on vacine adjuvant and immunology

1. TOPIC
ADJUVANTS
PRESENTER/STUDENT:
JONES OPOKU-MENSAH
SUPERVISOR/LECTURER
DANIEL DODOO (PhD)
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2. Current state and future trends
• the state of the adjuvant field and The future
directions to adjuvant development.
• Impediments and barriers to development
and registration of new human adjuvants
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3. NEW GENERATION VACCINE ADJUVANTS
• INTRO
• Vaccines are considered to be the most safe and
effective medical intervention available
• Vaccines have contributed to the steady decline in
mortality and morbidity caused by infectious disease.
• The currently available vaccines prevent up to 3
million deaths and 750 000 children are protected
from serious disabilities every year.
• Vaccine improvement include the addition of new
adjuvants which are able to induce a higher immune
response that covers a broad antigenic diversity
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4. THE NEED FOR NEW AND IMPROVED
VACCINES
• Despite the success of current vaccines, there is
the clear need for the development of vaccines
against a number of infectious disease for which
vaccines are not yet available, or inadequate. Eg
HIV, HEP C, TB, Malaria, Neisseria meningitides
etc
• There is also the need for vaccines against
emerging and re-emerging infectious disease like
SARS, Hanta, Ebola etc
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5. What are adjuvants
• Adjuvants are compounds that
enhance the specific immune
response against co-inoculated
antigens.
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6. The role of Adjuvant
improve the immunogenicity of antigens/vaccines. Esp
recombinant Proteins/peptides which lack most of the
features of the original pathogen and often weak
immunogens.
Reduce the dose of antigen or the number of immunizations
needed for protective immunity.
Improve the efficacy of vaccines in newborns, the elderly or
immuno-compromised persons.
As Antigen delivery systems for the uptake of antigens by the
mucosa.
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7. The challenge of adjuvants
• Adjuvant industry= To improve the safety and
less reactogenic subunit vaccine.
• Lower reactogenicity adjuvants came with
reduced vaccine efficacy.
• Safety and tolerability are critical regulatory
issues facing the adjuvants.
• In most cases increased adjuvant potency is
associated with increased reactogenicity and
toxicity. Eg CFA
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8. Non-adverse reactions Factors
1 should be cheap to produce
2 not induce immune responses against themselves
But promote an appropriate immune response i.e.
cellular or antibody immunity depending on
requirements for protection.
3 Adjuvants affordability
4 be stable with long shelf life
5 biodegradable (advax)
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9. Adjuvant-caused adverse effects
• classified into 1) local and 2)systemic.
1) Local Reactions:
local injection site Pain, inflammation, swelling, and
necrosis, lymphadenopathy, granulomas, Ulcers
and the generation of sterile abscesses etc
2) Systemic reactions:
• induction of Acquired
immunodeficiency, immunosuppression, eosinop
hilia, allergy, anaphylaxis, Nausea, fever, adjuvant
arthritis, organ specific toxicity and
immunotoxicity etc
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10. The main problem with adjuvant
production
• Unsolved problem is how to achieve potency
whiles avoiding reactogenicity or toxicity
• This make their acceptance into community
prophylactic vaccination particularly in
paedics difficult.
• Even alum which is FDA-approve still has
significant adverse effect like local injection
site Pain, inflammation, lymphadenopathy
• Alum limitation: inability to induce CTL (CMI)
response hence ineffective for some Ags.
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11. Factors affecting Adjuvant selection
1) the antigen e.g. alum not good for CTL
response
2) species to be vaccinated- some adjuvants may
be safe in one species but not another species
3) route of administration e.g.
intramuscular, mucosa
4) side effects- weigh the risk and benefits at
that time
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12. Classification of Adjuvant
classified according to their source, mechanism of
action or physicochemical properties and
administration route, namely mucosal or parenteral.
a) three groups:
1) active immunostimulants, being substances that
increase the immune response to the antigen;
2) carriers, being immunogenic proteins that provide
T-cell help
3) vehicle adjuvants; being oil emulsions or
liposomes that serve as a matrix for antigens as well
as stimulating the immune response.
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13. Classification of Adjuvant 2
• Classified based on route of administration-
mucosal or parenteral
• Classified based physicochemical properties
Groups of gel- based, tensoactive agents, oil
emulsions, particulate, fusion protein, Alum
salts and other mineral adjuvants
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14. adjuvant challenges
• Toxicity
• Stability
• Bioavailability
• Cost
• Production difficulty
• Epitope modification potential during
formulation.
• Pre-existing immunity to carrier protein
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15. Adjuvant regulatory reguirement
• Need for pre-clinical studies (toxicology) prior
to phase 1 trail
• Dose and frequency of adjuvants to be
increased during pre-clinical studies to identify
any potentials safety problens
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16. Few adjuvants types
• Oil-in-Water emulsion- eg montanide, adjuvant
65, lipovant etc. they are irritants, local inlfammation
common, induces chemotactic signal => macropahge
invasion=> rapid ingestion. Used in cancer and HIV
• formation of a depot at the injection site,
• enabling the slow release of antigen
• stimulation of antibody producing plasma cells.
• Limitations: Excessive reactogenicity, Frequent side-
effects of emulsions include inflammatory
reactions, granulomas and ulcers at the injection site.
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17. Saponins are tensoactive glycosides. Eg Bark of tree,
QS21(Saponin)
they integrate into cell through interaction with
cholesterol/ membrane of macrophages, resulting in
pores through which antigens enter macrophages.
Subsequently, peptides from these antigens may be
processed and presented via MHC class I, stimulating a
CD8 CTL response.
Limitations: Severe injection site pain is a major limiting
factor in QS21 use.
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18. Bacteria-derived adjuvants
Eg LPS and TDM(trehalose dimycolate).
MPL is a chemically detoxified derivative of native Lipid A
from Salmonella minnesota R595, which is used in
complex adjuvant formulations with
alum, QS21, liposomes, and emulsions.
Mechanism: interacts with TLR4 on
macrophages, resulting in the release of proinflammatory
cytokines including TNF, IL-2 and IFN-gamma, which
promote the generation of Th1 responses.
Limitations: consistency of preparation, formulation, and
cost.
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19. MF 59
a replacement for CFA. Too toxic for human.
Current version now used in inflenza. Superior
to alum in inducing Ab response to hep B in
humans and baboons.
ISCOMs
immunostimulating complexes containing
saponin, a sterol and opatioally a phospholipid.
Generate CTL response to Ags like HIV
enveloped in GP. == cost, manufacturing
difficulty, malaise, reactogenic and safety issues
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20. Liposomes
synthetic phospholid spheres encapsulating Ag.
Act as Ag delivery vehicle and adjuvant.
Mech= fuses with macrophage and delivers Ag
to the cytoplasm.
Limit= cost, manufacturing difficulty, stability.
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21. carbohydrate adjuvant - Advax
• Nanocrystal of inulin (plant derived
polysac, linear chain of fructose capped with
glucose)
• Enhances both CMI and HI responses without
reactogenic effects. Long shelf life, no safety
issues, not metabolized in man but secreted
unchanged in urine as fructose and small qntt
os glucose.
•
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22. Aluminium Salts (Alum)
inorganic salt that binds to proteins and causes
them to precipitate. The trapping of soluble antigen
in the alum gel may also increase the duration of
antigen interaction with the immune system.
Alum is the only adjuvant approved for use in
humans. induce antibody (th2) response cellular
(th1) response
LIMITATIONS: potential to cause severe local and
systemic side-effects including sterile
abscesses, eosinophilia and myofascitis.
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23. Polymeric microspherical adjuvants
• These are compactible and biodegradable
microspheres of lipids able to incorporate
different Ags.
• Controlles time of Ag release.
• Cytokines adjuvants
• IFN-y enhances CMI through a variety of
mechanism
• Others are GM-CSF
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24. Adjuvant formulations
• New adjuvant formulations have resulted from
the mixture of different adjuvants in the same
formulation.
• As a general rule, two or more adjuvants with
different mechanisms of action are combined to
enhance the potency and type of the immune
response to the vaccine antigen.
 For example, alum salts can be formulated in
combination with other adjuvants such as Lipid A
to increase immunogenicity.
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25. Conclusions
• There are major barriers rather than scientific
knowledge about adjuvants standing in the
way of new adjuvants availability
1) Unacceptable side-effects and toxicity
preclude the use of many candidate adjuvants
2) Since the invention of alum as the first
adjuvant, there has been significantly raised
standards by regulatory bodies
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26. Conclusions 2
3) Some adjuvants have not been approved as a
result of their conjunction with a vaccine. It is
possible that good adjuvants have failed due to
the vaccine adjuvant combinations. So they are
rejected whiles the fault may be from the
vaccine not the adjuvant. Thus throwing out the
baby with the bath water .
4) Funding/cost of development
Etc etc etc
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