In 2007, the Joint United Nations Programme on HIV/AIDS estimated that 33.2 million people were living with HIV/AIDS globally. The US HIV prevalence data reported in October 2008 by the Centers for Disease Control and Prevention estimates that 1.1 million adults and adolescents were living with diagnosed or undiagnosed HIV infection in the United States at the end of 2006. Nearly half of all US HIV infections (48.1%) were found in men who have sex with men (MSM). Given the difficulty of maintaining behaviors that prevent HIV transmission over a lifetime and the occurrence of non-consensual sex, the need for a safe and effective vaccine is clear. The primary purpose of this study is to determine the safety and efficacy of a VRC DNA/rAd5 vaccine regimen in healthy, at-risk, circumcised MSM.

Participants will be randomly assigned to one of two arms. Participants in Arm 1 will receive a recombinant DNA plasmid vaccine injection at study entry and on Days 28, and 56, followed by a recombinant adenoviral serotype vector vaccine injection on Day 168. Participants in Arm 2 will receive placebo injections at study entry and on Days 28, 56, and 168.

This is an event-driven study. Participants will be tested for HIV approximately every 3 months until a sufficient number of HIV infections have accumulated for assessment of the primary endpoints.

Participants who do not become HIV-infected will be actively followed for a minimum of 12 months and will continue to be contacted by the study for long-term safety surveillance for a total of 5 years following enrollment. Participants will be contacted annually during the period of long-term safety surveillance.

Participants who become HIV-infected prior to the primary evaluation time point and primary data analysis will be followed for 18 months post-diagnosis.

Participants who are infected after that point will be offered follow-up through another study.

Inclusion Criteria:

• HIV-1 and -2 negative
• Good general health
• Circumcised
• Anal intercourse within 24 weeks prior to study entry. More information on this criterion can be found in the protocol.
• ALT less than 2.6 times the upper limit of normal (ULN)
• Ad5 nAb titer less than 1:18
• Have access to a participating study site and are willing to be followed during the study
• Demonstrate understanding of the study
• Willing to receive HIV test results
• Willing to discuss HIV infection risks and amenable to risk reduction counseling

Exclusion Criteria:

• HIV vaccines in prior HIV vaccine trial. Participants who can provide documentation that they received a placebo in a prior HIV trial may be eligible.
• Used PEP more than 2 times within 12 months or has used PEP within 60 days prior to first vaccination
• Used PrEP more than 5 times within 6 months or for 30 consecutive days within 60 days prior to first vaccination
• Circumcised within 90 days prior to first vaccination or displays evidence that surgical site is not fully healed
• Immunosuppressive medications within 168 days prior to first study vaccination. Participants who have used corticosteroid nasal sprays for allergic rhinitis, topical corticosteroids for mild, uncomplicated dermatitis, or oral/parenteral corticosteroids for non-chronic conditions are not excluded.
• Blood products within 90 days prior to first study vaccination
• Immunoglobulin within 90 days prior to first study vaccination
• Live attenuated vaccines within 30 days prior to first study vaccination
• Investigational research agents within 90 days prior to first study vaccination
• Any vaccines that are not live attenuated within 14 days prior to first study vaccination
• Allergy treatment with antigen injections within 30 days prior to first study vaccination or that are scheduled within 14 days after first vaccination
• Clinically significant medical condition, abnormal physical exam findings, abnormal laboratory results, or past medical history that may affect current health. More information about this criterion can be found in the protocol.
• Any medical, psychiatric, or job-related responsibility that would interfere with the study. More information about this criterion can be found in the protocol.
• Any concern that, in the opinion of the investigator, may interfere with a participant's completion of the post-vaccination symptom log
• History of anaphylaxis or allergy to any of the vaccine's components
• Autoimmune disease
• Immunodeficiency
• Bleeding disorder
• History of malignancy
• Seizure disorder
• Asthma other than mild, well-controlled asthma. More information on this criterion can be found in the protocol.
• Angioedema within the last 3 years if episodes are considered serious or have required medication within the last 2 years prior to study entry