Abstract
DNA priming has previously been shown to elicit augmented immune responses when administered by electroporation (EP) or codelivered with a plasmid encoding interleukin-12 (pIL-12). We hypothesized that the efficacy of a DNA prime and recombinant adenovirus 5 boost vaccination regimen (DNA/rAd5) would be improved when incorporating these vaccination strategies into the DNA priming phase, as determined by pathogenic simian immunodeficiency virus SIVmac239 challenge outcome. The whole SIVmac239 proteome was delivered in 5 separate DNA plasmids (pDNA-SIV) by EP with or without pIL-12, followed by boosting 4 months later with corresponding rAd5-SIV vaccine vectors. Remarkably, after repeated low-dose SIVmac239 mucosal challenge, we demonstrate 2.6 and 4.4 log reductions of the median SIV peak and set point viral loads in rhesus macaques (RMs) that received pDNA-SIV by EP with pIL-12 compared to the median peak and set point viral loads in mock-immunized controls (P < 0.01). In 5 out of 6 infected RMs, strong suppression of viremia was observed, with intermittent "blips" in virus replication. In 2 RMs, we could not detect the presence of SIV RNA in tissue and lymph nodes, even after 13 viral challenges. RMs immunized without pIL-12 demonstrated a typical maximum of 1.5 log reduction in virus load. There was no significant difference in the overall magnitude of SIV-specific antibodies or CD8 T-cell responses between groups; however, pDNA delivery by EP with pIL-12 induced a greater magnitude of SIV-specific CD4 T cells that produced multiple cytokines. This vaccine strategy is relevant for existing vaccine candidates entering clinical evaluation, and this model may provide insights into control of retrovirus replication.
Highlights
DNA priming has previously been shown to elicit augmented immune responses when administered by electroporation (EP) or codelivered with a plasmid encoding interleukin-12
To assess whether vaccination efficacy was improved if the immunogenicity of the DNA priming component was enhanced, we delivered the whole SIVmac239 genome in 5 separate pDNASIV plasmids (Gag, Pol, Env, Nef, and Vif/Vpr/Vpx/Tat/Rev fusion) in 3 successive primes delivered by EP with or without plasmid encoding interleukin-12 (pIL-12)
In rhesus macaques (RMs) that received plasmid DNA (pDNA)-simian immunodeficiency virus (SIV) codelivered with pIL-12, 6 became infected following a maximum of 9 challenges, and the other 2 remained uninfected after all 13 challenges (Fig. 1B)
Summary
DNA priming has previously been shown to elicit augmented immune responses when administered by electroporation (EP) or codelivered with a plasmid encoding interleukin-12 (pIL-12). A replicating rhesus cytomegalovirus (rhCMV) vector expressing the full SIV proteome recently demonstrated suppression of acute-phase virus replication and seemingly prevented the acquisition of infection in over half of the vaccinated rhesus macaques (RMs) following repeated low-dose challenge with the highly pathogenic simian immunodeficiency virus SIVmac239 [21, 22]. ELECTROPORATION AND IL-12 PLASMID ENHANCE DNA PRIME 9579 by 1.4 and 2.4 log at peak and set point, respectively, following a single intravenous challenge with SIVmac251 [34] Both the rhCMV and rAd26/rAd5 regimens were characterized by broad, robust, antigen-specific multifunctional CD4 and CD8 T-cell responses that effectively influenced early events in virus dissemination. These results indicate that vaccination can elicit sustained suppression of viral replication and reemphasize the potential importance of T-cell immunity, in the wake of the unsuccessful Merck rAd5-HIV phase II trial [8, 13]
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