Adjuvants

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Lecture No. 12. March 25th, 2004 Formulation
and Delivery K.I. Dayalu
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The Ideal Vaccine

• Single dose
• Neonatal Administration
• Needle-less administration
• 100 Effective
• 100 Safe
• Life-long protection
• Affordable

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Vaccine Reality

• Multiple doses
• Poor Neonatal Immune Responsiveness
• Injectable administration
• Variable Effectiveness
• Variable Safety
• Generally short lived protection
• Affordable

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Historical Formulation
Not Fancy(Perhaps even rude and crude --- But
it worked!!!!

• Inactivated Diluted Culture Fluids

• Modified Live Lyophilized Plugs

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Historical Adjuvants

• Freunds Complete, Incomplete
• Aluminum salts Hydroxide, Phosphate

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How Do We Achieve the Ideal?
Defined Vaccines

Modified-Live Sub-unit Genetic
Vaccine Components Antigen(s) Adjuvant(s)
Vehicle(s)/Delivery
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ITS NOT ALL MAGIC
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Adjuvant Mechanisms

• Influence antigen processing and trafficking
• Activate immune cells
• Influence magnitude quality of immune response

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Adjuvant Types
Enhance immune response to antigens

• Immunostimulants
• Vehicles
• Surfactants
• Particulates
• Conjugates
• Molecular

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Adjuvants - Immunostimulants
Bacterial Extracts

• TDM
• MPL, MDP
• CT/LT-oral, mucosal

Plant Extracts and Synthetic

• Lipoidal Amines
• Saponins

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Adjuvants - Vehicles

• Oil - Emulsions
• Liposomes
• Microparticles

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Adjuvants - Surfactants

• Saponins
• Non-ionic Co-block Polymers

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Saponins

• Quil A, QS-21
• S. American tree bark
• Quillja saponaria molina
• induces humoral cellular immunity

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Non-ionic Co-Block Polymers

• BASF Pluronic Series
• (i.e. L-121)

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Adjuvants- Particulate

• VLP
• ISCOM
• Microparticles
• Liposomes, etc
• Alum salts.

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Adjuvants - Conjugates

• Link antigens to carriers
• Enhance immunogenicity of poorly immunogenic
  antigens( i.e.peptides)
• Change TI antigen to TD antigen
• (eg., Hib conjugate vaccines)

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Adjuvant Selection

• Immune response desired
• Nature of antigen
• Formulation
• Complexity
• Stability
• Scalability
• Safety concerns
• Regulatory issues

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ITS A FINE BALANCE
EFFICACY
SAFETY
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We Need to Break our Paradigms
There are no Magic Bullets
Novel SystemsTechnology gtgt Differentiation
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Adjuvants - Molecular

• HSP
• Immunoregulatory Oligomers CpG
• PADRE
• C5a

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The best adjuvant will never correct the choice
of the wrong epitope.
Edelman Tacket, 1990
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Antigen
Vehicle
Vaccine System
Adjuvant
DELIVERY
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New Methods in Delivery

• Vesicles
• microparticulates of proteins, lipids,
  carbohydrates, polymers
• passive or active targeting
• eg. Liposomes

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New Methods in Delivery

• Controlled Release
• nearly independent of environmental conditions
  (pH)
• pumps
• synthetic polymeric materials
• diffusion
• chemical reaction (degradation/cleavage)
• solvent activation(swelling/osmotic effects)

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New Methods in Delivery

• Polymers
• Degradable
• poly-lactide co-glycolide (PLG)
• Lupron Depot
• protein released over 30 d
• Non-degradable
• Ocusert
• continuous pilocarpine release for 1 week
• Norplant
• 5 yr release

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Degradable Polymers (PLG)

• Problems
• variable release rates
• protein particle size
• loading
• protein solubility
• molecular weight
• polymer composition
• size/shape of matrix
• protein stability

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Vaccine Delivery RoutesHow do we get it in
there?

• Intramuscular
• Subcutaneous
• Intradermal
• Intranasal/Aerosol
• Oral/Enteric
• Transdermal
• Other

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Vaccine Delivery RoutesIntramuscular
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Vaccine Delivery RoutesSubcutaneous
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Vaccine Delivery RoutesIntradermal
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Vaccine Delivery RoutesIntranasal/Aerosol
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Vaccine Delivery RoutesOral
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Vaccine Delivery RoutesTransdermal
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New Delivery Devices

• Jet Injection
• needle free
• liquid stream lt 0.005 in.
• 25 ga needle 0.040 in.
• high pressure (gt4000 psi)
• SC, ID (?), or IM (?)
• conventional vaccines
• individual or multiple dose
• suitable for mass vaccination

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New Delivery Devices

• Ballistic impaction
• needle-free
• supersonic spray
• skin or mucous membrane
• gt1 square cm area
• intradermal or intraepidermal
• access to Langerhans APCs
• dry powder or coated particles
• proteins, peptides, DNA

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New Delivery Devices

• Transdermal Delivery
• Occluded Patch
• Microneedle array
• needle free
• skin or mucous membranes
• access to Langerhans APCs
• limited volume capacity