Enhanced Control of Pathogenic Simian Immunodeficiency Virus SIVmac239 Replication in Macaques Immunized with an Interleukin-12 Plasmid and a DNA Prime-Viral Vector Boost Vaccine Regimen

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.

DNA and virus particle vaccination protects against acquisition and confers control of viremia upon heterologous simian immunodeficiency virus challenge

“…These results extend our previous work, where we reported that SIVmac239-based DNA only vaccine was effective in inducing strong and protective immune responses able to reduce viremia upon a single high-dose challenge using a broad (15) SIVmac251 stock administered 8 mo after the last vaccination (5). The results also are in agreement with our study of a DNA prime-recombinant Ad5 virus boost protocol in the presence of IL-12 DNA, where we reported potent control of peak and chronic viremia (18).…”

HIV-1 vaccines

“…Several rhesus macaque studies support the role of CD8+ T cells in preventing HIV-1 infection and disease [92][93][94] but results widely differ depending on the modes of administration, virus challenge, and immunological endpoints used. [95][96][97][98] Rhesus macaques were generally immunologically more responsive to vaccination than humans while the hierarchy in potency of single-modality (same vaccine product) prime-boost regimens using several vector approaches seem well predicted. In contrast, prime-boost vaccine regimens and vaccines using adjuvant formulations did not correlate between rhesus macaques and humans.…”

“…DNA administered intramuscularly by electroporation augmented elicited T-cell immune responses compared with needle injection. 126 While successful in macaques, 95 the adjuvant effect of added genes expressing IL-12 or IL-15 cytokines did not dramatically improve T-cell immune responses in humans. 127 The degree of live-attenuated SIV vaccine-mediated protection against SIVmac239 challenge strongly correlated with the magnitude and function of SIV-specific, effector-differentiated T cells in the lymph node but not with the responses of such T cells in the blood or with other cellular, humoral, and innate immune parameters.…”

A Novel Self-Replicating Chimeric Lentivirus-Like Particle

“…Significant advances in the fields of molecular biology, virology, and immunology have led to the development of novel vaccine technologies, including plasmid DNA vaccines, virus-like particle (VLP)-based vaccines, and recombinant viral or other microbial vaccine vectors which have been used to deliver simian immunodeficiency virus (SIV) or HIV immunogens (47). The most promising design thus far has involved the delivery of SIV or HIV genes by live, recombinant viral vectors with or without priming the immune response with plasmid DNA expressing the desired immunogen (18,26,56). Although there has been significant success in lowering viral loads after challenge with pathogenic SIV or simian-human immunodeficiency virus (SHIV) and long-term control of viremia in rhesus macaques, none of these technologies have induced complete protection against disease much less against infection (11).…”