Clinical Trial to Evaluate the Safety and Immunogenicity of a Priming Regimen of 426c.Mod.Core-C4b Followed by HxB2.WT.Core-C4b Boosts, Both Adjuvanted With 3M-052 AF + Alum, in Adult Participants Without HIV and in Overall Good Health

Inclusion Criteria:

1. Demonstrates an understanding of the study and is able and willing to complete theinformed consent process.

2. 18 to 55 years old, inclusive, on day of enrollment.

3. Available for clinic follow-up through the last clinic visit, willing to undergoleukapheresis, and willing to be contacted after the last study-productadministration, including for potential participation in additional studies.

4. Agrees not to enroll in another study of an investigational agent duringparticipation in the trial. If a potential participant is already enrolled inanother clinical trial, approvals from the other trial sponsor and the HVTN 320 PSRTare required prior to enrollment into HVTN 320.

5. In good general health according to the clinical judgment of the site investigator.

6. Physical examination and laboratory results without clinically significant findingsthat would interfere with assessment of safety or reactogenicity in the clinicaljudgment of the site investigator.

7. Agrees to discuss their potential for HIV acquisition and agrees to preventioncounseling.

8. Hemoglobin (Hgb):

• ≥11.0 g/dL for AFAB volunteers

• ≥13.0 g/dL for cisgender AMAB volunteers or for volunteers who have been onmasculinizing hormone therapy for more than 6 consecutive months

• ≥12.0 g/dL for AMAB volunteers who have been on feminizing hormone therapy formore than 6 consecutive months

• For volunteers who have been on gender-affirming hormone therapy for less than 6 consecutive months, determine Hgb eligibility based on their sex assigned atbirth.

9. White blood cell (WBC) count = 2,500 to 12,000/mm3 (WBC over 12,000/mm3 is notexclusionary if further evaluation shows general good health and if PSRT approval isgranted).

10. Platelets = 125,000 to 550,000/mm3.

11. Alanine aminotransferase (ALT) < 2.5 × upper limit of institutional reference range.

12. Serum creatinine ≤ 1.1 × upper limit of normal (ULN) based on the institutionalnormal range.

13. Corrected total serum calcium level of ≥ 8.5 mg/dL. "Corrected" includes measurementof serum albumin.

14. Systolic blood pressure of 90 to < 140 mmHg and diastolic blood pressure of 50 to < 90 mmHg at screening visit. The average blood pressure between the screening visitand the enrollment visit must be below 140 mmHg systolic and 90 mmHg diastolic. Asingle measurement ≥ 160 systolic mmHg or 100 mmHg diastolic during the currentstudy evaluation is exclusionary.

15. Negative HIV test results by one of the following options:

• US Food and Drug Administration (FDA)-approved enzyme immunoassay (EIA)

• Chemiluminescent microparticle immunoassay (CMIA)

• Two negative results on HIV rapid tests (one of which must be FDA-approvedCMIA)

16. Negative for anti-hepatitis C virus (HCV) Abs (anti-HCV) or negative HCV nucleicacid test (NAT) if anti-HCV Abs are detected.

17. Negative for hepatitis B surface antigen (HBsAg).

18. For AFAB or intersex at birth volunteers who are capable of becoming pregnant (hereafter referred to as "persons of pregnancy potential"):

• Must agree to use effective means of contraception from at least 21 days priorto enrollment through 8 weeks after their last scheduled vaccination timepoint.

• Must have a negative beta human chorionic gonadotropin (β-HCG) pregnancy test (urine or serum) on day of enrollment. Note: Persons who are NOT of pregnancy potential due to total hysterectomy orbilateral oophorectomy (verified by medical records) or menopause (no menses for ≥1year) are not required to undergo pregnancy testing.

19. AFAB or intersex at birth volunteers must agree to not seek pregnancy throughalternative methods, such as oocyte retrieval, artificial insemination, or in vitrofertilization from at least 21 days prior to enrollment through 8 weeks after theirlast scheduled vaccination timepoint.

Exclusion Criteria:

1. Volunteer who is breastfeeding/chestfeeding or pregnant.

2. Body mass index (BMI) ≥ 40. Enrollment of individuals with BMI ≥ 40, whom the siteinvestigator assesses are in good health, may be considered by PSRT approval.

3. Diabetes mellitus (DM). Type 2 DM controlled with diet alone (and confirmed byHgbA1c ≤ 8% within the last 6 months) or a history of isolated gestational diabetesare not exclusionary. Enrollment of individuals with type 2 DM that is wellcontrolled on hypoglycemic agent(s) may be considered by the PSRT on a case-by-casebasis, provided that the HgbA1c is ≤ 8% within the last 6 months (sites may drawthese at screening).

4. Previous or current recipient of an investigational HIV vaccine (previousplacebo/control recipients are not excluded).

5. Receipt of non-HIV investigational vaccine(s) received within the last 1 year.Exceptions include vaccines that have subsequently undergone licensure or EmergencyUse Authorization (EUA) by the FDA or World Health Organization (WHO) Emergency UseListing (EUL), or if outside the US, by the national Regulatory Authority (RA)authorizing this clinical trial.

6. Congenital or acquired immunodeficiency, including systemic medication use likely toimpair immune response to vaccine in the opinion of the site investigator, such asglucocorticoid use, ≥ prednisone 10 mg/day within 3 months prior to enrollment.

7. Blood products or immunoglobulin within 16 weeks prior to enrollment; receipt ofimmunoglobulin within 16 weeks prior to enrollment requires PSRT approval.

8. Previous receipt of VRC01 mAb or other CD4bs mAbs.

9. Receipt of any of the following within 4 weeks prior to enrollment:

• Live replicating vaccine

• Any mRNA-based vaccine with FDA licensure, FDA EUA, or WHO EUL

• ACAM2000 vaccine > 28 days prior with a vaccination scab still present.

10. Receipt of any vaccine that is not covered in exclusion criterion #9 within 14 daysprior to enrollment. Please note this includes replication-incompetent vaccines suchas the Jynneos vaccine for the prevention of mpox (formerly known as monkeypox)disease.

11. Initiation of antigen-based immunotherapy for allergies within the previous year (stable immunotherapy is not exclusionary); inclusion of participants who initiatedimmunotherapy within the previous year requires PSRT approval.

12. Receipt of investigational research agents with a half-life of 7 or fewer dayswithin 4 weeks prior to enrollment. If a potential participant has receivedinvestigational agents with a half-life of more than 7 days (or unknown half-life)within the past year, PSRT approval is required for enrollment.

13. History of serious reaction (eg, hypersensitivity, anaphylaxis) to any relatedvaccine or component of the study-vaccine regimen (eg, imiquimod).

14. Hereditary angioedema, acquired angioedema, or idiopathic forms of angioedema.

15. Idiopathic urticaria within the past year.

16. Bleeding disorder diagnosed by a clinician that would make study procedures acontraindication.

17. History of seizure(s) within the past 3 years. Also exclude if volunteer has usedmedications to prevent or treat seizure(s) at any time within the past 3 years.

18. Asplenia or functional asplenia.

19. Active duty and reserve US military personnel.

20. Any other chronic or clinically significant condition that, in the clinical judgmentof the investigator, would jeopardize the safety or rights of the study participant,hinder their ability to participate in the study, or affect their immune responsesto study products. Such conditions include but are not limited to clinicallysignificant forms of substance use or alcohol use disorder(s), serious psychiatricdisorders, any suicide attempt within the past 1 year (if between 1 and 2 years,consult PSRT for approval), or cancer that, in the clinical judgment of the siteinvestigator, has potential for recurrence (excluding basal cell carcinoma).

21. Asthma is excluded if the participant has ANY of the following:

• Required either oral or parenteral corticosteroids for an exacerbation 2 ormore times within the past year; OR

• Needed emergency care, urgent care, hospitalization, or intubation for an acuteasthma exacerbation within the past year (eg, would NOT exclude individualswith asthma who meet all other criteria but sought urgent/emergent care solelyfor asthma medication refills or coexisting conditions unrelated to asthma); OR

• Uses a short-acting rescue inhaler more than 2 days per week for acute asthmasymptoms (ie, not for preventive treatment prior to athletic activity); OR

• Uses medium- to high-dose inhaled corticosteroids (> 250 mcg fluticasone ortherapeutic equivalent per day), whether in single-therapy or dual-therapyinhalers (ie, with a long-acting beta agonist [LABA]); OR

• Uses more than 1 medication for maintenance therapy daily. Inclusion of anyoneon a stable dose of more than 1 medication for maintenance therapy daily forgreater than 2 years requires PSRT approval.

22. A participant with a history of a PIMMC, either active or remote. Not exclusionary: (1) remote history of Bell's palsy (> 2 years ago) not associated with otherneurologic symptoms and (2) mild psoriasis or other mild, uncomplicated, localizedor dermatologic condition that does not require ongoing systemic treatment.

23. History of allergy to local anesthetic (Novocaine, Lidocaine).

24. Investigator concern for difficulty with venous access based on clinical history andphysical examination. For example, persons with a history of intravenous (IV) druguse or substantial difficulty with previous blood draws.