Vaccination Student Notes

8/14/2019 Vaccination Student Notes

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Travel Medicine

Darragh MurnaneEmail:[email protected]

Vaccination strategies & formulation


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To gain an understanding ofimmunization

To gain an understanding of vaccination

strategies

To gain an understanding of vaccine

formulations

Learning Objectives


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References

Antibodies, vaccines and adjuvants (Chp. 13) inPharmaceutical 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


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Some definitions

Vaccine: an agent to promote activeimmunization 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 immunityAdaptive 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 MHC1differentiate into killer or

memory cells

Killer T-cells kill cellsexpressing antigen on

surface (apoptosis)

Memory T-cells activated6

Cell communication throughhelping molecules calledinterleukins. Using surfacereceptors to produce therequired response.


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Humoral immunityAntigens presented on

MHC2 in lymphatic system.

Only specific cells do this

(e.g. macrophages)

Specific Th2 cell binds toantigen-presenting cell.

Stimulates proliferation of

Th2 cells by interleukins

Th2 cells stimulate plasma

and memory B-cells

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Plasma B cells produce antibodies, memory cells allow faster

activation on re-exposure


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Humoral immunity - antibodies

Immunoglobulin proteins which bindspecifically to an antigen

Fc region binds to host cell surface

receptors (e.g. macrophages)Neutralize and immobilize pathogens

IgG/IgMmain circulating Abs

IgAfound on mucosal surfaces

IgEallergic reactions/exoparisites

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Antibodies from initial infection take up to 2 weeks to peak

Second infectionpeak faster (2 days) and levels remain higher


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Infectious diseasetravel

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

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Vaccination

Vaccines are preparations containing antigenscapable of inducing a specific and active

immunity in man against an infecting agent or

the toxin or antigen elaborated by it

British Pharmacopoeia 2010

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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 vaccinemucosal immunity

Inhalationmucosal immunity (Flumist)

Stronger protective response than injection

(Vaccine 26:383-98)

Intramuscularinteraction with lymph and

circulatory systems

Subcutaneous/intradermal routesgood

interaction with dendritic cells

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Types of vaccine preparations

Inactivated (killed) organisms

Attenuated (avirulent) live organisms

Secreted products (antigens). Tetnus anddiptheria

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 preparationIsolate toxin from growth, inactivatetoxoid

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 viralcontamination

Future techniques??

Peptide synthesis, live non-pathogenic viruses14


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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 toevoke/increase an immune response

Required for non-live vaccine systems

Must be co-administered, mechanism poorly

understood

Stablelong 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 productionallergenic

Emulsion

Saponins Non-ionic surfactants

Derivatives of lipopholysaccharides

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Formulation componentsPreservatives

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 dosescompliance?

Poor immunological responsenovel systems

ISCOMSimproved Th1 response

Increase potency

Microparticle pulsatile releasee.g. PLGA

Particulate may stabilize vaccine but sterile reconstitution?

Particulates may promote Th1 response

Mucosal vaccination approaches?20


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Some recent advances

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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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ISCOMSImmunostimulating 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 A22


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DNA VaccinesDNA injected i.m.immune trigger

Broad immune response (1990s)

Poor immunogenicity (e.g. HIV)

2nd

generationuse 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

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Examples of HIV are PennvaxB delivered with IL12 (molecular

adjuvant) and electroporesis.

Documents

Vaccination Student Notes