DNA vaccines: a review.

Therapeutic and prophylactic DNA vaccine clinical trials for a variety of pathogens and cancers are underway (Chattergoon et al., 1997; Taubes, 1997). The speed with which initiation of these trials occurred is no less than astounding; clinical trials for a human immunodeficiency virus (HIV) gp160 DNA-based vaccine were underway within 36 months of the first description of "genetic immunization" (Tang et al., 1992) and within 24 months of publication of the first article describing intramuscular delivery of a DNA vaccine (Ulmer et al., 1993). Despite the relative fervor with which clinical trials have progressed, it can be safely stated that DNA-based vaccines will not be an immunological "silver bullet." In this regard, it was satisfying to see a publication entitled "DNA Vaccines--A Modern Gimmick or a Boon to Vaccinology?" (Manickan et al., 1997b). There is no doubt that this technology is well beyond the phenomenology phase of study. Research niches and models have been established and will allow the truly difficult questions of mechanism and application to target species to be studied. These two aspects of future studies are intricately interwoven and will ultimately determine the necessity for mechanistic understanding and the evolution of target species studies. The basic science of DNA vaccines has yet to be clearly defined and will ultimately determine the success or failure of this technology to find a place in the immunological arsenal against disease. In a commentary on a published study describing DNA vaccine-mediated protection against heterologous challenge with HIV-1 in chimpanzees, Ronald Kennedy (1997) states, "As someone who has been in the trenches of AIDS vaccine research for over a decade and who, together with collaborators, has attempted a number of different vaccine approaches that have not panned out, I have a relatively pessimistic view of new AIDS vaccine approaches." Kennedy then goes on to summarize a DNA-based multigene vaccine approach and the subsequent development of neutralizing titers and potent CTL activity in immunized chimpanzees (Boyer et al., 1997). Dr. Kennedy closes his commentary by stating. "The most exciting aspect of this report is the experimental challenge studies.... Viraemia was extremely transient and present at low levels during a single time point. These animals remained seronegative ... for one year after challenge" and "Overall, these observations engender some excitement". (Kennedy, 1997). Although this may seem a less than rousing cheer for DNA vaccine technology, it is a refreshingly hopeful outlook for a pathogen to which experience has taught humility. It has also been suggested that DNA vaccine technology may find its true worth as a novel alternative option for the development of vaccines against diseases that conventional vaccines have been unsuccessful in controlling (Manickan et al., 1997b). This is a difficult task for any vaccine, let alone a novel technology. DNA-based vaccine technology represents a powerful and novel entry into the field of immunological control of disease. The spinoff research has also been dramatic, and includes the rediscovery of potent bacterially derived immunomodulatory DNA sequences (Gilkeson et al., 1989), as well as availability of a methodology that allows extremely rapid assessment and dissection of both antigens and immunity. The benefits of potent Th1-type immune responses to DNA vaccines must not be overlooked, particularly in the light of suggestions that Western culture immunization practices may be responsible for the rapid increases in adult allergic and possibly autoimmune disorders (Rook and Stanford, 1998). The full utility of this technology has not yet been realized, and yet its broad potential is clearly evident. Future investigations of this technology must not be hindered by impatience, misunderstanding, and lack of funding or failure of an informed collective and collaborative effort.