Inclusion Criteria:

• HIV-1 and -2 negative
• Good general health
• Fully circumcised

• Experienced one or both of the following HIV risk criteria in the 6 months before study entry:

  1. Unprotected anal intercourse with one or more male or male-to-female (MTF) transgender partner(s)
  2. Anal intercourse with two or more male or MTF transgender partners
• ALT 2.5 or less 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
• Agrees not to enroll in another study of an investigational research agent before unblinding of this study
• NOTE: MTF transgender volunteers who have undergone gender reassignment surgery (GRS) are eligible to participate if they provide documentation from a health care provider confirming that they were fully circumcised prior to GRS. MTF transgender volunteers who have not undergone GRS are eligible to participate if they meet all enrollment criteria. Receipt of hormonal therapy does not make a transgender volunteer ineligible.

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 3 or more times within 12 months or has used PEP within 60 days prior to first vaccination
• Used PrEP 6 or more 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 other than influenza vaccine within 30 days prior to first study vaccination
• Investigational research agents within 90 days prior to first study vaccination
• Influenza vaccine or 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 serious adverse reactions to vaccinations, including anaphylaxis or allergy to any of the vaccine's components
• Current anti-tuberculosis prophylaxis or therapy
• 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