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the immediate release of more than the tolerated amount of properly emulsified vaccine in sensitive persons, or the breaking of the emulsion with the release of all or part of the full content of the allergen within a brief period of time. Long-term delayed reactions include the development of nodules, cysts or sterile abscesses requiring surgical incision. It is also likely that some allergens used, such as house dust or mould, might have acted like mycobacteria to potentiate the inflammatory response. Such reactions have been reduced with the use of properly tested and standardised reagins. One must also consider that the first application of Freund's adjuvants was made at a time when modern concepts of safety were non-existent. Indeed, mineral oil adjuvants have not been approved for human use in some countries, including the USA. should be used instead of aluminium compounds. They are used combined with glutaraldehyde-inactivated pertussis vaccine. Calcium phosphate adjuvant has been used for simultaneous vaccination with diphtheria, pertussis, tetanus, polio, BCG, yellow fever, measles and hepatitis B vaccines and with allergens (Coursaget et al., 1986). The advantage of this adjuvant has been seen to be that it is a normal constituent of the body and is better tolerated and absorbed than other adjuvants. It entraps antigens very efficiently and allows slow release of the antigen. Additionally, it elicits high amounts of IgG-type antibodies and much less of IgE-type (reaginic) antibodies. says -- were non-existent. Indeed, mineral oil adjuvants have not been Bacterial Products approved for human use in some countries, including the USA. Micro-organisms in bacterial infections and the administration of vaccines containing whole killed bacteria and some metabolic Mineral Compounds products and components of various micro-organisms have been Aluminium phosphate or aluminium hydroxide (alum) are the known to elicit antibody response and act as immunostimulants. mineral compounds most commonly used as adjuvants in human _‘ The addition of such micro-organisms and substances into vac- vaccines. Calcium phosphate is another adjuvant that is used in cines augments the immune response to other antigens in such many vaccines. Mineral salts of metals such as cerium nitrate, vaccines. zinc sulphate, colloidal iron hydroxide and calcium chloride were The most commonly used micro-organisms, whole or their observed to increase the antigenicity of the toxoids, but alum gave _ parts, are Bordetella pertussis components, Corenybacterium- the best results. derived P40 component, cholera toxin The use of alum was applied more and mycobacteria. than 70 years ago by Glenny et al. (1926), who discovered that a sus- - B. pertussis components pension of alum-precipitated diphthe- Despite these conflicting results, The killed Bordetella pertussis has ria toxoid had a much higher a strong adjuvant effect on the diph- immunogenicity than the fluid tox- aluminium compounds are theria and tetanus toxoids in the DPT oid. Even though a number of universally used as adjuvants vaccines. However, there are a num- reports stated that alum-adjuvanted ber of admitted and well-described vaccines were no better than plain for the DPT (diphtheria- reactions to it, such as convulsions, vaccines (Aprile and Wardlaw, ice A infantile spasms, epilepsy, sudden 1966), the use of alum as an adjuvant pertussis tetanus) vaccine. infant death syndrome (SIDS), Reye's is now well established. The most widely used is the antigen solution mixed with pre-formed aluminium hydroxide or aluminium phosphate syndrome, Guillain-Barre syndrome, transverse myelitis and cerebral atax- ia. Needless to say, the causal link to it is often (even though not always) under controlled conditions. Such vaccines are now called alu - | vehemently disputed and generally considered "coincidental". minium-adsorbed or aluminium-adjuvanted. However, they are Paradoxically, in one case of shaken baby syndrome in which difficult to manufacture in a physico-chemically reproducible the baby developed subdural and retinal haemorrhages from the way, which results in a batch-to-batch variation of the same vac- disease whooping cough, doctors accused the father of causing cine. Also, the degree of antigen absorption to the gels of alu- these injuries and strenuously denied that the disease pertus: minium phosphate and aluminium hydroxide varies. To minimise and does cause such haemorrhages—forgetting that th the variation and avoid the non-reproducibility, a specific prepara- very reason why pertussis vaccine was developed agains tion of aluminium hydroxide (Alhydrogel) was chosen as the stan- potentially devastating disease in the first place. Such devastating dard in 1988 (Gupta et al., 1993). effects are caused by the pertussis toxin, the causative agent of the The aluminium adjuvants allow the slow release of antigen, disease (pertussis is a toxin-mediated disease), employed as the prolonging the time for interaction between antigen and antigen- active ingredient in all pertussis vaccines whether whole-cell or presenting cells and lymphocytes. However, in some studies, the acellular (Pittman, 1984). potency of adjuvanted pertussis vaccines was more than that of Gupta et al. (1993) concluded that PT is too toxic to be admin- the plain pertussis vaccines, while in others no effect was noted. istered to humans, but chemically detoxified or genetically inacti- The serum agglutinin titres, after vaccination with adjuvanted per- vated PT may not exhibit the adjuvant effects comparable to the tussis vaccines, were higher than those of the plain vaccines, with _ native PT. no difference in regard to protection against the disease (Butler et al., 1962). Despite these conflicting results, aluminium com- - Corynebacterium-derived P40 pounds are universally used as adjuvants for the DPT (diphtheria- P40 is a particulate fraction isolated from Corynebacterium pertussis-tetanus) vaccine. Hypersensitivity reactions following granulosum, composed of the cell wall peptidoglycan associated their administration have been reported which could be attributed with a glycoprotein. In animals, it displays a number of activities to a number of factors, one of which is the production of IgE such as stimulation of the reticulo-endothelial system, enhance- along with IgG antibodies. ment of phagocytosis and activation of macrophages. It was suggested that polymerased toxoids, such as the so-called P40 abolishes drug-induced immunosuppression and increases glutaraldehyde-detoxified purified tetanus and diphtheria toxins, non-specific resistance to bacterial, viral, fungal and parasitic - Corynebacterium-derived P40 P40 is a particulate fraction isolated from Corynebacterium granulosum, composed of the cell wall peptidoglycan associated with a glycoprotein. In animals, it displays a number of activities such as stimulation of the reticulo-endothelial system, enhance- ment of phagocytosis and activation of macrophages. P40 abolishes drug-induced immunosuppression and increases non-specific resistance to bacterial, viral, fungal and parasitic NEXUS 39 DECEMBER 2000 — JANUARY 2001