VN October 2020

Vetnews | October 2020 31 In general, adjuvants augment the immune response in one of the following ways 5, 6 : 1. Regulating antigen release to prolong persistence 2. Enhanced response to antigen exposure 3. Regulation of the quality of the immune response EXAMPLESOF ADJUVANTSTHEIRMECHANISMSOF ACTION 1,4,6,7 : Aluminium salts are the first licenced adjuvants used and have a long-standing safety record. Their ease of formulation and ability to induce high antibody titres with relative long-lasting immunity, make them a popular choice of adjuvant. The enhanced immune response they elicit is thought to be as a result of a slow-release (depot) effect based on their ability to adsorb antigens to their surface. Recent evidence also suggests activation of the innate immune response as mechanism of action. Following uptake by antigen- presenting cells, the antigen is released slowly (thus prolonging exposure to the immune system) and it stimulates inflammasomes responsible for activating inflammatory responses. Aluminium hydroxide is also used for its ability to adsorb and inactivated bacterial endotoxin, but it is important to note that this ability is lost as an after effect of freezing. Emulsions are formed when two liquids are brought together that are unable to form a homogenous mixture. This allows the liquid present in lesser volume to form small droplets within the other and thismixture is then stabilisedby adding an interfacial surfactant layer. There are three emulsion adjuvants, the first being water in oil (W/O) that contains water droplets in an oil phase. Antigen is contained in these water droplets and the oil acts as a depot, slowly releasing antigen and enhances the immune response by decreasing clearance time and prolonging antigen exposure. Another very popular adjuvant for animal vaccines are oil in water (O/W) formulations. In contrast with W/O formulations, they do not increase the immune response by creating a slow-release depot, but rather by increasing inflammatory reaction and stimulating overall immune response. These formulations are believed to bemore potent adjuvants for viral vaccines than aluminium salts. Lastly the most advanced emulsion adjuvants are water inoil inwater (W/O/W) formulations. They contain the benefits of both the aforementioned emulsion adjuvants and have a slow release as well as an immediate stimulatory effect, thus creating a prime-boost effect with a single injection. Saponins are naturally occurring amphipathic compounds with many pharmaceutical uses, one of which is its use as an adjuvant. Their structure and size promote antigen phagocytosis by antigen- presenting cells and the sugar group in saponins bind to lectins on the antigen-presenting cells that consequently stimulate them to secrete cytokines that promote activation of cell-mediated and humoral immune pathways. Toll-like receptor (TLR) agonists are transmembrane receptors (expressed inmacrophages anddendritic cells) that recognise certain patterns of fungal-, bacterial- and viral pathogenic components, as well as by-products of cell and tissue destruction. When these receptors are activated, they stimulate cellular activation, phagocytic activation and induction of cytokines that are involved in the development of antigen specific immunity. For example, when TLR4 is stimulated by its natural ligand (or adjuvant agonist) it stimulates antigen presenting cells to secrete various interleukins. Some of these cytokines are responsible for the activation of Th1 cells that assist in the development of cell-mediated-, as well as humoral immunity against intracellular pathogens such as viruses. Examples of TLR agonists from bacterial origin, is lipopolysaccharide (LPS) from gram negative cell membranes, and the protein flagellin. These agents have not been included in commercial adjuvants to date but are garnering attention from the scientific research community due to their promising potential as adjuvants. Cytokines are signalling molecules secreted by specific cells of the immune system. They are key components of the immune response stimulated byTLR agonists and the direct addition of thesemolecules as adjuvants is currently being investigated. Various cytokines could stimulate immunity against either intracellular or extracellular pathogens, depending on their physiological function. Polymers are (natural or synthetic) compounds of relatively high molecular weight, consisting of large numbers of repeated linked units. Chitosan is an example of a natural polymer utilised in vaccine technology, as well as other pharmaceutical applications. The exact mechanism of action by which polymers act as adjuvants is not yet determined, but one theory suggest that they create a slow-release depot by entrapping antigens in their large cross-linked structure. Adjuvantation provides many opportunities for future research and developmentsuchasinclusionofnovelantigensandthecombination of adjuvants to stimulate immunity via various pathways. In the years to come, it would be prudent to focus on the development of adjuvants that support single dose vaccination strategies with extended durations of immunity, as well as vaccines that are able to produce immunity in the presence of maternal antibodies. 6 It is evident that adjuvants will play an increasingly important role as we strive to overcome existing immunologic barriers and find solutions to improve the efficacy, safety and convenience of vaccine technology. v REFERENCES 1. Apostólico JD, Lunardelli VA, Coirada FC, Boscardin SB, Rosa DS. 2016. Adjuvants: classification, modus operandi, and licensing. Journal of immunology research . . 2. World Health Organization. 2017. The power of vaccines: still not fully utilized. Available on: https://www.who.int/publications/10 - year-review/vaccines/en/ [Last accessed: 2019, Apr 23] 3. Pasquale AD, Preiss S, Silva FT, Garçon N. 2015. Vaccine adjuvants: from 1920 to 2015 and beyond. Vaccines 3(2):320-43. 4. Burakova Y, Madera R, McVey S, Schlup JR, Shi J. 2018. Adjuvants for animal vaccines. Viral immunology 31(1):11-22. 5. Kindt TJ, Goldsby RA, Osborne BA. Kuby. 2007. Immunology Sixth Edition. WH Freeman and Company: 41 Madison Avenue, New York, NY 10010. p 63-65, 85. 6. Young AJ. 2019. Adjuvants: What a Difference 15 Years Makes. Veterinary Clinics: Food Animal Practice ;35(3):391-403. 7. McKee AS, Marrack P. 2017. Old and new adjuvants. Current opinion in immunology . 47:44-51. Regulars I Zoetis pages