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Vaccines for the 21st Century: A Tool for Decisionmaking
stranded DNA than in single strands. Tolerance is a more difficult issue, but researchers are monitoring it. One advantage of this approach is that there is no danger of viral disease, since the vaccine does not contain replicating virus.
On the question of efficacy, native protein is made endogenously, with the appropriate mammalian post-translational modifications, and it induces neutralizing antibody even across conformational epitopes. There are cytotoxic T-lymphocytes and cross-strain protection. The muscle cells, while they may not be antigen-presenting cells, definitely do transfer antigen, and there is good helper T-cell response.
On the question of production, it is (or will be) a generic technology. Once the manufacturing process is in place, producing different vaccines will be no different than producing different flavors of ice cream. The process is the same, and so is the host strain. The technology will also be useful as a laboratory tool for producing and screening antibodies.
In response to questions from the audience, Dr. Liu added the following:
It would appear that the DNA itself is modulating the Th1-like response. Recombinant nucleate proteins induce antibodies to recombinant nucleate proteins, but when you add plasma DNA—even if it doesn’t encode for anything—you get a Th1-like response with predominance of IgG2A. In a sense, the DNA acts as an adjuvant.
Researchers don’t know whether the muscle cells that are generating antigen will be attacked and lysed by antigen-specific CTLs. For one thing, they are multinucleated; for another, they are very large. In any event, very few muscle cells are transfected: the number of plasmic copies drops from 2,000 initially to about 1,500 at 4 weeks and 500 at 18 weeks.
Researchers have tried various routes of immunization. Subcutaneous injection produces good antibody response but no CTL or helper T-cell response. They have also applied DNA directly to mucosal tissues; the result was IgG antibody response without IgA, and no CTL response. Nevertheless, their goal is to move toward mucosal delivery if only because of the ease of delivery.
Researchers have not yet investigated the class II response in detail.
Histologic studies of transfected muscle cells reveal no inflammatory myopathies. The needle track remains visible and is infiltrated with lymphocytes, but the response was much less marked than the response to an antibiotic that is injected intramuscularly and known to be a mild irritant.
Researchers still don’t understand the exact mechanism by which antigen expressed in muscle cells induces antibodies. Clearly it makes it out of the cell, but that could be due to (1) transfer by the myoblasts or (2) transfection of antigen-presenting cells that happen to be in the muscle tissue. They plan to pursue this question using experiments in which transfected myoblasts are transplanted to bone marrow chimeras.