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The discovery of adjuvants dates back to 1925 and 1926, when Ramon (quoted by Gupta et al., 1993) showed that the antitoxin response to tetanus and diphtheria was increased by injection of these vaccines, together with other compounds such as agar, tapi- oca, lecithin, starch oil, saponin or even breadcrumbs. The term adjuvant has been used for any material that can increase the humoral or cellular immune response to an antigen. In the conventional vaccines, adjuvants are used to elicit an early, high and long-lasting immune response. The newly developed purified subunit or synthetic vaccines using biosynthetic, recombinant and other modern technology are poor immunogens and require adjuvants to evoke the immune response. The use of adjuvants enables the use of less antigen to achieve the desired immune response, and this reduces vaccine production costs. With a few exceptions, adjuvants are foreign to the body and cause adverse reactions. Part 1 deals with the following types of adjuvants (after Gupta et al., 1993): rack to 1925 and 1926, when The mechanism of action of Freund's adjuvants is associated 3) showed that the antitoxin —_ with the following three phenomena: vas increased by injection of 1. The establishment of a portion of the antigen in a persistent ympounds such as agar, tapi- form at the injection site, enabling a gradual and continuous en breadcrumbs. release of antigen for stimulating the antibody; d for any material that can 2. The provision of a vehicle for transport of emulsified anti- une response to an antigen. gen throughout the lymphatic system to distant places, such as its are used to elicit an early, lymph nodes and spleen, where new foci of antibody formation mse. The newly developed can be established; and, cines using biosynthetic, 3. Formation and accumulation of cells of the mononuclear ology are poor immunogens series which are appropriate to the production of antibody at the mune response. local and distal sites. se of less antigen to achieve The pathologic reaction to the Freund's adjuvants starts at the s reduces vaccine production injection site with mild erythema and swelling followed by tissue ants are foreign to the body necrosis, intense inflammation and the usual progression to the formation of a granulomatous lesion. Scar and abscess formation yes of adjuvants (after Gupta may occur. The reactions observed following the administration of the complete adjuvant are generally far more extensive than with the incomplete adjuvant. The earliest cellular response is polymorphonuclear, then it changes into mononuclear and later (complete and incomplete) includes plasmocytes. The adjuvant emulsion may be widely dis- seminated in various organs, depend- ing on the route of inoculation, with the development of focal granuloma- tous lesions at distal places. Various . . gram-negative organisms may show With a few exceptions, a potentiating effect of the adjuvant, similar to that displayed by mycobac- adjuvants are foreign teria, oo to the body and cause The earliest use of oil emulsion . adjuvants was made with the adverse reactions. influenza vaccine by Friedwald (1944) and by Henle and Henle (1945). Following their promising results on animals, Salk (1951) experimented with such adjuvants on soldiers under the auspices of the US Armed Forces Epidemiological Board. He used a highly refined mineral oil, and developed a purified Arlacel A emulsifier which was free of toxic substances, such as oleic acid which had caused sterile abscesses at the injection site, and he administered the vil and water-in-vegetable-oil vaccine by intramuscular route. imentally showed special Subsequently, Miller et al. (1965) reported their failure to munity" of long duration enhance the antibody and protective response to types 3, 4 and 7 ent of Freund's adjuvants adenovirus vaccines in mineral oil adjuvant compared with aque- Several researchers noticed — ous vaccine. Unpublished studies have revealed the need for an aals to various antigens were adequate minimal amount of antigen to trigger an antibody mal of living Mycobacterium response to the emulsified preparations. fycobacterium, the reaction Salk et al. (1953) applied Freund's adjuvant to poliomyelitis ansferrable with leukocytes. vaccine, and later followed with extensive testing of killed crude il oil in causing delayed-type as well as purified polio virus vaccine in animals and humans, ‘ia. There was a remarkable where the reactions in humans were considered inconsequential. body response as well as in Grayston et al. (1964) reported highly promising results with the trachoma vaccine using an oil adjuvant. However, the tra- ater-in-oil emulsion of aque- choma vaccine lost its relevance because, as demonstrated by of low specific gravity and Dolin et al. (1997) in their 37 years of research in a sub-Saharan icel A (mannide monooleate) village, the dramatic fall in the disease occurrence was closely connected with improvements in sanitation, water supply, educa- incomplete and complete. tion and access to health care. According to Dolin et al. (1997), ynsists of water-in-oil emul- the decline in trachoma occurred without any trachoma-specific > complete Freund's adjuvant intervention. it with 5 mg of dried, heat- Allergens in Freund's adjuvant deserve special attention because butyricum added. they can be dangerous. These dangers include an overdose, i.e., Oil emulsions Freund's emulsified oil adjuvants (complete and incomplete) Arlacel A Mineral oil Emulsified peanut oil adjuvant (adjuvant 65) Mineral compounds . Bacterial products With a few Bordetella pertussis Corynebacterium granulosum- adj uvants derived P40 component ! Lipopolysaccharide to the bod Mycobacterium and its adverse components Cholera toxin Liposomes Immunostimulating complexes (ISCOMs) TT Other adjuvants Squalene With a few exceptions, adjuvants are foreign to the body and cause Oil Emulsions In the 1960s, emulsified water-in-oil and water-in-vegetable-oil adjuvant preparations used experimentally showed special promise in providing exalted "immunity" of long duration (Hilleman, 1966). The development of Freund's adjuvants emerged from studies of tuberculosis. Several researchers noticed that immunological responses in animals to various antigens were enhanced by introduction into the animal of living Mycobacterium tuberculosis. In the presence of Mycobacterium, the reaction obtained was of the delayed type, transferrable with leukocytes. Freund measured the effect of mineral oil in causing delayed-type hypersensitivity to killed mycobacteria. There was a remarkable increase in complement-fixing antibody response as well as in delayed hypersensitivity reaction. Freund's adjuvant consists of a water-in-oil emulsion of aque- ous antigen in paraffin (mineral) oil of low specific gravity and low viscosity. Drakeol 6VR and Arlacel A (mannide monooleate) are commonly used as emulsifiers. There are two Freund's adjuvants: incomplete and complete. The incomplete Freund's adjuvant consists of water-in-oil emul- sion without added mycobacteria; the complete Freund's adjuvant consists of the same components but with 5 mg of dried, heat- killed Mycobacterium tuberculosis or butyricum added. 38 = NEXUS adverse reactions. DECEMBER 2000 — JANUARY 2001