Download VACCINE DELIVERY SYSTEMS - Lectures For UG-5

Course Contents
•An introduction to Vaccinology
•Vaccine history and types
•Epidemiologic basis of Vaccinology
•Role of combination vs. single vaccines
•The immune responses to the pathogen & vaccine
development
•Immunology of Vaccines
•Antigen and Vaccine Delivery Strategies
•Determinants of Vaccine Availability
•Vaccine development strategies: New approaches
•Live versus attenuated vaccines
•Role of multinational companies in vaccines production
•DNA as vaccine
•Peptide & Subunits vaccine
•Adjuvants in vaccines
•Population Genetic analysis: immunity
to vaccine
•Recombinant vaccine
•Animal models of vaccine testing
•Vaccine Delivery Systems
•Practical issues in relation to trials
•Ethical issues related to clinical
evaluation of vaccines
•Vaccine safety
•Review of vaccines in current use
•Vaccine-economics
•Future of Vaccines/Vaccination
Course Contents
PART 1 : INTRODUCTION
•
Definition
•
History
•
Types
•
Combination vs single vaccine
Part 2: Principles of Vaccine Design
Immunologic Memory: T and B Cells memory
• Antigen Processing and Presentation by MHC Class I, II, and Nonclassical
Molecules
• Understanding the Mucosal Immune System for Better Mucosal Vaccine Design
Part 3: ANIMAL MODELS FOR VACCNE TESTING
• Utility of Mouse Models in Vaccine Design and Development,
• Utility of Nonhuman Primate Models for Vaccines,
Part 4: Delivery Systems
•Transcutaneous Immunization via Vaccine Patch Delivery System
•Needle-free Jet Injection for Vaccine Administration
•Oral Vaccines: An Old Need and Some New Possibilities
Adjuvants:
Part 6: Regulatory Considerations
•Regulatory Issues
•Role of international companies
•Vaccine economics
PART 7: Population genetics and vaccines
• Ethical issues
• Vaccine safety
Part 5: Evaluating Vaccine Efficacy
• Trials in human and practical issues
VACCINE DELIVERY SYSTEMS
VACCINE DELIVERY SYSTEMS
1. VIRAL VECTORS BASED
2. NON VIRAL
VACCINE DELIVERY SYSTEMS
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MUCOSAL DELIVERY OF VACCINES
LIPOSOMAL DELIVERY SYSTEMS
VIROSOMES DELIVERY SYSTEMS
POLIMERIC NANOPARTICLE DELIVERY SYSTEMS
DENDRIMER-BASED DELIVERY SYSTEMS
NEEDLE-FREE DELIVERY
EDIBLE VACCINES
DNA VACCINES:
Nanopatch
A stamp-size patch similar to an adhesive bandage contains about
20,000 microscopic projections per square inch.
When worn on the skin, it will deliver vaccine directly to the skin,
which has a higher concentration of immune cells than the
muscle tissue does, which is one of the tissues where injections
commonly deliver vaccines.
1. Dermal administration by nanopatches thus increases the
effectiveness of vaccination,
2. requiring less vaccine than injection.
LIPOSOMAL DELIVERY SYSTEMS
• Liposomes and their derivatives “lipoplexes” (liposome/DNA
complexes) are hollow spherical constructs of phospholipid
bilayers capable of entrapping hydrophilic moieties in the
aqueous compartment and hydrophobic moieties in the lipid
bilayers with cholesterol imparting rigidity to the bilayer.
•Viruses, proteins, glycoproteins, nucleic acids, carbohydrates, and
lipids can be entrapped and targeted at cellular and subcellular
level for evoking immune responses
•Diphtheria liposomal vaccine shows good immunogenicity and
tolerance in humans
VIROSOMES DELIVERY SYSTEMS
Virosomes represent vesicular systems into which
antigens can be loaded into virosomes or adsorbed onto
the virosomal surface through hydrophobic interactions
VIROSOMES DELIVERY SYSTEMS
• Virosomes are small spherical
unilamellar lipid membranes
of nucleocapsid including
vesicles (150 nm) embedded
with viral membrane proteins
such as hemagglutin and
neuraminidase of influenza
virus but devoid the genetic
material of the source virus.
• Once they have delivered the
antigens, the virosomes are
completely degraded within
the cells
DENDRIMER-BASED DELIVERYSYSTEMS
•Dendrimers are branched, synthetic polymers with layered
Architectures. to bind the DNA and get it into the cell.
DENDRIMER-BASED DELIVERYSYSTEMS
•Dendrimers, available under the trademark name of “Starburst”
serve as nonviral gene transfer agents, enhancing the
transfection of DNA by endocytosis and, ultimately, into the cell
nucleus.
•A novel approach for the treatment of renal cell carcinomas uses
a chimeric molecule comprising a granulocyte macrophage colony
stimulating factor (GM-CSF) attached to a G250 kidney cancer
specific antigen which is transfected in to the cancerous cell by the
use of dendrimer
POLIMERIC NANOPARTICLE DELIVERY
SYSTEMS
Polymeric nanoparticles
because of their size are
preferentially taken up by
the mucosa associated
lymphoid tissue. They are
extensively reviewed for
nasal and oral delivery of
vaccines
EDIBLE VACCINES
CONCLUSION
• Vaccine drug delivery systems are gaining
popularity these days due to the benefits they
offer.
• As they avoid the need to administer booster
doses and provide a long term therapy in
small dose.
• Needle free technologies, Edible vaccines on
the other hand open an attractive avenue for
the oral delivery of vaccines.
VECTORS IN VACCINE DELIVERY
• To transfer the desired
gene into a target cell,
a carrier is required.
Such vehicles of gene
delivery are known
as vectors.
• 2 main classes
– Viral vectors
– Non viral vectors
Cancer Vaccines
CD4 T Cell
Activated
Dendritic
Cell
TCR
Class II MHC
Cytokines = HELP
TCR
Tumor Antigen
Class I MHC
CD8 T Cell
Activated CD8 T Cells Traffic to
Tumor and Lysis Cells
Burch et al, 2000; Small et al 2000; Fong et al, 1997.
Viral Vaccines – Same Idea: But Starting At A Different Step
Co-Stimulatory
Molecules
PSA
ProstVac VF
LFA-3 ICAM-1 B7-1
Target Antigen
Vaccinia Virus
Fowlpox Virus
Plasmid DNA
Packaging Cell Line
rV-PSA-TRICOM
rF-PSA-TRICOM
PSA= prostate-specific antigen.
Madan et al, 2009; Sonpavde et al, 2011; Drake, 2010.
Vaccine
ProstVac VF
CD4 T Cell
TCR
Class II MHC
TCR
Class I MHC
Epithelial Cells
CD8 T Cell
ACTIVATED
CD8 T Cell
Madan et al, 2009; Sonpavde et al, 2011.
1. he
antigen prostatic
acid
phosphatase (PAP),
which is present in
95% of prostate
cancer cells, and
2. an immune
signaling
factor granulocytemacrophage
colony stimulating
factor (GM-CSF)
that helps the
APCs to mature.
The only cell-based therapy currently approved for the treatment of prostate
cancer.
APPLICATIONS
Basic research
Gene therapy
vaccines
MOST COMMON VIRAL VECTORS
Retroviruses
can create double-stranded DNA copies of their RNA genomes. Can
integrate into genome. HIV, MuLV, Rous sarcoma virus
Adenoviruses
dsDNA viruses that cause respiratory, intestinal, and eye infections
in humans. Virus for common cold
Adeno-associated viruses
ssDNA viruses that can insert their genetic material
at a specific site on chromosome 19
Herpes simplex viruses
dsDNA viruses that infect a neurons. Cold sores virus
ADENOVIRUSES
As opposed to Lentiviruses, adenoviral DNA does not integrate into the
genome and is not replicated during cell division.
with adenoviruses, which cause respiratory, gastrointestinal and eye infections,
they trigger a rapid immune response with potentially dangerous
consequences. To overcome this problem scientists are currently
investigating adenovirusesto which humans do not have immunity.
1. their basic biology has been studied extensively
2.
the viral genome can accommodate large heterologous transgene
insertions,
3. they readily infect quiescent and dividing cells,
4.
they can be amplified to high titers and
5.
they have previously been shown to be relatively safe for use in
humans.
ADENO-ASSOCIATED VIRUSES
AAV is not currently known to cause disease and consequently the virus
causes a very mild immune response. AAV can infect both dividing and
non-dividing cells and may incorporate its genome into that of the host
cell. These features make AAV a very attractive candidate for creating viral
vectors for gene therapy
HERPEX SIMPLEX VIRUS VECTOR
VIRAL VECTORS
1) RETROVIRUS VECTOR SYSTEM
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The recombinant retroviruses have the ability to
integrate into the host genome in a stable fashion.
•
Can carry a DNA of
size – less than 3.4kb
•
Target cell - dividing
Retroviruses
 number of FDA-approved clinical trials such as the SCID-X1 trial.
 either be replication-competent or replication-defective..
involves the requirement for cells to be actively dividing for transduction.
cells such as neurons are very resistant to infection and transduction by
retroviruses.
There is concern that insertional mutagenesis due to integration into the
host genome might lead to cancer or leukemia
Retro virus
A PRACTICAL EXAMPLE OF RETROVIRAL VECTOR
LNGFR
AG
GP2-293
VIRAL VECTOR xlox(NGFR)TERT
GP2xTERT11 PRODUCER CELL
LINE
Staining with anti-NGFR ab beads
N
ENVELOPE CONSTRUCT
PACKAGED TERT
RECOMBINANT VECTOR
S
PRIMARY T CELLS