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Vaccines for the 21st Century: A Tool for Decisionmaking
Delivery of vaccines by intranasal immunization has shown that this is a very effective route for the induction of respiratory and parenteral immune responses. However, few recombinant, avirulent viruses and no bacteria are available to take advantage of this novel mode of immunization. One major exception is the adenovirus vectors, which have generated interest not only as a means for mucosal immunization but also as potential vectors to transfer the corrective CFTR gene for the treatment of cystic fibrosis. The major advantages of adenovirus are its cloning efficiency and its ability to accommodate large foreign DNA sequences. In this regard, most adenovirus-based vectors have been derived from group C adenoviruses, and the first generation of adenovirus vectors were made replication-defective by deletion of the viral one region (Yang et al., 1994). This region encodes the immediate-early gene products and is required for the initiation of viral replication. Although adenovirus vectors were rendered replication defective, a number of studies have shown that these vectors can induce unwanted inflammatory responses (Yang et al., 1994). Second-generation vaccines with additional deletions should obviate some side effects. It should be noted that an adenovirus vaccine has been given by the oral route to military recruits and has been successful. The next challenge will be to use the attenuated adenoviruses as vectors for effective intranasal immunization.
Recent studies have shown the feasibility of using recombinant plants for the generation of vaccines. Initial work with the tobacco plant showed that foreign gene expression could be accomplished. However, of more importance, it has now been shown that potato tubers may be used to express proteins including Escherichia coli labile toxin B subunit, rotavirus VLPs and HBV antigen (Haq et al., 1995; Thanavala et al., 1995). At present, the level of expression of recombinant protein is relatively low; however, it is anticipated that much higher levels can be achieved, making this approach one of the most promising ways of devising and producing an oral vaccine. Another interesting benefit from transgenic plant technology has been the production of a functional IgA antibody molecule (Ma et al., 1995), which again offers an alternative approach to the production of vaccines for passive mucosal immunity.
It has been known for a long time that the use of live, attenuated vaccines results in more appropriate and protective immune responses than does the use of inactivated vaccines. Expression of antigens in the host results in the correct protein conformation and glycosylation patterns. Even more important, intracellular protein processing can allow presentation by the class I MHC for effective CTL responses. A limitation to the development of vaccines against viruses such as the influenza virus is the diversity of viral envelope proteins among different strains. Therefore, efforts in vaccine development have focused on induction of memory CTLs that react to epitopes shared by different strains of virus. Most efforts to generate CTL responses have used replicating vectors to either produce the antigen in the host cell or to deliver peptides into the cytoplasm. However, the selection of peptide epitopes presented by MHC molecules is dependent on the structure of individual MHC molecules, and the peptide approach has been shown to have some limitations in humans.