Multiple factors affect immunogenicity of DNA plasmid HIV vaccines in human clinical trials

Abstract

Plasmid DNA vaccines have been licensed for use in domesticated animals because of their excellent immunogenicity, but none have yet been licensed for use in humans. Here we report a retrospective analysis of 1218 healthy human volunteers enrolled in 10 phase I clinical trials in which DNA plasmids encoding HIV antigens were administered. Elicited T-cell immune responses were quantified by validated intracellular cytokine staining (ICS) stimulated with HIV peptide pools. HIV-specific binding and neutralizing antibody activities were also analyzed using validated assays. Results showed that, in the absence of adjuvants and boosting with alternative vaccines, DNA vaccines elicited CD8+ and CD4+ T-cell responses in an average of 13.3% (95% CI: 9.8-17.8%) and 37.7% (95% CI: 31.9-43.8%) of vaccine recipients, respectively. Three vaccinations (vs. 2) improved the proportion of subjects with antigen-specific CD8+ responses (p=0.02), as did increased DNA dosage (p=0.007). Furthermore, female gender and participants having a lower body mass index were independently associated with higher CD4+ T-cell response rate (p=0.001 and p=0.008, respectively). These vaccines elicited minimal neutralizing and binding antibody responses. These findings of the immunogenicity of HIV DNA vaccines in humans can provide guidance for future clinical trials.

Trial registration: ClinicalTrials.gov NCT00069030 NCT00071851 NCT00111605 NCT00115960 NCT00125970 NCT00141024 NCT00270218 NCT00384787 NCT00528489 NCT00991354.

Keywords: Clinical trial; DNA vaccine; HIV; Immune response.

Figure 1. T-cell response rates in relation to the number of vaccinations

CD4+ and CD8+ T-cell responses were measured using intracellular cytokine staining assay for IFN-γ and IL-2. The total number of subjects included for CD4 and CD8 responses are 220 and 238, respectively. The number of subjects who completed 2 vaccination are 49 and 50 for CD4 and CD8 cell groups, respectively; 3 vaccinations are 145 and 161 for CD4 and CD8 cell groups, respectively, and 4 vaccination are 26 and 27 for CD4 and CD8 cell groups, respectively. The p-values were determined two-sided Fisher exact test (n.s.: no significance).

Figure 2. BMI affects vaccine elicited HIV-specific human CD4+ T-cell responses, but not CD8+ T-cell responses

In 7 clinical trials that demonstrated vaccine-elicited immune responses, the distribution of T-cell responses were plotted by low (BMI < 25), medium (25 ≤ BMI <30) and high groups (BMI ≥ 30). Results show that BMI affects the CD4+ T-cell response more than the CD8+ T-cell response. Results show that BMI significantly affects the CD4+ T-cell response between high and low BMI groups (p=0.02), but not for the CD8+ T-cell response (n.s.: no significance).