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different pathogens at the same time. At present, 60 percent of the cost of vaccine delivery is spent on refrigeration, and another large fraction on syringes and health professionals. Some of these vaccines would make it possible to immunize thousands or even millions of people in a single day without doctors, needles, or pain.

Mucosal Adhesives. Other researchers are developing new mucosal adhesives, which increase absorption by extending the period of time during which antigen is exposed to the mucosal surface. Substances such as carboxymethylcellulose adhere very nicely to the mucosal surfaces and could be used to deliver antigen to those tissues. Investigators in Iceland have tested mucosal adhesives containing influenza virus in the nasal cavity of animals and even humans. It produced stronger and longer-lasting immune response than the injectable vaccine.

Microspheres. Microspheres are already in common use for the delivery of drugs and are being developed for the delivery of hormones and insulin. Because M-cells preferentially internalize particles, it should be possible to use them to introduce soluble antigen to the macrophage. A company in Korea has applied to develop a hepatitis-B vaccine using microspheres that has the considerable advantage of requiring only one injection. (Compliance is a problem with the current vaccine, which requires 3 injections: only 60 percent of patients return for the second shot, and 40 percent for the third.) The spheres themselves are totally biodegradable and nontoxic; varying the composition regulates the rate (and hence the location) at which individual microspheres dissolve.

Injectable microspheres can be up to 50 microns and still be effective, and in the gut these larger spheres collect in the Peyer’s patch, where they induce a mucosal immune response (circulatory IgG). They must be less than 10 microns to be absorbed by the intestine. These smaller microspheres can later be found in the mesentery lymph nodes and spleen, as well as in circulation. In some cases (e.g., SIV) they can also induce T-cell-mediated immunity in cytotoxic T-cells, although this is not seen with other antigens (e.g., influenza and polio virus). The reasons for this difference should be addressed in future research.

Obviously, the prospect of a vaccine that could be eaten and would induce both mucosal and system immunity is very attractive. Because microspheres protect against degradation by gastric acid in the stomach, 100 percent of the antigen reaches the gut. At present, however, less than 1 percent of ingested microspheres are internalized. The rate of absorption might be increased through surface modifications or coadministration with CT or CPB, which has increased absorption in animals.

Other development problems also remain. In numerous animal experiments, antigen in microspheres induced much high titers of specific antigen that raw antigen. However, several vaccines that work in animals haven’t worked in humans. In some cases, the organic solvents used in preparing the microspheres can denature the antigen unless it is relatively stable. And improvements may be needed in the reproducibility of microsphere preparation.

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