Despite advances in treatment, HIV/AIDS rates remain high in low- and middle-income countries in resource-limited areas of the world. Preventive HIV vaccines would be an effective way to decrease the spread of HIV/AIDS. This study will evaluate an experimental HIV preventive vaccine followed by booster: the PENNVAX-G DNA vaccine and the Modified Vaccinia Ankara-Chiang Mai Double Recombinant (MVA-CMDR) booster vaccine. The MVA virus is a mild form of a vaccinia virus that is used in smallpox vaccines and does not cause smallpox infection. It has been safely used in vaccines for many years. Study researchers will examine if the combination of the two vaccines will provide an effective way for the body to build a defense against HIV. The PENNVAX-G vaccine will be administered to participants using one of two devices-the Biojector 2000 needleless device or the CELLECTRA intramuscular (IM) electroporation (EP) device-to evaluate how the immune response to the vaccine changes based on the device that is used. The purpose of this study is to evaluate the safety and immunogenicity of the PENNVAX-G vaccine, administered by either Biojector 2000 injection or CELLECTRA EP, followed by an MVA-CMDR vaccine boost, in healthy, HIV-uninfected adults.

This study will be conducted in two parts. Participants in the first part of the study will attend a baseline study visit, and they will undergo blood and urine collection, a medical history review, physical examination, and HIV testing counseling. All participants will receive the PENNVAX-G vaccine at baseline and Day 28. They will be randomly assigned to receive the vaccine by either the Bioinjector 2000 needleless device or the CELLECTRA IM EP device. On Days 84 and 168, all participants will receive the MVA-CMDR vaccine by IM injection delivered via needle and syringe. Participants will remain in the clinic for 1 hour after each vaccination for observation and vital sign monitoring, and they will record their temperatures and any symptoms in a diary for 7 days after each vaccination. Study staff will contact participants 1 to 2 days after each vaccination for follow-up monitoring. In addition to the vaccination study visits, participants will attend study visits at Weeks 1, 2, 4, 5, 6, 13, 14, 25, 26, 37, 50, and 52 and will repeat the baseline study procedures.

At the conclusion of the first part of the study, participants' study data will be reviewed and the safety of the vaccine regimen will be determined. If the regimen is found to be safe, then the second part of the study will begin. Participants in the second part of the study will be randomly assigned to receive the PENNVAX-G vaccine administered by either the Bioinjector 2000 device or the CELLECTRA EP device at baseline and Day 28, followed by the MVA-CDMR boost at Days 84 and 168, or they will receive placebo PENNVAX-G vaccine administered by either the Bioinjector 2000 device or the CELLECTRA EP device at baseline and Day 28, followed by a placebo MVA-CDMR boost at Days 84 and 168. All study visits and procedures that occurred during the first part of the study will also take place in the second part of the study.

Participants in the second part of the study will have the option of enrolling in a substudy. The purpose of the substudy is to evaluate the antibody response of the reproductive tract mucosa to the PENNVAX-G DNA, MVA-CDMR, and placebo vaccines administered in the main part of study. The substudy will also evaluate the effectiveness of using the Instead Softcup as a collection method to collect vaginal secretions for testing. Mucosal specimens and urine samples will be collected from participants at the screening visit and during the Week 2, 6, 14, 26, and 50 study visits.