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TOPICADJUVANTS

PRESENTER/STUDENT:JONES OPOKU-MENSAH

SUPERVISOR/LECTURERDANIEL DODOO (PhD)

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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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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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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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What are adjuvants• Adjuvants are compounds that

enhance the specific immune response against co-inoculated antigens.

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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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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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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 affordability4 be stable with long shelf life 5 biodegradable (advax)

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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, eosinophilia, allergy, anaphylaxis, Nausea, fever, adjuvant arthritis, organ specific toxicity and immunotoxicity etc

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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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Factors affecting Adjuvant selection

1) the antigen e.g. alum not good for CTL response2) species to be vaccinated- some adjuvants may be safe in one species but not another species3) route of administration e.g. intramuscular, mucosa4) side effects- weigh the risk and benefits at that time

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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 help3) 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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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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adjuvant challenges

• Toxicity • Stability• Bioavailability• Cost• Production difficulty• Epitope modification potential during

formulation.• Pre-existing immunity to carrier protein

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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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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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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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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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MF 59a 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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Liposomessynthetic 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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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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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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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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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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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 adjuvants2) Since the invention of alum as the first adjuvant, there has been significantly raised standards by regulatory bodies

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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