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Travel Medicine

Vaccination strategies & formulation

Darragh Murnane
Email:d.murnane@herts.ac.uk

Learning Objectives
To gain an understanding of immunization
To gain an understanding of vaccination strategies To gain an understanding of vaccine formulations

References
Antibodies, vaccines and adjuvants (Chp. 13) in Pharmaceutical Biotechnology, G Walsh.
Excipients used in vaccines (Chp. 18) in Excipient Development for Pharmaceutical, Biotechnology and Drug Delivery Systems, A Katdare & MV Chaubel (Eds)

The Green Book:


http://www.dh.gov.uk/en/Publicationsandstatistics/Publications/Publ icationsPolicyAndGuidance/DH_079917

Some definitions
Vaccine: an agent to promote active
immunization of an individual.
Prophylactic Traditionally an immunological agent to prevent infectious disease

Immunization: the production of immunity by


artificial means

Immunity: resistance of an organism to a


particular infection or toxin by the action of antibodies or sensitized white blood cells.
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Active immunity
Adaptive immunity:
Immune-mediating cells:
Macrophage, dendritic, neutrophils
Antigen presenting

T-cells
T-helper 1: cell-mediated immunity T-helper 2: involved in humoral response Natural killer cells (NK) kills own organism cells

B-cells
Humoral immunity (antibody production) Form memory cells
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Cell-mediated immunity
Antigen present within cell
Antigen presented on surface on MHC1 differentiate into killer or memory cells
Cell communication through helping molecules called interleukins. Using surface receptors to produce the required response.
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Killer T-cells kill cells expressing antigen on surface (apoptosis) Memory T-cells activated

Humoral immunity
Antigens presented on MHC2 in lymphatic system. Only specific cells do this (e.g. macrophages) Specific Th2 cell binds to antigen-presenting cell. Stimulates proliferation of Th2 cells by interleukins Th2 cells stimulate plasma and memory B-cells Plasma B cells produce antibodies, memory cells allow faster activation on re-exposure
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Humoral immunity - antibodies


Immunoglobulin proteins which bind specifically to an antigen

Fc region binds to host cell surface receptors (e.g. macrophages)


Neutralize and immobilize pathogens
IgG/IgM main circulating Abs IgA found on mucosal surfaces IgE allergic reactions/exoparisites Antibodies from initial infection take up to 2 weeks to peak Second infection peak faster (2 days) and levels remain higher
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Infectious disease travel


Immunity built over life-long exposure
Travel exposes individuals to unknown organisms Uncharacteristic behaviour (e.g. Hep B) Vaccination prevents against infection with serious diseases

See current UK vaccination: The Green Book


For information on travel vaccination:
http://www.nhs.uk/Conditions/Travel-immunisation/Pages/Introduction.aspx

Vaccination
Vaccines are preparations containing antigens capable of inducing a specific and active immunity in man against an infecting agent or the toxin or antigen elaborated by it British Pharmacopoeia 2010

Vaccines may consist of dead, live (attenuated) organisms or Organism-derived antigens in native or detoxified state
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Routes of administration
Oral polio vaccine mucosal immunity Inhalation mucosal immunity (Flumist)
Stronger protective response than injection (Vaccine 26:383-98)

Intramuscular interaction with lymph and circulatory systems


Subcutaneous/intradermal routes good interaction with dendritic cells
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Types of vaccine preparations


Inactivated (killed) organisms Attenuated (avirulent) live organisms Secreted products (antigens). Tetnus and diptheria Recombinant components (antigens) Components of cell walls (antigens) influenza vaccine
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Antigen production techniques


Growth
Bacteria in medium, viruses in fertilized eggs or cell culture

Inactivation
Chemical, heat treatment

Attenuation
chemical, heat treatment growth under adverse conditions or unnatural host
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Antigen preparation
Isolate toxin from growth, inactivate toxoid Traditional
Typically surface-derived polysaccharide antigens Conjugation to protein antigen

Recombinant techniques - subunit


Produce polypeptide in non-pathogenic host Unlimited supply of defined product, no viral contamination

Future techniques??
Peptide synthesis, live non-pathogenic viruses
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Vaccine presentations
Live attenuated:
Typically lyophilized for stability Reconstituted in a buffer system

Inactivated/subunit vaccines
Typically suspensions in buffer Cholera suspension mixed with effervescent granules Typically require preservative May contain residues of growth media

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The role of adjuvant


structurally heterogeneous compounds used to
evoke/increase an immune response Required for non-live vaccine systems Must be co-administered, mechanism poorly understood Stable long shelf-life Biodegradable Cheap Immunologically inert Promote immune response
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Adjuvant functions
Geographical immune reactivity Depot effect Stimulatory signals Induction of stimulatory signals

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Aluminium salts
Aluminium hydroxide/phosphate Biased to Th2 pathway May activate complement, depot effect. Increased IgE production allergenic
Emulsion Saponins

Non-ionic surfactants
Derivatives of lipopholysaccharides
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Formulation components
Preservatives
Phenol 2-Phenoxyethanol Thiomersal?

Salts
Na chloride, Na phosphate, succinate, Na borate Isotonicity, pH buffering.

Stabilizers
Sugars, amino acids, proteins Buffers, adsorption inhibition

Residues
Antibiotics, inactivating agents, cellular components
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Formulation performance
Temperature of storage 2 8 C The cold-chain difficulties Sterility and safe injection practices?

Requirement for booster doses compliance?


Poor immunological response novel systems
ISCOMS improved Th1 response Increase potency Microparticle pulsatile release e.g. PLGA Particulate may stabilize vaccine but sterile reconstitution? Particulates may promote Th1 response

Mucosal vaccination approaches?


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Some recent advances


Virus-like particles

First generation HepB (e.g. Engerix B)


Small viral envelope protein expressed in yeast form 22 nm particles.

Gardasil (human papilloma virus)


Self-assembled L1 capsid proteins Aluminium salt adjuvant - 90 % reduction in HPV infection

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ISCOMS
Immunostimulating complexes
protein antigen, cholesterol, phospholipid, Quil A (saponin adjuvant) Form cage-like nanopartilces (40 nm) that trap hydrophobic antigens in the core

ISCOMATRIX
Contains the same material (minus antigen)

Clinical experience for HPV, HIV, but concerns over toxicity of Quil A
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DNA Vaccines
DNA injected i.m. immune trigger
Broad immune response (1990s) Poor immunogenicity (e.g. HIV)

2nd generation use of plasmid vectors


(e.g. Liposomes), stimulate CD8+ cytotoxic cells PMED (Pfizer) plasmid/vector + gold nanoparticles with a high pressure delivery Antigen expressed by bodys own cells Potentially safe because no infectious agents
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Types of product

Examples of HIV are PennvaxB delivered with IL12 (molecular adjuvant) and electroporesis.
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