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  1. Glycopolymer is a polyoximer related to common compounds found in mouthwash, toothpaste, and even food products. It consists of a central segment of hydrophobic polyoxyl propylene polymer, with a hydrophilic polyoxyl ethylene at each end; the lengths of these segments are critical to the activity of the molecules. They enhance antibody, IgG1 and IgG2a, and cell-mediated responses. They appear to have a depot effect and have been shown to be effective as an adjuvant with peptides, proteins, and polysaccharides in oil and water emulsions. Currently available as an animal preparation under the name Titer-Max, it is fairly expensive but may be cheaper in broader human use. It is currently in Phase 1 trials.

  2. Cytokines are a logical target of research: if adjuvants stimulate cytokines, why not use the cytokines themselves? GM-CSF is a leading candidate because both stimulate the production of macrophages in bone marrow and activate the macrophages; it will soon be approved for use in cancer gene therapy. IL-12 preferentially stimulates the Th1 pathway in mice and might be attractive, but there are toxicity problems. IFN-gamma, IL-4, and anti-IL-4 might also be useful to preferentially activate or block certain response pathways, depending on the antigen.

Human Testing. One of the biggest hurdles in the development of new adjuvants is the difficulty of testing them in humans. Under FDA rules, new adjuvants can only be tested in cancer patients (where the standards of harm and side effects are lowered). Cancer vaccines aren’t really that similar to infectious disease vaccines, and adjuvants that fail in a cancer vaccine might still be excellent adjuvants for other applications. Moreover, no single adjuvant is going to be universally effective; many different adjuvants, each with their own particular application, might be needed.

Mucosal Immunization. Most pathogens invade or colonize the mucosal surfaces, and parenteral immunization does not protect mucosal surfaces. On the other hand, the majority of lymphoid cells in the body are at mucosal surfaces, particularly in the gut, which has more lymphoid cells than all other lymphoid organs put together. The lymphoid follicles in the gastrointestinal tract and the nose are important entry or inductive sites for mucosal immune responses. Cells that are induced in one site are transported to other mucosal surfaces, making it possible to immunize the respiratory epithelium (for example) by immunizing the gut or the nose. This has led to considerable interest in nasal immunization.

Unfortunately, there are at present no adjuvants for mucosal immunization that are approved for human use, nothing in human trials, and very little even in early stages of development. Experimentally, however, both cholera toxin (CT) and E. coli heat labile toxin (two molecules with similar three-dimensional structures) have been shown to have adjuvant effects at mucosal surfaces.

For example, when mice are fed keyhole limpet hemocyanin (KLH) there is no response in the gut, but when CT is mixed with the KLH there is an IgA response to KLH. This finding has been repeated with a wide spectrum on antigens, including not only proteins (e.g., KLH) but also polysaccharides,

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