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Vaccines for the 21st Century: A Tool for Decisionmaking
Prospects for Future Adjuvants. Adjuvants will be required for most of the emerging vaccine candidates, and it is likely that different adjuvants will be required for different antigens, particularly to shape the immune response in the most beneficial direction. At present, however, there is no detailed understanding of how the adjuvant mechanism operates at the molecular level; this understanding is needed in the future. Almost no work is being done on adjuvants for mucosal vaccines, and this should be a particular priority.
At present, the number of candidate vaccines greatly exceeds the number of candidate adjuvants, and this imbalance will only increase as genomes are sequenced for increasing numbers of pathogens. In this situation, the lack of new adjuvants may become the principal limiting factor in the development of human vaccines in general and mucosal vaccines in particular. Another limiting factor, however, will be the necessity of testing new vaccines on cancer patients; after all, is their immune system so normal?
In response to questions from the audience, Dr. Elson added the following:
Researchers have not yet repeated the CT experiments in mice at lower doses, but in all likelihood when it no longer works as an adjuvant it will also loses it effect on T-cells. The mouse experiments were done in the B6 mouse, which has the best response to CTV-89–100.
In countries where cholera is endemic, the IgA system is fully developed by age 1 or 2, whereas in the United States you would not see adult levels of IgA until the teenage years.
CT-vibrio vaccine (CTV) appears to be a stronger immunogen than CT itself, in humans if not in mice, and it may also prove to be a better adjuvant in humans. It represents one way to avoid the potential toxicity of CT.
Another way to avoid toxicity is to use multiple emulsions to sequester the toxin from the epithelium and deliver it instead to the lymphoid follicles of the intestine. This technique has been tested in mice and does not produce fluid secretion. It is much faster than developing correct microencapsulation, which also requires that the antigen be denatured. In addition, multiple emulsions seem to require smaller amounts of antigen and can contain several antigens at once.
Mucosal immune memory for antigens presented with CT extends for up to 1 year.
The adjuvanticity of CT seems to be tied to its immunogenicity; mutants that lack adjuvant activity also aren’t immunized to themselves. It might to identify a single-amino-acid mutation that lacks toxicity but retains adjuvant activity; but it is not clear how this would be accomplished.
A tremendous amount of very basic work remains to be done before this knowledge could be used to produce vaccines for use by providers. University research can handle some of the questions, but commercial partners will be needed for development.