Strategies for the Nonclinical Safety Assessment of Vaccines

  • Jayanthi J. Wolf
  • Lisa M. Plitnick
  • Danuta J. Herzyk


Over the past century, vaccines have made a large impact on public health. Prophylactic vaccines prevent disability and disease, saving millions of dollars in potential health-care spending. Since prophylactic vaccines are administered to healthy individuals, including infants and children, it is important to demonstrate the safety of vaccines preclinically prior to testing the vaccine in clinical studies. A benefit-to-risk profile is considered for each individual vaccine and depends on many factors including preclinical and clinical toxicities that are observed, frequency of administration and intended target population. For prophylactic vaccines, in particular, the concerns about potential risks often outweigh the perception of benefit [1]. Therefore, over the past decade, there has been an increased focus on nonclinical safety assessment of vaccines, including toxicity testing.


Vaccine Candidate Toxicology Study Vaccine Antigen Vaccine Formulation Therapeutic Vaccine 
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  1. 1.
    Gruber MF (2003) Non-clinical safety assessment of vaccines. In: CBER counter terrorism workshop, BethesdaGoogle Scholar
  2. 2.
    Dey AK, Srivastava IK (2011) Novel adjuvants and delivery systems for enhancing immune responses induced by immunogens. Expert Rev Vaccines 10:227–251PubMedCrossRefGoogle Scholar
  3. 3.
    Batista-Duharte A, Lindblad EB, Oviedo-Orta E (2011) Progress in understanding adjuvant immunotoxicity mechanisms. Toxicol Lett 203:97–105PubMedCrossRefGoogle Scholar
  4. 4.
    WHO guidelines on nonclinical evaluation of vaccines (2005) World Health Organization Technical Report Series, No. 927, Annex 1Google Scholar
  5. 5.
    EMA (1997) Note for guidance on preclinical pharmacological and toxicological testing of vaccines. CPMP/SWP/465/95Google Scholar
  6. 6.
    Ministry of Health, Labour and Welfare, Japan (2010) Guideline for non-clinical studies of vaccines for preventing infectious diseases. PFSB/ELD Notification No. 0527-1Google Scholar
  7. 7.
    State Food and Drug Administration, China (2010) Technical guidelines for preclinical research on preventive vaccines. Notice No. 140Google Scholar
  8. 8.
    CBER, FDA (2007) Guidance for Industry: considerations for plasmid DNA vaccines for infectious disease indicationsGoogle Scholar
  9. 9.
    WHO (2005) Guidelines for assuring the quality and nonclinical safety evaluation of DNA vaccines. WHO, GenevaGoogle Scholar
  10. 10.
    CBER, FDA (1998) Guidance for industry: guidance for human somatic cell therapy and gene therapyGoogle Scholar
  11. 11.
    EMA (2010) Guideline on quality, non-clinical and clinical aspects of live recombinant viral vectored vaccines. EMA/CHMP/VWP/141697/2009Google Scholar
  12. 12.
    EMA (2001) Note for guidance on the quality, preclinical and clinical aspects of gene transfer medicinal products. CPMP/BWP/3088/99Google Scholar
  13. 13.
    EMA (2001) Points to consider on the manufacture and quality control of human somatic cell therapy medicinal products. CPMP/BWP/41450/98Google Scholar
  14. 14.
    CBER, FDA (1985) Points to consider in the production and testing of new drugs and biologicals produced by recombinant DNA technologyGoogle Scholar
  15. 15.
    ICH Topic S6 (1997) Preclinical safety evaluation of biotechnology-derived pharmaceuticals. In: International conference on harmonizationGoogle Scholar
  16. 16.
    EMA (2005) Guideline on adjuvants in vaccines for human use. EMEA/CPMP/VEG/134716/2004Google Scholar
  17. 17.
    EMA (1998) Note for guidance on pharmaceutical and biological aspects of combined vaccines. CPMP/BWP/477/98Google Scholar
  18. 18.
    CBER, FDA (2006) Guidance for industry: considerations for developmental toxicity studies for preventative and therapeutic vaccines for infectious disease indicationsGoogle Scholar
  19. 19.
    CBER, FDA (2009) Draft guidance for industry: clinical considerations for therapeutic cancer vaccinesGoogle Scholar
  20. 20.
    CBER, FDA (2010) Characterization and qualification of cell substrates and other biological materials used in the production of viral vaccines for infectious disease indicationsGoogle Scholar
  21. 21.
    WHO (2010). Recommendations for the evaluation of animal cell cultures as substrates for the manufacture of biological medicinal products and for the characterization of cell banks. WHO, GenevaGoogle Scholar
  22. 22.
    ICH Topic Q5A(R1) (1997) Quality of biotechnological products: viral safety evaluation of biotechnology products derived from cell lines of human or animal origin. In: International conference on harmonization. CPMP/ICH/295/95Google Scholar
  23. 23.
    Wally JL, Kunder S (2010) Animal models and the preclinical assessment of safety of investigational vaccine products. Office of Vaccines Research and Review CBER/FDA. In: PDA/FDA vaccine conference, BethesdaGoogle Scholar
  24. 24.
    Good Laboratory Practice Regulations. Code of Federal Regulations, Title 21, Part 58 (21 CFR 58)Google Scholar
  25. 25.
    Maier M, Seabrook TJ, Lemere CA (2005) Developing novel immunogens for an effective, safe Alzheimer’s disease vaccine. Neurodegener Dis 2:267–272PubMedCrossRefGoogle Scholar
  26. 26.
    Lindblad EB (2006) Safety evaluation of vaccine adjuvants. In: Singh M (ed) Vaccine adjuvants and delivery systems. Wiley, Hoboken, pp 421–444Google Scholar
  27. 27.
    ICH Topic S7A (2000) Safety pharmacology studies for human pharmaceuticals. In: International conference on harmonizationGoogle Scholar
  28. 28.
    ICH Topic S2B (1997) Genotoxicity: a standard battery for genotoxicity testing of pharmaceuticals. International conference on harmonizationGoogle Scholar
  29. 29.
    Bal SM, Caussin J, Pavel S, Bouwstra JA (2008) In vivo assessment of safety of microneedle arrays in human skin. Eur J Pharm Sci 35:193–202PubMedCrossRefGoogle Scholar
  30. 30.
    Standard ISO-10993. Biological evaluation of medical devices. International Organization for StandardizationGoogle Scholar
  31. 31.
    Chapter <88> Biologics reactivity testing. United States PharmacopeiaGoogle Scholar
  32. 32.
    Lefesvre P, Attema J, Bekkum DA (2002) Comparison of efficacy and toxicity between electroporation and adenoviral gene transfer. BMC Mol Biol 47:12CrossRefGoogle Scholar
  33. 33.
    Medi BM, Singh J (2006) Skin targeted DNA vaccine delivery using electroporation in rabbits: II. Safety. Int J Pharm 308:61–68PubMedCrossRefGoogle Scholar
  34. 34.
    ICH Topic Q3A(R2) (2006) Impurities in new drug substances. In: International conference on harmonization. CPMP/ICH/142/95Google Scholar
  35. 35.
    ICH Topic Q3B(R2) (2006) Impurities in new drug products. In: International conference on harmonization. CPMP/ICH/2738/99Google Scholar
  36. 36.
    ICH Topic Q3C(R5) (2011) Impurities: guidelines for residual solvents. In: International conference on harmonization. CPMP/ICH/2738/99Google Scholar
  37. 37.
    Kroes R, Renwick AG, Cheeseman M, Kleinerd J, Mangelsdorf I, Piersma A, Schilter B, Schlatter J, van Schothorst F, Vos JG, Wurtzen G (2004) Structure-based thresholds of toxicological concern (TTC): guidance for application to substances present at low levels in the diet. Food Chem Toxicol 42:65–83PubMedCrossRefGoogle Scholar
  38. 38.
    EMA (2006) Guideline on the limits of genotoxic impurities. EMEA/CHMP/QWP/251344/2006Google Scholar
  39. 39.
    Wolf JJ, Kaplanski CV, Lebron JA (2010) Nonclinical safety assessment of vaccines and adjuvants. Methods Mol Biol 626:29–40PubMedCrossRefGoogle Scholar
  40. 40.
    Opalka D, Lachman CE, MacMullen SA, Jansen KU, Smith JF, Chirmule N, Esser MT (2003) Simultaneous quantitation of antibodies to neutralizing epitopes on virus-like particles for human papillomavirus types 6, 11, 16, and 18 by a multiplexed luminex assay. Clin Diagn Lab Immunol 10:108–115PubMedGoogle Scholar
  41. 41.
    Casimiro DR, Tang A, Perry HC, Long RS, Chen M, Heidecker GJ, Davies ME, Freed DC, Persaud NV, Dubey S, Smith JG, Havlir D, Richman D, Chastain MA, Simon AJ, Fu TM, Emini EA, Shiver JW (2002) Vaccine-induced immune responses in rodents and nonhuman primates by use of a humanized human immunodeficiency virus type 1 pol gene. J Virol 76:185–194PubMedCrossRefGoogle Scholar
  42. 42.
    Kaplanski C, Lebron J, Wolf J, Ledwith B (2008) Immunotoxicological concerns for vaccines and adjuvants. In: Herzyk DJ, Bussiere JL (eds) Immunotoxicology strategies for pharmaceutical safety assessment. Wiley, Hoboken, pp 229–237CrossRefGoogle Scholar
  43. 43.
    Johnson DA, Baldridge JR (2007) TLR4 agonists as vaccine adjuvants. In: Singh M (ed) Vaccine adjuvants and delivery systems. Wiley, Hoboken, pp 131–156CrossRefGoogle Scholar
  44. 44.
    Portielje J, Kruit W, Eerenberg A, Schuler M, Sparreboom A, Lamers C (2005) Subcutaneous injection of interleukin 12 induces systemic inflammatory responses in humans: implications for the use of IL-12 as vaccine adjuvant. Cancer Immunol Immunother 54:37–43PubMedCrossRefGoogle Scholar
  45. 45.
    Egilmez NK (2007) Cytokines as vaccine adjuvants. In: Singh M (ed) Vaccine adjuvants and delivery systems. Wiley, Hoboken, pp 327–354CrossRefGoogle Scholar
  46. 46.
    Liu L, Shen L, Liu X, Yu Y, Li Y, Wang L, He C, Sun J, Li B (2012) A safety study of a B-class CpG ODN in Sprague-Dawley rats. J Appl Toxicol 32:60–71. doi:10.1002/jat.1683PubMedCrossRefGoogle Scholar
  47. 47.
    Ott G, Barchfeld GL, Chernoff D, Radhakrishnan R, van Hoogevest P, Van Nest G (1995) MF59. Design and evaluation of a safe and potent adjuvant for human vaccines. Pharm Biotechnol 6:277–296PubMedCrossRefGoogle Scholar
  48. 48.
    Kashala O, Amador R, Valero MV, Moreno A, Barbosa A, Nickel B, Daubenberger CA, Guzman F, Pluschke G, Patarroyo ME (2002) Safety, tolerability and immunogenicity of new formulations of the Plasmodium falciparum malaria peptide vaccine SPf66 combined with the immunological adjuvant QS-21. Vaccine 20:2263–2277PubMedCrossRefGoogle Scholar
  49. 49.
    Schenk D (2002) Amyloid-β immunotherapy for Alzheimer’s disease: the end of the beginning. Nat Rev Neurosci 3:824–828PubMedCrossRefGoogle Scholar
  50. 50.
    Cribbs DH, Ghochikyan A, Vasilevko V, Tran M, Petrushina I, Sadzikava N, Babikyan D, Kesslak P, Kieber-Emmons T, Cotman CW, Agadjanyan MG (2003) Adjuvant-dependent modulation of Th1 and Th2 responses to immunization with beta-amyloid. Int Immunol 15:505–514PubMedCrossRefGoogle Scholar
  51. 51.
    Drane D, Gittleson C, Boyle J, Maraskovsky E (2007) ISCOMATRIX adjuvant for prophylactic and therapeutic vaccines. Expert Rev Vaccines 6:761–772PubMedCrossRefGoogle Scholar
  52. 52.
    Wang I-M, Cristescu R, Su W-L, Goldman P, Loboda A, Dubey S, Meschino S, Casimiro D, Chastain M, Bett A (2010) Blood profiling of vaccines and adjuvants in non-human primates to study mode of action, immunogenicity and predict adverse events. In: Keystone symposia immunological mechanisms of vaccination, SeattleGoogle Scholar
  53. 53.
    Lebron JA, Wolf JJ, Kaplanski CV, Ledwith BJ (2006) Nonclinical safety assessment of vaccines and the evaluation of novel adjuvants and delivery systems. In: Singh M (ed) Vaccine adjuvants and delivery systems. Wiley, Hoboken, pp 403–420Google Scholar
  54. 54.
    van der Laan JW, Forster R, Ledwith B, Gruber M, Gould S, Segal L, Penninks A (2009) Nonclinical testing of vaccines: report from a workshop. Drug Inf J 43:97–107CrossRefGoogle Scholar
  55. 55.
    Viral safety evaluation of biotechnological products derived from cell lines of human or animal origin. Chapter <1050>. United States PharmacopeiaGoogle Scholar
  56. 56.
    Vaccines for human use. Monograph 0153. European PharmacopoeiaGoogle Scholar
  57. 57.
    Vaccines for human use. Chapter <1235>. United States PharmacopeiaGoogle Scholar
  58. 58.
    General biological products standards. Code of Federal Regulations, Title 21, Part 610 (21 CFR 610)Google Scholar
  59. 59.
    CBER, FDA (1999) FDA guidance for industry: content and format of chemistry, manufacturing and controls information and establishment description information for a vaccine or related productGoogle Scholar
  60. 60.
    Good Manufacturing Practice. Medicinal products for human and veterinary use. In: The rules governing medicinal products in the European Union. EudraLex, SANCO/C8/AM/sl/ares/(2010)1064597. vol 4Google Scholar
  61. 61.
    cGMP in Manufacturing, Processing, Packing, or Holding of Drugs and Finished Pharma­ceuticals. Code of Federal Regulations, Title 21, Part 210, 211 (21 CFR 210, 211)Google Scholar
  62. 62.
    cGMP in Manufacturing, Processing, Packing, or Holding of Drugs and Finished Pharmaceuticals, Title 21, Part 610.11 (21 CFR 610.11)Google Scholar
  63. 63.
    Abnormal toxicity. Monograph 2.6.9. European PharmacopoeiaGoogle Scholar
  64. 64.
    Pyrogens. Monograph 2.6.8. European PharmacopoeiaGoogle Scholar
  65. 65.
    Pyrogen test. Chapter <151>. United States PharmacopeiaGoogle Scholar
  66. 66.
    Purity. Code of Federal Regulations, Title 21, Part 610.13 (21 CFR 610.13)Google Scholar
  67. 67.
    Tests for extraneous agents in viral vaccines. Monograph 2.6.16. European PharmacopoeiaGoogle Scholar
  68. 68.
    Cell substrates for production of vaccines for human use. Monograph 5.2.3. European PharmacopoeiaGoogle Scholar
  69. 69.
    Test for neurovirulence of live virus vaccines. Monograph 2.6.18. European PharmacopoeiaGoogle Scholar
  70. 70.
    Potency. Code of Federal Regulations, Title 21, Part 610.10 (21 CFR 610.10)Google Scholar
  71. 71.
    Hoffmann S, Peterbauer A, Schindler S, Fennrich S, Poole S, Mistry Y, Montag-Lessing T, Spreitzer I, Löschner B, van Aalderen M, Bos R, Gommer M, Nibbeling R, Werner-Felmayer G, Loitzl P, Jungi T, Brcic M, Brügger P, Frey E, Bowe G, Casado J, Coecke S, de Lange J, Mogster B, Naess LM, Aaberge IS, Wendel A, Hartung T (2005) International validation of novel pyrogen tests based on human monocytoid cells. J Immunol Methods 298:161–173PubMedCrossRefGoogle Scholar
  72. 72.
    Monocyte-activation test. Monograph 2.6.30. European PharmacopoeiaGoogle Scholar
  73. 73.
    The Organisers, IABs (2006) IABs scientific workshop on neurovirulence tests for live virus vaccines. Biologicals 34:233–236CrossRefGoogle Scholar
  74. 74.
    Measles Vaccine (Live) Monograph 0213. European PharmacopoeiaGoogle Scholar
  75. 75.
    Mumps Vaccine (Live) Monograph 0538. European PharmacopoeiaGoogle Scholar
  76. 76.
    Rubella Vaccine (Live) Monograph 0162. European PharmacopoeiaGoogle Scholar
  77. 77.
    Varicella Vaccine (Live) Monograph 0648. European PharmacopoeiaGoogle Scholar
  78. 78.
    Rubin SA, Afzal MA, Powell CL, Bentley ML, Auda GR, Taffs RE (2005) The rat-based neurovirulence safety test for the assessment of mumps virus neurovirulence in humans: an international collaborative study. J Infect Dis 191:1123–1128PubMedCrossRefGoogle Scholar
  79. 79.
    Rubin SA, Afzal MA (2011) Neurovirulence safety testing of mumps vaccines—historical perspective and current status. Vaccine 29:2850–2855PubMedCrossRefGoogle Scholar

Copyright information

© Springer Science+Business Media New York 2013

Authors and Affiliations

  • Jayanthi J. Wolf
    • 1
  • Lisa M. Plitnick
    • 1
  • Danuta J. Herzyk
    • 1
  1. 1.Merck Research LaboratoriesMerck & Co., Inc.West PointUSA

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