Recent Advances in Vaccine Adjuvants for Systemic and Mucosal Administration

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Abstract
Although vaccines produced by recombinant DNA technology are safer than traditional vaccines, which are based on attenuated or inactivated bacteria or viruses, they are often poorly immunogenic. Therefore, adjuvants are often required to enhance the immunogenicity of these vaccines. A number of adjuvants which are particulates of defined dimensions (< 5 μm) have been shown to be effective in enhancing the immunogenicity of weak antigens in animal models. Two novel adjuvants which possess significant potential for the development of new vaccines include an oil-in-water microemulsion (MF59) and polymeric microparticles. MF59 has been shown to be a potent and safe adjuvant in human subjects with several vaccines (for example HSV-2, HIV-1 and influenza virus). An MF59 adjuvanted influenza has been recommended for approval in Italy. Microparticles prepared from the biodegradable polymers the poly(lactide-co-glycolides) (PLG) are currently undergoing extensive pre-clinical evaluation as vaccine adjuvants. Because of their controlled release characteristics, microparticles also possess considerable potential for the development of single dose vaccines. The development of single dose vaccines would offer significant advantages and would improve vaccination uptake rates in at risk populations, particularly in the developing world. In addition to systemic administration, microparticles have also also been shown to enhance the immunogenicity of vaccines when administered by mucosal routes. Therefore microparticles may allow the development of novel vaccines which can be administered by non-parenteral routes. Mucosal administration of vaccines would significantly improve patient compliance by allowing immunization to be achieved without the use of needles. An alternative approach to the development of mucosally administered vaccines involves the production of genetically detoxified toxins. Heat labile enterotoxin (LT) from Escherichia coli and cholera toxin from Vibrio cholerae are two closely related bacterially produced toxins, which are the most potent adjuvants available. However, these molecules are too toxic to be used in the development of human vaccines. Nevertheless, these toxins have been modified by site-directed mutagenesis to produce molecules which are adjuvant active, but non-toxic. The most advanced of these molecules (LTK63), which has a single amino acid substitution in the enzymatically active subunit of LT, is active as an adjuvant, but non-toxic in pre-clinical models. The approach of genetically detoxifying bacterial toxins to produce novel adjuvants offers significant potential for the future development of mucosally administered vaccines.