Vaccine adjuvants

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a seminar onVaccine adjuvants: Current state and future trends : 

a seminar onVaccine adjuvants: Current state and future trends M. ALAGUSUNDARAM DEPT. OF PHARMACEUTICS ANNAMACHARYA COLLEGE OF PHARMACY, RAJAMPET, ANDHRA PRADESH

CONTENTS : 

CONTENTS ADJUVANT ORGIN DEFINITION ADJUVANT ROLES ADJUVANT PROPERTIES ADJUVANT SELECTION ADVERSE REACTIONS CLASSIFICATION FORMULATION MAJOR ADJUVANT TYPES REFERENCES CONCLUSION

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ADJUVANT ORIGIN IN 1920s injection of diptheria toxoid in horses In 1926,alum was demonstrated with diptheria toxoid In 1936,FREUND complete adjuvant was developed Later FREUND incomplete adjuvant was discovered Several hundred synthetic and natural adjuvants have been identified

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DEFINITION Adjuvants are compounds that enhance the specific immune response against coinoculated antigens. Adjuvant comes from the Latin word adjuvare, which means to help or to enhance.It was coined by RAMON.

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Adjuvant Roles Enhance the immunogenicity of highly purified or recombinant antigens. Reduce the amount 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.

ADJUVANTS=INNATE IMMUNITY ACTIVATING SUBSTANCES : 

ADJUVANTS=INNATE IMMUNITY ACTIVATING SUBSTANCES ADJUVANTS VACCINE ADAPTIVE IMMUNITY SYSTEM (T cell,B cell,Ab) INNATE IMMUNE SYSTEM (ANTIGEN PRESENTING CELL) (DENDRITIC CELL)

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Adjuvant properties Ideally, adjuvants should be stable with long shelf life biodegradable cheap to produce not induce immune responses against themselves promote an appropriate immune response i.e. cellular or antibody immunity depending on requirements for protection.

Adjuvant selection Features involved in adjuvant selection are: the antigen species to be vaccinated route of administration side effects : 

Adjuvant selection Features involved in adjuvant selection are: the antigen species to be vaccinated route of administration side effects

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Adjuvant adverse reactions Adjuvant incorporation into any vaccine formulation have to be balanced with the risk of adverse reactions. Adverse reactions to adjuvants can be classified as local or systemic. One of the major challenges in adjuvant research is to gain potency while minimizing toxicity.

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Adjuvant classification Adjuvants can be classified according to their source, mechanism of action or physicochemical properties and administration route, namely mucosal or parenteral. Edelman classified adjuvants into three groups: active immunostimulants, being substances that increase the immune response to the antigen; carriers, being immunogenic proteins that provide T-cell help; 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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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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ADJUVANT TYPES ALUMINIUM SALTS TENSOACTIVE ADJUVANTS ADJUVANT EMULSIONS BACTERIA DERIVED ADJUVANTS LIPOSOME ADJUVANTS CARBOHYDRATE ADJUVANTS

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Aluminium Salts (Alum) Mechanism of action: Alum is an 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. LIMITATIONS: In addition, alum has the potential to cause severe local and systemic side-effects including sterile abscesses, eosinophilia and myofascitis. antigen ALUM INDUCE ANTIBODY (Th2) RESPONSE CELLULAR (Th1) RESPONSE

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Tensoactive adjuvants Saponins are tensoactive glycosides. Example: Mechanism of action: Saponins integrate into cell through interaction with cholesterol, resulting in pores through which antigens enter. 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. Quillija saponaria Bark of tree QS21(Saponin)

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Adjuvant emulsions This class includes oil in water or water in oil emulsions. Examples: FIA, Montanide, Adjuvant 65, and Lipovant. Mechanism of action: formation of a depot at the injection site, enabling the slow release of antigen stimulation of antibody producing plasma cells. Limitations: Frequent side-effects of emulsions include inflammatory reactions, granulomas and ulcers at the injection site.

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Bacteria-derived adjuvants Examples: MDP, LPS, TDM, MPL. 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 of action: MPL 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, cost.

TLR4 on macrophages releasing proinflammatory cytokines : 

TLR4 on macrophages releasing proinflammatory cytokines

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Liposome adjuvants Liposomes are synthetic spheres consisting of lipid layers that can encapsulate antigens and act as both a vaccine delivery vehicle and adjuvant. Mechanism of action: Liposomes fuse with the cell membranes of macrophages, enabling delivery of proteins into the cytoplasm where they can enter the MHC class I pathway and activate CD8 CTLs. Limitations: Liposomes use is limited due to manufacturing difficulties, stability, high cost.

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Carbohydrate adjuvants Several complex carbohydrates of natural origin stimulate cells from the immune and reticulo-endothelial system. Mechanism of action: Gamma inulin is effective at boosting cellular immune responses without the toxicity exhibited by other adjuvants such as FCA. Polysaccharide-based adjuvant candidate, Advax, that enhances immunogenicity without reactogenicity, suggesting that potent and well-tolerated vaccines for both adult and pediatric use. Limitations: Polysaccharides based adjuvants are metabolisable into simple sugars like fructose and glucose.

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Conclusion The limited immunogenicity of new and novel vaccine antigens has increased the importance of adjuvant research in vaccine development. Adjuvants will be needed to enhance and extend immune responses while reducing the amount of antigen necessary in each dose. Unlikely, all the adjuvants have got limitations due to their toxicity and side-effects. Some of the adjuvants like Advax and Liposomes has lack of reactogenicity and produce sufficient immunogenicity.

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Hence there is a need for development of safe and non-toxic adjuvants, particularly for adjuvants capable of strongly boosting cellular immune responses which are not associated with undue toxicity. Given the increasing importance of adjuvants to modern vaccines, national and international funding agencies urgently need to institute policies to address this imbalance and provide major new support for adjuvant basic science and clinical development.

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References Bomford R. Will adjuvants be needed for vaccines of the future. In: Brown F, Haaheim LR, (eds). Modulation of the Immune Response to Vaccine Antigens. Dev. Biol. Stand, Vol. 92. Basel: Karger 1998; p. 13–8. Vogel FR. Adjuvants in Perspective. In: Brown F, Haaheim LR (eds). Modulation of the Immune Response to Vaccine Antigens. Dev. Biol. Stand, Vol. 92. Basel: Karger 1998; p. 241–8. Ramon G. Sur l’augmentation anormale de l’antitoxine chez les chevaux producteurs de serum antidiphterique. Bull. Soc. Centr. Med. Vet 1925; 101: 227–34. Ramon G. Procedes pour accroïtre la production des antitoxins. Ann. Inst. Pasteur 1926; 40: 1–10. Glenny AT, Pope CG, Waddington H, Wallace V. The antigenic value of toxoid precipitated by potassium-alum. J. Path. Bacteriol. 1926; 29: 38–45. Vogel FR, Powell MF. A summary compendium of vaccine adjuvants and excipients. In: Powell MF, Newman MJ (eds). Vaccine Design: the Subunit and Adjuvant Approach. New York: Plenum Publishing Corp, 1995; p. 234–50. Freund J, Casals J, Hosmer EP. Sensitization and antibody formation after injection of tubercle bacili and parafin oil. Proc. Soc. Exp. Biol. Medical 1937; 37: 509–13.

Thank you : 

Thank you