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Y. or electroporation at baseline and week 4 followed by intramuscular injection of 108 plaque forming models of MVA-CMDR at weeks 12 and 24. The open-label part A was conducted in the United States, followed by a double-blind, placebo-controlled part B in East Africa. Solicited and unsolicited adverse events were recorded, and immune responses were measured. Results Eighty-eight of 100 enrolled participants completed all study injections, which were generally safe and well tolerated, with more immediate, but transient, pain in the electroporation group. Cellular responses were observed in 57% of vaccine recipients tested and were CD4 predominant. High rates of binding antibody responses to CRF01_AE antigens, including gp70 V1V2 scaffold, were observed. Neutralizing antibodies were detected in AZD-5991 Racemate a peripheral blood mononuclear cell assay, and moderate antibody-dependent, cell-mediated cytotoxicity activity was exhibited. Conversation The PVG/MVA-CMDR HIV-1 vaccine regimen is usually safe and immunogenic. Substantial differences in safety or immunogenicity between modes of DNA delivery were not observed. Clinical Trials Registration NCT01260727. Keywords: HIV vaccine, altered vaccinia Ankara, electroporation, needle-free injection An effective preventative vaccine is usually urgently needed to combat the global human immunodeficiency computer virus (HIV) epidemic. Although several advanced-stage clinical trials have been performed, only the RV144 Thai trial has shown protection against HIV type 1 (HIV-1) contamination, achieving modest efficacy with an ALVAC-HIV/AIDSVAX B/E regimen [1C6]. Poxvirus AZD-5991 Racemate vectors, such as the canarypox ALVAC-HIV, represent a encouraging strategy for vaccination against HIV-1 [7]. Modified vaccinia Ankara (MVA), a replication-deficient, attenuated vaccinia computer virus, is usually a poxvirus vector developed during the smallpox eradication campaign [8]. Human immunodeficiency computer virus vaccine regimens including MVA-vectored vaccines with and without DNA priming have been demonstrated to be safe and immunogenic in early phase clinical trials [9C17]. AZD-5991 Racemate Cognate DNA/MVA prime-boost simian immunodeficiency computer virus vaccine regimens have also shown promise in the macaque model [18C21]. Novel DNA delivery methods may improve the immunogenicity of DNA priming [22C26]: in human clinical trials, both electroporation and needle-free injection devices have demonstrated improved cellular immunogenicity in DNA-containing regimens compared with standard intramuscular injection [23, 27, 28]. In RV262, we evaluated the security and immunogenicity of PENNVAX-G (PVG) DNA, administered by Biojector 2000 (Biojector) or CELLECTRA electroporation device, boosted by altered vaccinia AnkaraCChiang Mai double recombinant (MVA-CMDR) in healthy HIV-uninfected adults in the United States and East Africa. This study represents the first-in-human experience of PVG DNA delivered by either method and of the PVG DNA/MVA-CMDR prime-boost combination. It is also the first direct comparison of HIV DNA administration by electroporation or needle-free injection device. METHODS Participants and Study Design The study was a multicenter, randomized trial to evaluate security and immunogenicity of a prime-boost regimen of 4 mg of PVG DNA delivered intramuscularly by needle-free AZD-5991 Racemate injection or electroporation at baseline (week 0) and 4 weeks, followed by intramuscular injection of 108 plaque-forming models of MVA-CMDR at 12 and 24 weeks (Supplementary Table 1). The open-label part A was conducted in Rockville, Maryland. Security evaluation of part A was performed before initiation of part B, which was placebo controlled and conducted in Kampala, Uganda; Kericho, Kenya; and Mbeya, Tanzania. Study participants were healthy, at low risk of HIV acquisition, and experienced normal baseline electrocardiograms. The protocol was approved by institutional and ethical review boards at the Walter Reed Army Institute of Research, Kenya Medical Research Institute, Tanzanian National Institute of Medical Research, and Ugandan National HIV/AIDS Research Committee. Written informed consent was obtained from each participant. The study was registered at ClinicalTrials.gov (NCT01260727). All vaccines were administered in the deltoid muscle mass. Except for the assessment of immediate pain, reactogenicity was assessed at 45 moments, 6 hours, and then daily for 6 days after injection. Adverse events were recorded at all study visits from baseline to study completion. After screening, laboratory monitoring included routine hematology, chemistry, and creatine phosphokinase measured at weeks 0, 2, 6, 12, 14, 24, 26, 37, and 50, with troponin I measured 2 weeks after each MVA/placebo injection. Immunogenicity assessments were performed on cryopreserved specimens collected at baseline and at weeks 6, 14, 26, and 50. All participants provided phlebotomy specimens for ELISpot and binding antibody evaluations; a subset were selected for additional evaluation by intracellular cytokine staining (ICS), neutralizing antibody (NAb), and antibody-dependent cell-mediated Rabbit Polyclonal to BORG3 cytotoxicity (ADCC) assays. Participants were given the option of participating in a mucosal substudy that collected semen and cervico-vaginal mucus for quantification of binding antibodies. Cervico-vaginal mucus was collected using the Instead Softcup (The Flex Organization, Venice, CA). Vaccine Product and Delivery PENNVAX-G is usually a mixture of 4 DNA plasmids that encode consensus HIV immunogens selected to develop an internationally.