:8285-92. https://doi.org/10.1016/j.vaccine.2011.08.108
  20. Holmgren J, Svennerholm AM. Bacterial enteric infections and vaccine development. Gastroenterol Clin North Am 1992;21:283-302.
  21. Qadri F, Ryan ET, Faruque AS, et al. Antigen-specific immunoglobulin A antibodies secreted from circulating B cells are an effective marker for recent local immune responses in patients with cholera: comparison to antibody-secreting cell responses and other immunological markers. Infect Immun 2003;71:4808-14. https://doi.org/10.1128/IAI.71.8.4808-4814.2003
  22. Robbins JB, Schneerson R, Szu SC. Perspective: hypothesis: serum IgG antibody is sufficient to confer protection against infectious diseases by inactivating the inoculum. J Infect Dis 1995;171:1387-98. https://doi.org/10.1093/infdis/171.6.1387
  23. Aktar A, Rahman MA, Afrin S, et al. Plasma and memory B cell responses targeting O-specific polysaccharide (OSP) are associated with protection against Vibrio cholerae O1 infection among household contacts of cholera patients in Bangladesh. PLoS Negl Trop Dis 2018;12:e0006399. https://doi.org/10.1371/journal.pntd.0006399
  24. Nandy RK, Albert MJ, Ghose AC. Serum antibacterial and antitoxin responses in clinical cholera caused by Vibrio cholerae O139 Bengal and evaluation of their importance in protection. Vaccine 1996;14:1137-42. https://doi.org/10.1016/0264-410X(96)00035-7
  25. Klose KE. The suckling mouse model of cholera. Trends Microbiol 2000;8:189-91. https://doi.org/10.1016/S0966-842X(00)01721-2
  26. Butterton JR, Ryan ET, Shahin RA, Calderwood SB. Development of a germfree mouse model of Vibrio cholerae infection. Infect Immun 1996;64:4373-7.
  27. Russo P, Ligsay AD, Olveda R, et al. A randomized, observer-blinded, equivalence trial comparing two variations of Euvichol(R), a bivalent killed whole-cell oral cholera vaccine, in healthy adults and children in the Philippines. Vaccine 2018;36:4317-24. https://doi.org/10.1016/j.vaccine.2018.05.102

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