Rational vaccine design through the use of molecular adjuvants

Nucleic acid or DNA inoculation is an important vaccination technique which is being explored as an immunization strategy against a variety of infectious diseases as well as cancer. Current DNA vaccines have demonstrated some successes in rodents. However, there are concerns if such vaccines will be potent enough to perform adequately in humans. I postulated that clinically efficacious DNA vaccines may require greater control of the magnitude and direction (humoral or cellular) of the immune responses, and that such refinement could be accomplished by co-delivering genes for immunologically important molecules as molecular adjuvants. To test this hypothesis, I constructed the molecular adjuvants by cloning genes for costimulatory molecules and cytokines into mammalian expression vectors. These cDNA expression plasmids were co-immunized into mice and rhesus monkeys, and their effects on the modulation of immune responses were studied. Moreover, the immunized rhesus monkeys were challenged with a chimeric SHIV (SIV/HIV) virus, and the results of this challenge were characterized in detail. I observed that significant manipulation of the host immune response was possible through this technology. Both antigen-specific humoral and cellular immune responses were modulated dramatically by co-immunizing with the molecular adjuvant in rodents and in primates. The immunization of rhesus monkeys extended and confirmed the ability of DNA vaccines to generate protective responses in primates. Modulation of monkey immunity towards a Th1 phenotype gave 50% protection from a challenge with a chimeric SIV/HIV (SHIV) IIIB virus. These results suggest that co-administration of Th1 type molecular adjuvants should be further examined against the SHIV challenge in rhesus monkeys. Taken together, this work demonstrates that the direction and magnitude of immune responses induced by DNA vaccines could be modulated by the co-administration of molecular adjuvants. The development of this genetic adjuvant network underscores a new level of control in the induction of specific immune responses to tailor the vaccination programs more closely to the correlates of protection which vary from disease to disease. These findings demonstrate the establishment of this strategy as the basis for optimizing current DNA immunization programs and a new generation of rationally designed vaccines and immunotherapies.