Inclusion Criteria:
* 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.
* 18-55 years old, inclusive, on day of enrollment.
* Available for clinic follow-up through the last clinic visit, willing to undergo lymph node fine needle aspiration and leukapheresis, and willing to be contacted 12 months after the last vaccine administration.
* Agrees not to enroll in another study of an investigational agent during participation in the trial.
* In good general health according to the clinical judgement of the site investigator.
* 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.
* Assessed as low risk for HIV acquisition per low risk guidelines (see protocol for more information), 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 PrEP (pre- exposure prophylaxis) as prescribed for 6 months or longer.
* Hemoglobin \>12.5 mg/dL to 18 mg/dL
* White blood cell (WBC) count \> 3,500/mm³
* Platelets ≥125,000 /mm³
* Alanine aminotransferase (ALT) \< 2.5 x ULN based on the institutional normal range
* Serum creatinine ≤1.1 x ULN based on the institutional normal range
* Blood pressure in the range of 90 to \< 160 mmHg systolic and 50 to \< 100 mmHg diastolic.
* Negative results for HIV infection by an FDA-approved enzyme immunoassay (EIA) or chemiluminescent microparticle immunoassay (CMIA).
* Negative for anti-Hepatitis C antibodies (anti-HCV) or negative HCV nucleic acid test (NAT) if anti-HCV antibodies are detected.
* Negative for Hepatitis B surface antigen.
* 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 8 weeks after their fifth vaccination timepoint (see Appendix E).
* Has negative β-HCG (human chorionic gonadotropin) pregnancy test (urine or serum) on day of enrollment.
Exclusion Criteria:
* Volunteer who is breast-feeding or pregnant.
* Previous or current recipient of an investigational HIV vaccine (previous placebo recipients are not excluded).
* Systemic glucocorticoid use equal to or greater than prednisone10 mg/day within 3 months prior to enrollment, congenital or acquired immunodeficiency or other systemic medication use likely to impair immune response to vaccine in the opinion of the site investigator.
* Blood products or immunoglobulin within 16 weeks prior to enrollment; receipt of immunoglobulin within 16 weeks prior to enrollment requires PSRT approval.
* Receipt of any live attenuated vaccine within 4 weeks prior to enrollment.
* Receipt of any vaccines that are not live attenuated within 14 days prior to enrollment; replication incompetent vaccines such as the Jynneos vaccine for the prevention of monkeypox disease are not considered to be live vaccines.
* ACAM2000 vaccine for Monkeypox received within 30 days prior to enrollment or receipt of study product, or if ACAM2000 received greater than 30 days prior to enrollment or receipt of study product, vaccination scab still present; or planned administration within 30 days after enrollment or receipt of study product.
* 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.
* 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.
* Serious reactions to vaccines that preclude receipt of study injections as determined by the principal investigator or designee. History of serious reaction (eg. hypersensitivity, anaphylaxis) to any vaccine or any component of the study vaccine, including imidazoquinolone (eg, imiquimod).
* Hereditary angioedema, acquired angioedema, or idiopathic forms of angioedema.
* Idiopathic urticaria within the past year.
* Bleeding disorder diagnosed by a doctor (e.g., factor deficiency, coagulopathy, or platelet disorder requiring special precautions).
* Seizure disorder; febrile seizures as a child or seizures secondary to alcohol withdrawal more than 5 years ago are not exclusionary.
* Asplenia or functional asplenia.
* Active duty and reserve US military personnel.
* 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).
* 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 \[LABA\]);
* 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.
* A participant with a history of an immune-mediated disease, either active or remote. Specific examples are listed in Appendix F (AESI index). Not exclusionary:
* remote history of Bell's palsy (\>2 years ago) not associated with other neurologic symptoms,
* mild psoriasis that does not require ongoing systemic treatment
* History of allergy to local anesthetic (Novocaine, Lidocaine).
* Investigator concern for difficulty with venous access based upon clinical history and physical examination. For example, history of IV drug abuse or substantial difficulty with previous blood draws.
