Adjuvants vaccines with substances other

Vaccines adjuvanted with substances other than oil 10.4.1 Alum... 

Although there are a number of advantages associated with the use of subunit vaccines (e.g., highly purified peptides, proteins or DNA) as vaccines (e.g., specificity), one feature they all have in common is that they are generally poorly immunogenic. The more traditional vaccines contain many other components, some of which elicit additional T-cell assistance or function as adjuvants. An adjuvant is a substance that acts as an immunostimulator, one example being the bacterial DNA in a whole cell vaccine. The overall result is a more robust immune response than that provided by the antigen alone. 

Independent use patents offer the weakest patent protection. They almost invite others to seek possibilities to circumvent them and they do not cover the products that result from the invented new use. Wherever the necessary requirements are fulfilled, product patents should be applied for. In the first example given above, it seems hardly justified to construct product claims for (all) products made by the modified fermentation process. The excipient with adjuvant effects could probably be patented as a product patent, claiming "vaccines containing substance X as a novel adjuvant" with the non-obvious advantage of a better tolerability or efficacy over existing adjuvants. As for the third example, any advantageous characteristic of the resulting product may be used to justify a product patent. 

Adjuvants are substances which can modify the immune response of an antigen (139,140). With better understanding of the functions of different arms of the immune system, it is possible to explore the effects of an adjuvant, such that the protective efficacy of a vaccine can be improved. At present, aluminum salt is the only adjuvant approved for use in human vaccines. New adjuvants such as QS-21, 3D-MPL, MF-59, and other liposome preparations are being evaluated. Several of these adjuvants have been in clinical trial, but none have been approved for human use. IL-12 has been proposed as an adjuvant which can specifically promote T-helper 1 ceU response, and can be a very promising adjuvant for future vaccine development. 

Very often, vaccines are formulated with certain substances to enhance the immune response. These substances are called adjuvants (from the Latin adju-vare, which means to help ). The most common adjuvants for human use are aluminum hydroxide, aluminum phosphate, and calcium phosphate. Other adjuvants being used include bacteria and cholesterol. Mineral oil emulsions are normally the adjuvants used in animal studies. The adjuvant known as Freund s complete adjuvant consists of killed tubercle bacilli in water-inmineral oil emulsion, and Freund s incomplete adjuvant is a water-in-oil emulsion. Both these adjuvants are effective in stimulating an immune response, but they cause unacceptable side effects in humans (see Table 4.2). 

Vaccine excipients (adjuvants and other substances used in the formulation) are treated in the same way as chemical substances. If new substances are introduced, a full safety assessment is required. It may be necessary to assess their toxic potential separately from the vaccine, since the vaccine formulation may interfere with a proper testing. In addition the normal pharmacological and safety tests for vaccines must be performed with the final, formulated product. 

Based on the promising data obtained using cationic peptides as adjuvant in the sense of antigen delivery systems in the context of vaccines, the question arose as to whether these systems could also be used in combination with other adjuvants. As in earlier experiments cationic peptides were used to transport DNA molecules into cells, it was clear that poly-L-arginine should be tested in combination with oli-godeoxynucleotides containing CpG-motifs (CpG-ODN), which were described to be immunostimulatory substances on their own, and to analyze the immunostimulatory effect of the combined adjuvants. 

Other factors that affect the acceptability of vaccines for clinical use can be ascribed to the chemical nature of the surfactant used in water-in-oil emulsion. Frequently W/O emulsions have proved to be unsatisfactory clinically due to local abscess at the site of injection. It has been suggested that this can be due to the oleic acid which occurs in some batches of Arlacel used as an emulsifer [205]. Hydrolysis of Arlacel A has been shown to occur in vaccine preparations with the liberation of free oleic acid [209]. Asherson and Allwood [205] have considered the various possible modes of action of adjuvant substances. These include delaying absorption of the antigen, causing aggregation of the various cell types involved in the immune responses, an action on membranes, leading to the release of chemotactic factors. One can deduce that surfactant adjuvants may participate in some of these effects but little direct evidence has been adduced. 

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