Mucosal vaccines: non toxic derivatives of LT and CT as mucosal adjuvants

Most vaccines are still delivered by injection. Mucosal vaccination would i ncrease compliance and decrease the risk of spread of infectious diseases d ue to contaminated syringes. However, most vaccines are unable to induce im mune responses when administered mucosally, and require the use of strong a djuvant on effective delivery systems. Cholera toxin (CT) and Escherichia c oli enterotoxin (LT) are powerful mucosal adjuvants when co-administered wi th soluble antigens. However, their use in humans is hampered by their extr emely high toxicity. During the past few years. site-directed mutagenesis h as permitted the generation of LT and CT mutants fully non toxic or with dr amatically reduced toxicity, which still retain their strong adjuvanticity at the mucosal level. Among these mutants. are LTK63 (serine-to-lysine subs titution at position 63 in the A subunit) and LTR72 (alanine-to-arginine su bstitution at position 72 in the A subunit). The first is fully non toxic, whereas the latter retains some residual enzymatic activity. Both of them a re extremely active as mucosal adjuvants. being able to induce very high ti ters of antibodies specific for the antigen with which they are co-administ ered. Both mutants have now been tested as mucosal adjuvants in different a nimal species using a wide variety of antigens. Interestingly, mucosal deli very (nasal or oral) of antigens together with LTK63 or LTR72 mutants also conferred protection against challenge in appropriate animal models (e.g. t etanus, Helicobacter pylori, pertussis, pneumococci, influenza. etc). In co nclusion, these LTK63 and LTR72 mutants are safe adjuvants to enhance the i mmunogenicity of vaccines at the mucosal level. and will be tested soon in humans. (C) 2001 Elsevier Science Ltd. All rights reserved.