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whether DNA introduced through the Peyer’s patch will lead to the synthesis of desired antigens, as it does when injected into muscle or skin.

Barriers to Vaccine Development. Tolerance is a major problem with some of these delivery systems. In addition to reducing the immune response, this can also lead to systemic unresponsiveness or even collapse at the T-cell level, the B-cell level, and even the antibody level. This can be addressed by changing the form or delivery of the antigen—globulin given in large oral doses induces tolerance, but globulin in microspheres continues to produce a good immune response. Frequency and timing of exposure also plays a role. Studies of humans immunized with keyhole limpet hemocyanin (KLH) demonstrated that oral administration “primes” the systemic response and reduces both hypersensitivity and tolerance. The nasal route appears to be more effective than eating the antigen.

Other Applications. These delivery systems might be used to introduce proteins that would treat or protect against autoimmune diseases such as rheumatoid arthritis and multiple sclerosis. Another possible application might be in the control of fertility—researchers working with rats have found that the sperm antigen SP-10, introduced orally, produces specific secretory antibodies against sperm in the female genital tract. The result is a temporary infertility mediated by specific IgA, temporary because IgA immune response is not long-lasting.

In response to questions from the audience, Dr. Mestecky added the following:

  • “Immune tolerance” is the wrong name for what happens in oral adminisration. “Mucosal deviation” might be better, since it changes the response rather than causing total unresponsiveness.

  • The intranasal route induced better tolerance that the oral route with the same antigen in mice. This work involved animal models of arthritis.

  • Antigens produced by plants may not be as “naked” as desired. Antigens like HIV, SIV, and GP-120 and 160 are generally heavily glycosylated, but glycosylation in plants is different from that in mammalian cells.

  • Since the immune response to the vector is a limiting factor, systems that are inert might be preferable to live vectors.

  • Parenteral immunization is relatively ineffective in inducing mucosal immunity. Studies with a variety of antigens demonstrated that it is almost never possible to boost the secretory IgA response by systemic immunization. Similarly, IgG in the genital tract is not derived from the circulation; systemic IgG cannot prevent the pathogen from crossing the mucosal membrane.

Systemic, intranasal, and internal immunization produce very different patterns of potential homing receptors on the surface of B-cells. Researchers have not looked at receptors on T-cells yet.

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