Safety and comparative immunogenicity of an HIV-1 DNA vaccine in combination with plasmid interleukin 12 and impact of intramuscular electroporation for delivery

Abstract

Background: DNA vaccines have been very poorly immunogenic in humans but have been an effective priming modality in prime-boost regimens. Methods to increase the immunogenicity of DNA vaccines are needed.

Methods: HIV Vaccine Trials Network (HVTN) studies 070 and 080 were multicenter, randomized, clinical trials. The human immunodeficiency virus type 1 (HIV-1) PENNVAX®-B DNA vaccine (PV) is a mixture of 3 expression plasmids encoding HIV-1 Clade B Env, Gag, and Pol. The interleukin 12 (IL-12) DNA plasmid expresses human IL-12 proteins p35 and p40. Study subjects were healthy HIV-1-uninfected adults 18-50 years old. Four intramuscular vaccinations were given in HVTN 070, and 3 intramuscular vaccinations were followed by electroporation in HVTN 080. Cellular immune responses were measured by intracellular cytokine staining after stimulation with HIV-1 peptide pools.

Results: Vaccination was safe and well tolerated. Administration of PV plus IL-12 with electroporation had a significant dose-sparing effect and provided immunogenicity superior to that observed in the trial without electroporation, despite fewer vaccinations. A total of 71.4% of individuals vaccinated with PV plus IL-12 plasmid with electroporation developed either a CD4(+) or CD8(+) T-cell response after the second vaccination, and 88.9% developed a CD4(+) or CD8(+) T-cell response after the third vaccination.

Conclusions: Use of electroporation after PV administration provided superior immunogenicity than delivery without electroporation. This study illustrates the power of combined DNA approaches to generate impressive immune responses in humans.

Keywords: electroporation; plasmid cytokine adjuvant; vaccination.

Figure 1.

Allocation, follow-up, and analysis for HIV Vaccine Trials Network (HVTN) study 070 and HVTN study 080. Abbreviations: EP, electroporation; IL-12, interleukin 12; IL-15, interleukin 15; PV, PENNVAX-B DNA vaccine.

Figure 1.

Allocation, follow-up, and analysis for HIV Vaccine Trials Network (HVTN) study 070 and HVTN study 080. Abbreviations: EP, electroporation; IL-12, interleukin 12; IL-15, interleukin 15; PV, PENNVAX-B DNA vaccine.

Figure 2.

Reactogenicity symptoms. Maximum severity of local pain or tenderness (A and B) and of systemic symptoms (C and D) following each study injection. A and C, Intramuscular administration. B and D, Intramuscular administration with electroporation. No severe symptoms were reported. Onset of a reaction was within the first 3 days following a study injection. Reactions were followed to resolution to determine the maximum severity. Systemic reactions included malaise and/or fatigue, headache, chills, myalgia, arthralgia, nausea, and vomiting. For intramuscular administration, the interleukin 15 (IL-15) 0.8-mg and 2-mg dose groups are combined because there were no differences in the reactogenicity profiles. Abbreviations: EP, electroporation; IL-12, interleukin 12; PV, PENNVAX-B DNA vaccine.

Figure 3.

Magnitude of the human immunodeficiency virus (HIV)–specific CD4⁺ and CD8⁺ T-cell response magnitude. The percentage of CD4⁺ T-cells (A) and CD8⁺ T-cells (B) producing interferon γ (IFN- γ) and/or interleukin-2 (IL-2) in response to Env, Gag, or Pol global potential T-cell epitope (PTE) peptide pools 2 weeks after the indicated immunization, as measured by intracellular staining assay. Responders are shown in red colored circles, and nonresponders are shown in blue circles. Box plots show the distribution of the magnitude of response in positive responders only. The box indicates the median and interquartile range (IQR); whiskers extend to the furthest point within 1.5 times the IQR from the upper or lower quartile. Numbers at the top of each panel show the number of responders/number with an assay result and the percentage with positive response. Data from the groups that received PENNVAX-B DNA vaccine (PV) plus 0.8 mg of interleukin 15 (IL-15) intramuscularly are not shown. Abbreviations: EP, electroporation; IFN-γ, interferon γ; IL-12, interleukin 12.

Figure 4.

T-cell response rates for PENNVAX-B DNA vaccine plus interleukin 12 arms, comparing intramuscular (IM) delivery and IM delivery with electroporation (EP). Vertical bars denote 95% confidence intervals calculated by the score method. P values are from Fisher exact tests.

Figure 5.

Body mass index (BMI; calculated as the weight in kilograms divided by the height in meters squared) by human immunodeficiency virus (HIV)–specific CD4⁺ and CD8⁺ T-cell responses for individuals who received PENNVAX-B DNA vaccine plus interleukin 12 intramuscularly with electroporation. P values are from Wilcoxon rank sum tests comparing the distribution of BMI between responders (Resp) and nonresponders (NR).