The clinical study is designed to evaluate the ability of two priming vaccine regimens to activate and induce the maturation of cross-reactive CD4 binding site (CD4-bs) antibodies, including VRC01-class antibodies. VRC01- class antibodies are highly desirable to elicit via vaccination because they have broad cover all clades of HIV and passive administration of VRC01 monoclonal antibodies has been demonstrated to prevent acquisition of susceptible HIV strains in clinical trials. The study will assess whether B cells expressing VRC01-like B cell receptors proliferate following immunization with a 'germline-targeting' recombinant Env immunogen. The study will also test whether an immunization strategy based upon fractionated dose delivery of the immunogen may improve the maturation of VRC01-class B cells when compared to traditional bolus dosing. In addition, the study will test whether alterations in the dose of the subsequent boost immunizations affects VRC01-class B cell activation and the rate of antibody affinity maturation.

The primary hypothesis of the optional boost regimen is that BG505 SOSIP.GT1.1 gp140 adjuvated with 3M-052-AF + Alum is safe and well-tolerated and will further mature B-cell lineages elicited by 426c.Mod.Core-C4b priming regimens.

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 any questionnaire items answered incorrectly.

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

3. Available for clinic follow-up through the last clinic visit, willing to under go lymph node fine needle aspiration, and willing to be contacted 12 months after the last vaccine administration.

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:

   • ≥ 11.0 g/dL for volunteers who were assigned female sex at birth
   • ≥ 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
   • ≥ 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. Blood pressure in the range of 90 to ≤ 150 mmHg systolic and 50 to ≤ 95 mmHg diastolic.

14. Negative results for HIV infection by an FDA-approved enzyme immunoassay(EIA) or chemiluminescent microparticle immunoassay (CMIA).

15. Negative for anti-Hepatitis C antibodies (anti-HCV) or negative HCV nucleic acid test (NAT) if anti-HCV antibodies are detected.

16. Negative for Hepatitis B surface antigen.

17. 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 last vaccination timepoint.
    • Has negative β-HCG (human chorionic gonadotropin) pregnancy test (urine or serum) on day of enrollment.

Exclusion Criteria:

1. Volunteer who is breast-feeding or pregnant.

2. Morbid Obesity. Enrollment of individuals with body mass index (BMI) ≥40, who the site investigator assesses are in good health, may be considered by PSRT on a case-by-case basis.

3. Diabetes mellitus (DM). Type 2 DM, controlled with diet alone, or a history of isolated gestational diabetes are not exclusionary. Enrollment of individuals with Type 2 DM that is well-controlled on hypoglycemic agent(s) may be considered, provided the HgbA1c is ≤8% within the last 6 months (sites may draw these at screening).

4. International normalized ratio (INR) >1.2.

5. Previous or current recipient of an investigational HIV vaccine (previous placebo recipients are not excluded).

6. Receipt of non-HIV experimental vaccine(s) received within the last 1 year. Exceptions may be made by the PSRT for vaccines that have subsequently undergone licensure or Emergency Use Authorization by the FDA or, if outside the United States, by the national regulatory authority or World Health Organization. For volunteers who have received control/placebo in an experimental vaccine trial, the PSRT will determine eligibility on a case-by-case basis.

7. Systemic glucocorticoid use equal to or greater than prednisone 10 mg/day within 3 months prior to enrollment, other systemic medication use likely to impair immune response to vaccine in the opinion of the site investigator, or congenital or acquired immunodeficiency.

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

9. Previous receipt of VRC01 monoclonal antibody.

10. Receipt of any live replicating vaccine within 4 weeks prior to enrollment. For receipt of ACAM2000 vaccine >28 days prior with a vaccination scab still present.

11. Receipt of any vaccines that are not covered in exclusion criterion #10 within 14 days prior to enrollment. Please note this includes replication incompetent vaccines such as the Jynneos vaccine for the prevention of monkeypox disease

12. 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.

13. 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.

14. History of serious reaction (eg, hypersensitivity, anaphylaxis) to any vaccine or any component of the study vaccine, including imidazoquinolone (eg, imiquimod).

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

16. Idiopathic urticaria within the past year.

17. Bleeding disorder diagnosed by a doctor (eg, factor deficiency, coagulopathy, or platelet disorder requiring special precautions).

18. Seizure disorder; febrile seizures as a child or seizures secondary to alcohol withdrawal more than 5 years ago are not exclusionary.

19. Asplenia or functional asplenia.

20. Active duty and reserve US military personnel.

21. 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).

22. 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.

23. 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.

24. 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.

Whether a participant receives a bolus dose or fractionated dose will be known, but randomization will occur within a given arm and both participants and clinicians will be blinded within a given arm.