The current vaccine arsenal, developed over two centuries, was implemented in what approximates its present splendor during the 1960s. Since then, worldwide vaccine efforts have done much to defuse the fear of many dreaded infectious diseases, such as smallpox, polio, diphtheria, pertussis, and measles. And yet despite these very real accomplishments, effective vaccines for tough challenges like HIV, malaria, and cancer sometimes seem to be nowhere in sight. Given these current shortcomings, many ask of our modern army of vaccinologists:“What have you done for us lately?” Established principles in vaccine development (like killing or attenuating the infectious agent) have not been direct solutions to these new vaccine challenges. There is currently no consensus about what form these new vaccines will have or how they will be deployed.

One vaccine technology that has gotten many hearts racing is “naked” DNA. Naked DNA vectors are relatively easy to engineer and produce. Unlike vaccines based on recombinant viruses, they need not be covered with proteins or lipids. Irrelevant antigenic components of recombinant immunogens can detract from their function. But what nucleic acid vaccines may gain in elegance, they may lose in power. They simply do not elicit immune responses that are strong enough for the prophylaxis or therapy required in many current experimental models.