Abstract
BackgroundDNA vaccines are a promising approach to vaccination since they circumvent the problem of vector-induced immunity. DNA plasmid cytokine adjuvants have been shown to augment immune responses in small animals and in macaques.Methodology/Principal FindingsWe performed two first in human HIV vaccine trials in the US, Brazil and Thailand of an RNA-optimized truncated HIV-1 gag gene (p37) DNA derived from strain HXB2 administered either alone or in combination with dose-escalation of IL-12 or IL-15 plasmid cytokine adjuvants. Vaccinations with both the HIV immunogen and cytokine adjuvant were generally well-tolerated and no significant vaccine-related adverse events were identified. A small number of subjects developed asymptomatic low titer antibodies to IL-12 or IL-15. Cellular immunogenicity following 3 and 4 vaccinations was poor, with response rates to gag of 4.9%/8.7% among vaccinees receiving gag DNA alone, 0%/11.5% among those receiving gag DNA+IL-15, and no responders among those receiving DNA+high dose (1500 ug) IL-12 DNA. However, after three doses, 44.4% (4/9) of vaccinees receiving gag DNA and intermediate dose (500 ug) of IL-12 DNA demonstrated a detectable cellular immune response.Conclusions/SignificanceThis combination of HIV gag DNA with plasmid cytokine adjuvants was well tolerated. There were minimal responses to HIV gag DNA alone, and no apparent augmentation with either IL-12 or IL-15 plasmid cytokine adjuvants. Despite the promise of DNA vaccines, newer formulations or methods of delivery will be required to increase their immunogenicity.Trial RegistrationClinicaltrials.gov NCT00115960 NCT00111605
Highlights
DNA vaccines theoretically have potential to generate immune responses to common pathogens
20 participants were randomized to 3 doses and 30 to 5 doses of gag DNA alone; 10 each to 3 doses of gag DNA and IL-12 or IL-15 DNA at an adjuvant dose of either 100 or 500 ug; 30 to 3 doses and 30 to 5 doses of gag DNA+IL-12 DNA at the maximum dose of 1500 ug ; 10 to 3 doses and 30 to 5 doses of gag DNA+IL-15 DNA at the 1500 ug, 30 to 3 doses of gag DNA+IL-15 DNA at the 1500 ug dose followed by 2 doses with gag DNA+IL-12 DNA (1500 ug); and 20 to 3 doses and 24 to 5 doses of placebo (Figure 2)
Site investigators discontinued vaccinations for 4 vaccine recipients due to adverse events deemed probably not related to vaccination
Summary
DNA vaccines theoretically have potential to generate immune responses to common pathogens. DNA expresses the antigen of interest without the need for a vector delivery system; this non-live vaccine approach circumvents the problem of vectorinduced immune responses. In addition to the safety of this approach, DNA vaccines have the ability to induce cellular immune responses, which is in contrast to killed or subunit-based vaccines [6]. Several delivery methods for DNA vaccines have been tested in animals and in humans. The basic concept is the uptake of DNA into cells (skin, subcutaneous cells, muscle, and antigen presenting cells), where it reaches the nucleus via the host cellular machinery. DNA vaccines are a promising approach to vaccination since they circumvent the problem of vector-induced immunity.
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