Inclusion Criteria:
1. Able and willing to complete the informed consent process, including an Assessment of Understanding: volunteer demonstrates understanding of this study; completes a questionnaire prior to first vaccination with verbal demonstration of understanding of all questionnaire items answered incorrectly.
2. 18-55 years old, inclusive, on day of enrollment.
3. Agrees to comply with planned study procedures and be available for clinic follow-up through the last clinic visit.
4. Agrees not to enroll in another study of an investigational agent during participation in the trial.
5. In good general health according to the clinical judgement of the site investigator.
6. Physical examination and laboratory results without clinically significant findings that would interfere with assessment of safety or reactogenicity in the clinical judgement of the site investigator.
7. Assessed as low risk for HIV acquisition per low risk guidelines, agrees to discuss HIV infection risks, agrees to risk reduction counseling, and agrees to avoid behavior associated with high risk of HIV exposure through the final study visit. Low risk may include persons stably taking pre-exposure prophylaxis (PrEP) as prescribed for 6 months or longer.
8. Hemoglobin
* Greater than or equal to 11.0 g/dL for volunteers who were assigned female sex at birth
* Greater than or equal to 13.0 g/dL for volunteers who were assigned male sex at birth and transgender males who have been on hormone therapy for more than 6 consecutive months
* Greater than or equal to 12.0 g/dL for transgender females who have been on hormone therapy for more than 6 consecutive months
* For transgender participants who have been on hormone therapy for less than 6 consecutive months, determine hemoglobin eligibility based on the sex assigned at birth
9. White blood cell (WBC) count \> 3,500/mm3
10. Platelets ≥125,000 /mm3
11. Alanine aminotransferase (ALT) \< 2.5 x upper limit of normal (ULN) based on the institutional normal range
12. Serum creatinine ≤1.1 x ULN based on the institutional normal range
13. Negative results for HIV infection by an (US) Food and Drug Administration (FDA)-approved enzyme immunoassay (EIA) or chemiluminescent microparticle immunoassay (CMIA).
14. Negative for anti-Hepatitis C antibodies (anti-HCV) or negative HCV nucleic acid test (NAT) if anti-HCV antibodies are detected.
15. Negative for Hepatitis B surface antigen.
16. For a volunteer capable of becoming pregnant:
* Volunteers who were assigned female sex at birth and are of reproductive potential must agree to use effective means of birth control from at least 21 days prior to enrollment through 3 months after their third vaccination timepoint
* Has negative β-HCG (beta human chorionic gonadotropin) pregnancy test (urine or serum) at screening and prior to study product administration on day of enrollment.
Exclusion Criteria:
1. Volunteer who is breast-feeding or pregnant.
2. Hypertension that is not well controlled. If a person has been found to have elevated blood pressure or hypertension during screening or previously, exclude for blood pressure that is not well controlled. Well-controlled blood pressure is defined in this protocol as consistently \< 140 mm Hg systolic and \< 90 mm Hg diastolic, with or without medication, with only isolated, brief instances of higher readings, which must be ≤ 150 mm Hg systolic and ≤ 100 mm Hg diastolic. For these volunteers, blood pressure must be \< 140 mm Hg systolic and \< 90 mm Hg diastolic at enrollment. If a person has NOT been found to have elevated blood pressure or hypertension during screening or previously, exclude for systolic blood pressure ≥ 150 mm Hg at enrollment or diastolic blood pressure ≥ 100 mm Hg at enrollment.
3. Diabetes mellitus type 1 or type 2. (Not exclusionary: type 2 cases controlled with diet alone or a history of isolated gestational diabetes).
4. Previous or current recipient of an investigational HIV vaccine (previous placebo recipients are not excluded).
5. Acutely ill or febrile (temperature ≥ 38.0°C/100.4°F) on the day of the first vaccination. Participants meeting this criterion may be rescheduled within the enrollment window period. Afebrile participants with minor illnesses can be enrolled at the discretion of the Investigator.
6. Immunosuppressive medications received within 168 days before first vaccination (Not exclusionary: \[1\] corticosteroid nasal spray; \[2\] inhaled corticosteroids; \[3\] topical corticosteroids for mild, uncomplicated dermatologic condition; or \[4\] a single course of oral/parenteral prednisone or equivalent at doses \< 60 mg/day and length of therapy \< 11 days with completion at least 30 days prior to enrollment).
7. Blood products or immunoglobulin within 16 weeks prior to enrollment; receipt of immunoglobulin within 16 weeks prior to enrollment requires PSRT approval.
8. Receipt of any of the following:
* Within 4 weeks prior to enrollment:
* Any licensed live, attenuated vaccine
* Any emergency use authorized (EUA) or licensed mRNA-based SARS-CoV-2 vaccine
* Within 2 weeks prior to enrollment:
* Any licensed killed/subunit/inactivated vaccine
* Any EUA or licensed adenoviral-vectored or protein SARS-CoV-2 vaccines Receipt of any SARS-CoV-2 vaccination series should be completed 4 weeks prior to enrollment when possible; however, exceptions may be made by approval of the HVTN 302 PSRT.
9. Initiation of antigen-based immunotherapy for allergies within the previous year (stable immunotherapy is not exclusionary); inclusion of participants who initiated immunotherapy within the previous year requires PSRT approval.
10. Receipt of investigational research agents with a half-life of 7 or fewer days within 4 weeks prior to enrollment. If a potential participant has received investigational agents with a half-life greater than 7 days (or unknown half-life) within the past year, PSRT approval is required for enrollment.
11. History of serious reaction (eg, hypersensitivity, anaphylaxis) to any vaccine or any component of the study vaccine.
12. History of myocarditis and/or pericarditis.
13. Hereditary angioedema, acquired angioedema, or idiopathic forms of angioedema.
14. Idiopathic urticaria within the past year.
15. Bleeding disorder diagnosed by a doctor (eg, factor deficiency, coagulopathy, or platelet disorder requiring special precautions).
16. Seizure disorder; febrile seizures as a child or seizures secondary to alcohol withdrawal more than 5 years ago are not exclusionary.
17. Asplenia or functional asplenia.
18. Active duty and reserve US military personnel.
19. Any other chronic or clinically significant condition that in the clinical judgement of the investigator would jeopardize the safety or rights of the study participant, including, but not limited to: clinically significant forms of drug or alcohol abuse, serious psychiatric disorders, or cancer that, in the clinical judgement of the site investigator, has a potential for recurrence (excluding basal cell carcinoma).
20. Asthma is excluded if the participant has ANY of the following:
* Required either oral or parenteral corticosteroids for an exacerbation two or more times within the past year; OR
* Needed emergency care, urgent care, hospitalization, or intubation for an acute asthma exacerbation within the past year (eg, would NOT exclude individuals with asthma who meet all other criteria but sought urgent/emergent care solely for asthma medication refills or co-existing conditions unrelated to asthma); OR
* Uses a short-acting rescue inhaler more than 2 days/week for acute asthma symptoms (ie, not for preventive treatment prior to athletic activity); OR
* Uses medium-to-high-dose inhaled corticosteroids (greater than 250 mcg fluticasone or therapeutic equivalent per day), whether in single-therapy or dual-therapy inhalers (ie, with a long-acting beta agonist \[LABA\]); OR
* Uses more than one medication for maintenance therapy daily. Inclusion of anyone on a stable dose of more than one medication for maintenance therapy daily for greater than two years requires PSRT approval.
21. A participant with a history of an immune-mediated disease, either active or remote. Not exclusionary: 1) remote history of Bell's palsy (\>2 years ago) not associated with other neurologic symptoms, 2) mild psoriasis that does not require ongoing systemic treatment.
22. Immunodeficiency
