Prospects for control of emerging infectious diseases with plasmid DNA vaccines

Moss, Ronald B

An area of potentially paramount importance for DNA vaccines is formulations and adjuvants. Adjuvants are common to most licensed vaccines and are included to potentiate the immune responses elicited by vaccination. For DNA vaccines, various delivery systems and adjuvants have been tested. One of the earliest promising adjuvants for plasmid DNA vaccines was poly-lactide coglycolide (PLG), cationic microparticles. Ulmer and colleagues at Chiron Corporation evaluated HIV DNA vaccines formulated with PLG microparticles and found strong antibody and T-cell responses in macaques [28] . Poloxamers represent another class of adjuvants tested with DNA vaccines. Some poloxamers are nonionic block copolymers, and when combined with a cationic surfactant, bond with DNA to form small particles. A study by Wloch and colleagues at Vical Incorporated examined DNA immunizations of human volunteers with cytomegalovirus (CMV) plasmids formulated with a specific poloxamer adjuvant. In that study CMV-specific T-cell responses were detected in a majority of CMV sero-negative individuals who were vaccinated [29] . Vaxfectin ® is another example of a delivery system and adjuvant for DNA vaccines that has been recently tested in humans. Vaxfectin ® is a cationic lipid-based adjuvant that bears a positive charge that binds electrostatically to negatively charged DNA. Studies in animals also demonstrated that Vaxfectin ® -adjuvanted DNA vaccines can be protective against lethal viral challenges. For example, Webby and colleagues at St. Jude Children's Research Hospital and Vical Incorporated, immunized ferrets with three plasmids containing DNA components of the H5N1 pandemic influenza virus formulated with Vaxfectin ® [30] . After one or two immunizations, all animals were completely protected from lethal pandemic influenza virus challenge, while unvaccinated control animals died. Similarly, Griffin and colleagues at Johns Hopkins immunized juvenile and infant rhesus macaques by intramuscular and intradermal routes with measles antigen encoding plasmids formulated with Vaxfectin ® [31] . All of the vaccinated monkeys developed strong and durable neutralizing antibodies and they were challenged with high doses of measles virus after one year. All of the unvaccinated control animals developed viremia and became ill with rashes in contrast to the vaccinated ani-mals which remained healthy and had no detectable virus levels. Lastly, the first human clinical trial of a DNA vaccine formulated with Vaxfectin ® has been completed with plasmids that encode pandemic influenza virus antigens (H5N1). The preliminary results reported from this trial by Smith and colleagues at Vical Incorporated suggest that vaccination with H5 DNA plasmids formulated with this adjuvant were well-tolerated and stimulated strong H5 antibody responses in up to 67% of subjects [32] . Notably, the antibody response rate and safety profile observed in this trial are comparable to most conventional proteinbased vaccines for pandemic influenza.