title: 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.
authors: International AIDS Vaccine Initiative, Design and Development Laboratory, Brooklyn Army Terminal, 140 58th Street, Brooklyn, NY 11220, USA. nwinstone@iavi.org
authors: Nicola
authors: N
authors: Winstone
authors: Aaron J
authors: AJ
authors: Wilson
authors: Gavin
authors: G
authors: Morrow
authors: Cesar
authors: C
authors: Boggiano
authors: Maria J
authors: MJ
authors: Chiuchiolo
authors: Mary
authors: M
authors: Lopez
authors: Marina
authors: M
authors: Kemelman
authors: Arielle A
authors: AA
authors: Ginsberg
authors: Karl
authors: K
authors: Mullen
authors: John W
authors: JW
authors: Coleman
authors: Chih-Da
authors: CD
authors: Wu
authors: Sandeep
authors: S
authors: Narpala
authors: Ian
authors: I
authors: Ouellette
authors: Hansi J
authors: HJ
authors: Dean
authors: Feng
authors: F
authors: Lin
authors: Niranjan Y
authors: NY
authors: Sardesai
authors: Holly
authors: H
authors: Cassamasa
authors: Dawn
authors: D
authors: McBride
authors: Barbara K
authors: BK
authors: Felber
authors: George N
authors: GN
authors: Pavlakis
authors: Alan
authors: A
authors: Schultz
authors: Michael G
authors: MG
authors: Hudgens
authors: C Richter
authors: CR
authors: King
authors: Timothy J
authors: TJ
authors: Zamb
authors: Christopher L
authors: CL
authors: Parks
authors: Adrian B
authors: AB
authors: McDermott
mesh_terms: D000256:Adenoviridae / Q000235:genetics; D000276:Adjuvants, Immunologic / Q000008:administration & dosage / Q000235:genetics; D000818:Animals; D005822:Genetic Vectors; D007117:Immunization, Secondary / Q000379:methods*; D018664:Interleukin-12 / Q000008:administration & dosage* / Q000235:genetics; D008198:Lymph Nodes / Q000821:virology; D008253:Macaca mulatta; D012367:RNA, Viral / Q000302:isolation & purification; D018449:SAIDS Vaccines / Q000008:administration & dosage / Q000276:immunology*; D016097:Simian Acquired Immunodeficiency Syndrome / Q000517:prevention & control* / Q000821:virology; D015302:Simian Immunodeficiency Virus / Q000235:genetics / Q000276:immunology*; D014611:Vaccination / Q000379:methods*; D019444:Vaccines, DNA / Q000008:administration & dosage / Q000276:immunology*; D014614:Vaccines, Synthetic / Q000008:administration & dosage / Q000276:immunology; D019562:Viral Load; D014766:Viremia / Q000517:prevention & control
chemical_list: D000276:Adjuvants, Immunologic; D012367:RNA, Viral; D018449:SAIDS Vaccines; D019444:Vaccines, DNA; D014614:Vaccines, Synthetic; D018664:Interleukin-12