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Vaccines for the 21st Century: A Tool for Decisionmaking
peptide, this is a CD8 response. Protection does not appear to persist as long as the CTL response.
Another group has done similar experiments with aged mice. They were able to get CTLs with the same precursor frequencies in the aged mice as in younger mice, with good antibodies and good small-dose protection. This is an important issue in diseases like influenza, where the elderly are the population at greatest risk.
To determine whether is would also be possible to get efficacious B-cell and antibody responses, as well as CTL response, researchers repeated the experiment using the gene encoding for influenza hemagglutin, a surface glycoprotein that is the antigen against which the major neutralizing antibody is directed. (These proteins change frequently, which is why the current influenza vaccine must be reformulated every year.) The result was a very good level of functional antibodies, with titers comparable to live infection and probably high enough to be protective in humans. These antibody levels have been sustained for 20 months, although duration might not be as great in humans. Researchers are uncertain whether antigen is still being expressed after this interval; one study suggests that the DNA persists and expresses for up to 24 months.
One unexpected finding was that the DNA vaccine encoding for hemaglutin induced antibodies with a different profile from those induced by commercial vaccines containing inactivated influenza, notably a greater predominance of IgG2a. The latter is thought to be important in providing protection from influenza. Doses as low as 1 microgram, given twice 3 weeks apart, provide 100 percent survival in mice and little or no morbidity as measured by weight loss and grooming behavior. Further tests indicate that DNA vaccines also stimulated greater lymphocyte proliferation from splenocytes and higher levels of IL-2 and IFN-gamma on restimulation. This and the absence of IL-4 point to a Th1-like helper response.
HIV DNA Vaccines. It is increasingly accepted that the same kind of Th1-like helper response and CTLs are major factors in preventing HIV infection, or at least prolonging the phase of latent disease. This is supported by recent findings that high-risk individuals who remain seronegative have good Th blood-type responses, and that those with the less virulent HIV-2 are at decreased risk for HIV-1.
Initial work on HIV envelope proteins focused on surface antigens such as B3, GP-120, and GP-160, looking for a neutralizing epitope and trying to make it recombinant. It has become increasingly clear that the antibody response is more complicated, and that memorization in particular involves dimeric dimers of GP-160 that form conformational epitopes. Accordingly, effort has shifted from peptide vaccines to ways of making intact oligomeric GP-160. DNA vaccines offer the advantage that the protein is synthesized in situ, with normal glycosylation.
Researchers gave African green monkeys two injections of a DNA vaccine based on a truncated GP-160-like construct. Animals developed relatively high antibody titers that show diverse neutralizing responses, which is desirable given