The ideal attributes for a vaccine are: (1) safe for all ages; (2) effective, long-lasting immunity; (3) requires only a single, or two closely spaced, immunizations; (4) provides protection within 2 weeks; (5) can be delivered without need of a needle and syringe; (6) may be administered in a formulation with other vaccines; (7) is stable at high and low temperatures; and (8) is inexpensive to produce.63
The initial era of vaccine development was based on the use of killed or attenuated whole organisms as immunogens. Usually these produced reasonable immune responses because of their recruitment of innate immunity, but in some cases they are associated with adverse reactions. Examples of adverse reactions would include the encephalopathic responses to the older formulations of killed Bordetella pertussis vaccine and the allergy to contaminating egg protein of influenza vaccine, which is produced by growing the virus in chicken eggs. To avoid such issues, many newer vaccines use purified molecules as immunogens.
Subunit vaccines are composed of purified recombinant proteins or synthetic peptides encoding defined epitopes of potential pathogens. Four reasons have led to the recent emphasis on using subunits of organisms as vaccines: (1) avoidance of the potential toxicities of whole organisms, such as those associated with killed pertussis vaccine; (2) provision of more stable vaccines, especially as compared with the care needed to keep live, attenuated strain vaccines active; (3) obviation of the high cost of growing fastidious organisms or organisms with complicated life cycles, such as malarial parasites; and (4) the feasibility of the subunit approach using molecular biologic recombinant technology.
Although there are benefits to recombinant subunit vaccines, one limitation is they are not very immunogenic when administered by themselves. Highly purified immunogens may not stimulate the innate immune system and fail to upregulate the costimulatory molecules on antigen-presenting cells, and thus fail to induce an immune response. The advantage of using whole organisms is that the innate immune system can recognize the organism as foreign, and thereby use complement and the upregulation of costimulatory molecules to induce an immune response.
One way to compensate for their lack of immunogenicity is to combine the purified subunits with more immunogenic adducts or administer them with newer adjuvants. A complex of the recombinant immunogen and recombinant complement C3dg is an appealing adduct because of its potential to recruit not only the B cell receptor, but also the CD21/CD19 complex, which potentiates the B cell response. Newer and more potent adjuvants include MF59, which is a lipid-detergent mixture containing squalene; F127, a copolymer that can be mixed with the immunogen and other immunomodulators at a cool temperature and, when injected, the mixture gels at body temperature providing a solid phase depot of immunoreac-tants; and the use of unmethylated CpG DNA, which is able to directly Toll-like receptor 9, which in humans is primarily expressed on B cells and plasmacytoid dendritic cells.64,65 Although the development of new adjuvants is a burgeoning field, acceptance of this technology for human use has lagged because of concerns of inducing autoimmunity.66
A major innovation in vaccine delivery systems developed in the 1990s has been the transfection of mammalian cells with "naked DNA." This method of vaccination simply requires that the coding DNA for the candidate vaccine antigen be placed into a plasmid, usually containing a strong eukaryotic promoter such as cytomegalovirus. Purified plas-mid in saline is then injected intradermally or intramuscularly and transfection of cells occurs. The transfected cells produce the candidate antigen, which, being intracellular, is processed and then expressed on the cell surface via class I MHC. If the cell is lysed, additional candidate antigen is released, which can then be processed via the extracellular class II pathway, or the cross-presentation pathway (see Fig. 11-4). Thus, via this methodology it is possible to generate MHC class I- and MHC class II-dependent responses to the candidate antigen.
Advantages of this method are that no adjuvants are required, the vaccine does not require special storage because DNA is stable, and the purification of plasmid DNA is relatively simple compared with purification of recombinant proteins. It is possible to enhance DNA vaccine efficacy by the coinjection of other plasmid DNA, which either contains the coding regions for molecules that will function as adjuvants or includes noncoding regions of DNA that themselves elicit adjuvant activity. Notably, the costimulatory molecules CD80 and CD86 have been incorporated into plasmid DNA, as well as the coding region for IL-12. Thus, one can attempt to direct the nature of the ensuing immune response via the local production of these molecules. For cytokines, this approach is particularly attractive, as the plasmid DNA stays local when injected intramuscularly.
There are potential drawbacks to the use of DNA vaccines. The most serious concern would be that the plasmid DNA becomes integrated into the genome, where any number of integration-related problems may later appear, such as the activation of oncogenes. Other concerns are that the long-term production of candidate vaccine antigen might induce tolerance to the antigen rather than a protective immune response. Additionally, there is the worry that the use of DNA vaccines may lead to autoimmune diseases, owing to lysis of the cells and release of cellular components including DNA.
Molecular biologic approaches also enable novel methods of introducing immunogens into hosts that are not dependent on adjuvants. One promising approach is to incorporate the DNA coding sequence for the relevant antigen into a micro-bial vector that can be made innocuous and suitable for administration to humans. Several vectors, including genetically altered, avirulent Salmonella bacteria, vaccinia virus, bacille Calmette-Guerin (BCG) mycobacteria, as well as edible plants are being studied. In addition, formulations of vaccines that allow transdermal or transmucosal immunization would greatly facilitate large scale, or emergency immunization programs.
Was this article helpful?
All Natural Immune Boosters Proven To Fight Infection, Disease And More. Discover A Natural, Safe Effective Way To Boost Your Immune System Using Ingredients From Your Kitchen Cupboard. The only common sense, no holds barred guide to hit the market today no gimmicks, no pills, just old fashioned common sense remedies to cure colds, influenza, viral infections and more.