March 5th at the CROI conference 2013
Potent Cellular Immune Responses Induced after Therapeutic Immunization of HIV+ Patients with PENNVAX-B DNA Vaccine Delivered by Electroporation
Lorenzo Ramirez*1, T Arango1, D Shah2, M Morrow2, J Lee2, M Naji1, K Maffei3, M Bagarazzi2, P Tebas3, and J Boyer1
1Univ of Pennsylvania Perelman Sch of Med, Philadelphia, US; 2Inovio Pharmaceuticals, Blue Bell, PA, US; and 3Univ of Pennsylvania, Philadelphia, US
Background: The goal of eradicating the HIV reservoir has renewed interest in immunotherapeutic approaches to boost T cell responses against HIV+ cells. However, individuals chronically infected with HIV respond poorly to T cell vaccines. We evaluated the use of PENNVAX-B vaccine (a gag, pol, and env combination DNA vaccine) delivered by in vivo electroporation (EP) that has proven immunogenic in HIV– individuals (HVTN 080).
Methods: We conducted a phase 1 study in well controlled, ART treated, HIV+ individuals (HIV RNA <75 copies/mL, current CD4 >400/µL, and nadir CD4 cells >200 cells/µL). Subjects received 4 doses (at day 0, weeks 4, 8, and 16) of 3 mg PENNVAX-B (consisting of consensus sequence HIV gag, pol, and env immunogens) intramuscularly followed by EP. Standard IFN-? ELISpot assays were performed. Positive responses were determined using a one-way ANOVA followed by Dunnett’s test, comparing each time-point to baseline. We measured the potential of cells to lyse HIV-1+ cells by measuring CD8+CD107a+ Perforin+ Granzyme B+ responses, by standard flow cytometry. Subjects were considered responders to the vaccine if responses were 50% greater than baseline. Also, the subjects’ pre-vaccination cytokine profiles were examined using a 30 cytokine Luminex plasma assay. We compared baseline cytokine profiles of the subjects who responded via ELISpot or Flow assays to those who did not respond.
Results: 12 subjects were included. 92% were male and 58% black. The vaccine was safe and well tolerated. 10 of the 12 subjects (83%) showed significant vaccine-specific T cell responses in the form of IFN-? ELISpot to at least 1/3 vaccine antigens (gag, pol, or env) throughout the immunizations. ELISpot responses were primarily mediated by CD8+ T cells. 9/11 subjects tested showed a positive CD8+CD107a+ Perforin+ Granzyme B+ response. HIV-1+ individuals, despite having well-controlled viral replication showed significantly different cytokine profiles compared to healthy controls. Importantly, baseline IL-12 p70, and MCP-1 levels were directly associated with response to the HIV-1 therapeutic vaccine.
Conclusions: PENNVAX-B induced HIV-specific CTL responses in well-controlled HIV+ individuals. The pre-vaccination cytokine environment may provide the necessary signals for T cells to respond to therapeutic vaccination, suggesting that the cytokines examined could serve as potential adjuvants in a therapeutic vaccine strategy.
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