Inclusion Criteria
* Age of 18 to 35 years
* Sexually active, defined as having had sexual intercourse at least twice in the past 30 days prior to screening, and is considered by the site staff to be at risk for HIV infection.
* Access to a participating HVTN CRS and willingness to be followed for the planned duration of the study
* Ability and willingness to provide informed consent
* Assessment of understanding: volunteer demonstrates understanding of this study prior to first vaccination with verbal demonstration of understanding of all questions.
* Agrees not to enroll in another study of an investigational research agent until the participant is unblinded or their study participation ends, whichever occurs last
* Good general health as shown by medical history, physical exam, and screening laboratory tests
* Willingness to receive HIV test results
* Willingness to discuss HIV infection risks and willing to receive HIV risk reduction counseling.
* Alanine aminotransferase (ALT) \< 2.5 times the institutional upper limit of normal
* Negative HIV-1 and -2 blood test within 30 days prior to enrollment: Sites may use locally available assays that have been approved by HVTN Laboratory Operations.
* Volunteers who were born female: negative serum or urine beta human chorionic gonadotropin (β-HCG) pregnancy test performed prior to vaccination on the day of initial vaccination. Persons who are NOT of reproductive potential due to having undergone total hysterectomy or bilateral oophorectomy (verified by medical records), are not required to undergo pregnancy testing.
* Reproductive status: A volunteer who was born female must:
* Agree to consistently use effective contraception (Appendix B and Appendix C) for sexual activity that could lead to pregnancy from at least 21 days prior to enrollment through 3 months after the last vaccination. Effective contraception is defined as using 2 methods of birth control. These include 1 of the following methods:
* Condoms (male or female)
* Diaphragm or cervical cap
PLUS 1 of the following methods:
* Intrauterine device (IUD),
* Hormonal contraception (in accordance with applicable national contraception guidelines), or
* Successful vasectomy in the male partner (considered successful if a volunteer reports that a male partner has \[1\] documentation of azoospermia by microscopy, or \[2\] a vasectomy more than 2 years ago with no resultant pregnancy despite sexual activity postvasectomy), or
* Any other contraceptive method approved by the protocol safety review team;
* Or not be of reproductive potential, such as having been diagnosed with premature menopause (with no menses for 1 year) or having undergone hysterectomy, bilateral oophorectomy, or tubal ligation.
* Volunteers who were born female must also agree not to seek pregnancy through alternative methods, such as artificial insemination or in vitro fertilization until 3 months after the last vaccination
Exclusion Criteria
* Blood products received within 90 days before first vaccination
* Investigational research agents received within 30 days before first vaccination
* Intent to participate in another study of an investigational research agent or any other study that requires non-HVTN HIV antibody testing during the planned duration of the study
* Pregnant or breastfeeding
* HIV vaccine(s) received in a prior HIV vaccine trial. For volunteers who have received control/placebo in an HIV vaccine trial, the HVTN 702 PSRT will determine eligibility on a case-by-case basis.
* Non-HIV experimental vaccine(s) received within the last 5 years in a prior vaccine trial. Exceptions may be made for vaccines that have subsequently undergone licensure. For volunteers who have received control/placebo in an experimental vaccine trial, the protocol safety review team will determine eligibility on a case-by-case basis. For volunteers who have received an experimental vaccine(s) greater than 5 years ago, eligibility for enrollment will be determined by the protocol safety review team on a case-by-case basis.
* Live attenuated vaccines other than influenza vaccine received within 30 days before first vaccination or scheduled within 14 days after injection (eg, measles, mumps, and rubella \[MMR\]; oral polio vaccine \[OPV\]; varicella; yellow fever)
* Influenza vaccine or any vaccines that are not live attenuated vaccines and were received within 14 days prior to first vaccination (eg, tetanus, pneumococcal, Hepatitis A or B)
* Immunosuppressive medications received within 168 days before first vaccination. (Not exclusionary: \[1\] corticosteroid nasal spray; \[2\] inhaled corticosteroids; \[3\] topical corticosteroids for mild, uncomplicated dermatitis; or \[4\] a single course of oral/parenteral corticosteroids at doses \< 2 mg/kg/day and length of therapy \< 11 days with completion at least 30 days prior to enrollment.)
* Serious adverse reactions to vaccines or to vaccine components such as eggs, egg products, or neomycin including history of anaphylaxis and related symptoms such as hives, respiratory difficulty, angioedema, and/or abdominal pain. (Not excluded from participation: a volunteer who had a non-anaphylactic adverse reaction to pertussis vaccine as a child.)
* Immunoglobulin received within 60 days before first vaccination
* Immunodeficiency
* Clinically significant medical condition, physical examination findings, clinically significant abnormal laboratory results, or past medical history with clinically significant implications for current health. A clinically significant condition or process includes but is not limited to:
* A process that would affect the immune response,
* A process that would require medication that affects the immune response,
* Any contraindication to repeated injections or blood draws,
* A condition that requires active medical intervention or monitoring to avert grave danger to the volunteer's health or well-being during the study period,
* A condition or process for which signs or symptoms could be confused with reactions to vaccine, or
* Any condition specifically listed among the exclusion criteria below.
* Any medical, psychiatric, occupational, or other condition that, in the judgment of the investigator, would interfere with, or serve as a contraindication to, protocol adherence, assessment of safety or reactogenicity, or a volunteer's ability to give informed consent
* Psychiatric condition that precludes compliance with the protocol. Specifically excluded are persons with psychoses within the past 3 years, ongoing risk for suicide, or history of suicide attempt or gesture within the past 3 years.
* Active tuberculosis (TB) disease
* Uncontrolled hypertension: systolic blood pressure (SBP) ≥ 160 mm Hg or diastolic blood pressure (DBP) ≥ 100 mm Hg
* Bleeding disorder (diagnosed by a doctor) contraindicating IM injection and/or blood draws, based on investigator's judgment
* Malignancy (Not excluded from participation: Volunteer who has had malignancy excised surgically and who, in the investigator's estimation, has a reasonable assurance of sustained cure or who is unlikely to experience recurrence of malignancy during the period of the study)
* History of hereditary angioedema, acquired angioedema, or idiopathic angioedema
