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Principles of WHO Guidelines on nonclinical evaluation of vaccines. Jan Willem van der Laan Pharmacological-Toxicological Assessment Section Centre for Biological Medicines and Medical Technology National Institute for Public Health and the Environment, Bilthoven. OUTLINE. History

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principles of who guidelines on nonclinical evaluation of vaccines

Principles of WHO Guidelines on nonclinical evaluation of vaccines.

Jan Willem van der Laan

Pharmacological-Toxicological Assessment Section

Centre for Biological Medicines and Medical Technology

National Institute for Public Health and the Environment, Bilthoven

  • History
  • Regulatory documents
  • WHO Guideline on nonclinical evaluation of vaccines
  • Toxicity testing of GMOs
  • Animal experiments as batch release testing
    • Potency testing
    • Abnormal Toxicity
    • Sensitizing potential
    • Immunogenicity
  • Adjuvants: No separate issue
    • Aluminium hydroxide,
    • Aluminium phosphate
regulational history
Regulational history
  • VACCINES under European legislation since 1993
    • differentiation of pharmaceutical and non-clinical parts
    • overlap between potency testing and vaccine pharmacodynamics
    • direct pharmacological effects adrenergic receptors in autonomous nervous system, e.g. pertussis toxin, Heamophilus influenza, cholera toxin
    • overlap between batch release abnormal toxicity, non-clinical safety (in view of the developments in biotechnology)

leading to

    • EU Guidance on Preclinical Pharmacological and Toxicological Testing of Vaccines CPMP/SWP/465/95
other non clinical guidance documents
Other Non-clinical Guidance Documents
  • Guideline on Adjuvants in Human Vaccines CHMP/VEG/17/03, draft released for consultation, March 2004final to be expected January 2005
  • WHO Guidelines on Nonclinical evaluation of vaccines, released November 2004
who guidelines on nonclinical evaluation of vaccines
WHO Guidelines on Nonclinical Evaluation of vaccines
  • Nonclinical evaluation plays an essential part in the overall development of vaccine candidates
    • Product characterization
    • Proof of concept/immunogenicity
    • Safety testing in animals
aims of non clinical testing of vaccines
Aims of Non-clinical Testing of Vaccines
  • Identify possible risks to the vaccinees
  • Help to plan protocols
limitations of animal experiments
Limitations of animal experiments
  • Pathogenesis and immune responses are frequently species-specific
  • Potential Safety concerns may not necessarily indicate a problem in humans
scope of the who guidelines
SCOPE of the WHO Guidelines
  • Vaccines are a heterogenous class of immmunogenic substances inducing specific active protective host immunity against infectious disease.
  • Inactivated Micro-organisms
  • Live Micro-organisms
  • Antigens extracted from micro-organisms
  • Chimeric micro-organisms
  • Antigens produced in vivo (DNA-vaccines)
characterization of candicate vaccines
Characterization of candicate vaccines
  • Vaccine production
  • Potency
  • Stability
immunogenicity and other pharmacodynamic studies
Immunogenicity and other Pharmacodynamic studies
  • Proof of concept
  • Establish immunological characteristics
  • Help to select the doses and schedules

Designed to assess relevant immune responses leading to protection


Specific adjuvant


Antigen presenting cell

Immune response is triggered


B-Cells, antibodies

basic toxicity assessment
Basic toxicity assessment
  • 4.1 General framework for designing pre-clinical toxicity of a vaccine (prior to initiation of clinical trials in humans)
  • 4.2 Additional considerations for specific toxicity assessments
study design
Study design
  • Relevant animal species/strain
  • Dosing schedule
  • Route of administration
  • Method of vaccine administration (specific device?)
  • Timing of evaluation of endpoints
animal species
Animal species
  • Ideally, sensitive to the pathogenic organism
  • Develop an immune response to the vaccine antigen

In general, one species is sufficient

dose schedule and route of administration
Dose, schedule and route of administration
  • Dose maximizing exposure and peak antibody response
  • Vaccine should be given as episodic doses based on the kinetics of the antibody response
  • Clinical route of administration is preferred
parameters monitored
Parameters monitored
  • In-life parameters
    • Daily observations
    • Weekly body weight and food consumption (1st week more frequent)
    • Interim analysis of heamatology and serum chemistry
  • Not only during treatment but also a few weeks after
parameters monitored 2
Parameters monitored (2)

At study termination:

  • Parameters mentioned
  • Immune response
  • Gross necropsy, tissue collection and preservation
tissue list
Tissue list
  • Pivotal organs: brain, liver, kidney, reproductive organs, SoA.
  • Special attention to immune organs
    • Lymph nodes
    • Thymus
    • Spleen
    • Bone marrow
    • Peyer’s patches
additional toxicity assessments
Additional toxicity assessments

Specific Immunologic Investigations

  • Precipitation of immune complexes
  • Humoral or cell-mediated immune response against self (molec. mimicry)
  • Exacerbation of the disease
additional toxicity assessments 2
Additional toxicity assessments (2)
  • Developmental toxicity studies
    • Usually not needed in case of paediatric vaccines
    • If WoCBP are included
  • Pre- and postnatal developmental study only
additional toxicity assessments 3
Additional toxicity assessments (3)
  • Developmental toxicity study design
    • premating treatment is recommended to assure maximal exposure
    • Number of doses depends on the response
    • Booster immunization may be necessary to expose the embryo to vaccine components
safety pharmacology
Safety pharmacology
  • If a vaccine (based on specific toxoids) is expected to affect physiological functions (CNS, respiratory, cardiovascular, renal) safety pharmacology studies should be performed
pharmacokinetic studies
Pharmacokinetic studies
  • Determining serum concentration is normally not needed
  • Local deposition studies at the site of injection and the draining lymph node
  • Distribution studies in case of new formulations, adjuvants or route of administration
special considerations
Special considerations
  • Adjuvants
  • Additives (excipients and preservatives)
  • Vaccine formation and delivery device
what about plant vaccines
What about plant vaccines?
  • Oral administration
    • Immunogenicity?
    • Immunobioavailability
    • What are the risks?
      • Immunotolerance
      • hypersensitivity
what about plant vaccines 2
What about plant vaccines? (2)
  • Plant constituents (alkaloids, proteins)?
    • Induces insertion pleiotrophic effects on plant toxoids?
gmo legislation
GMO Legislation
  • GM Crops – is there a safety issue?

Novel gene

Novel protein

Novel food/food ingredient

Gene transfer

Toxicity (animal tests)


Substantial equivalence

Toxicity (animal tests)

Unintended effects

Kleter and Kuiper (2002)

safety assessment of gm foods
Safety assessment of GM foods
  • Molecular characterization
  • Changes in agronomical characteristics, morphology, and food composition
  • Toxicity of newly inserted proteins and of the whole food
  • Allergenicity
  • Gene transfer
  • Changed pattern in pesticide residues
safety assessment of gm foods31
Safety assessment of GM foods
  • Principle of “Substantial Equivalence”
  • Assessment in a comparative way, i.e. new crop vs. conventionally bred crop
detection of unintended effects
Detection of unintended effects
  • Compared to convential crop based on phenotype based on:
    • Genomics - cDNA profile (microarray)
    • Proteomics – protein profile
    • Metabolomics – metabolite profile
toxicity studies for gm food proteins
Toxicity studies for GM food proteins
  • Acute oral toxicity – one high dose
  • Subchronic oral toxicity (28-90 days)
  • Comparison by computer of structure with known allergens
  • Reactions of antisera of patients
  • Simulated digestion of novel proteins
  • Animal models, e.g. Brown-Norway rat (IgE-hyperresponsive)