The Study of Immunization in People Living With HIV Undergoing an ATI for Elicitation of VRC01-lineage Antibodies

Inclusion Criteria:

1. Able and willing to complete the informed consent process, including an Assessmentof Understanding (AoU): Volunteer demonstrates an understanding of this study andcompletes a questionnaire prior to first vaccination with verbal demonstration ofunderstanding of questionnaire items that were answered incorrectly.

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

3. Confirmed HIV infection as documented by medical records or confirmatory HIV testingat screening.

4. On suppressive ART for at least 48 weeks prior to screening. ART is defined as acombination therapy regimen including at least 1 integrase inhibitor and 1nucleoside reverse transcriptase inhibitor (such as Dovato™) or 2 nucleoside reversetranscriptase inhibitors plus integrase inhibitors. Changes in ARVs for reasonsother than virologic failure (eg, tolerability, simplification, differentformulation, drug-drug interaction profile) are allowed within 48 weeks prior toscreening and up until 6 weeks prior to screening. A fully active alternative ARVregimen is available, in the opinion of the Investigator, in the event ofdiscontinuation of the current ARV regimen with development of resistance.

5. Plasma HIV RNA < 50 copies/mL (or lower limit of quantitation [LLOQ]) for at least 48 weeks prior to enrollment. NOTE: At least one viral load measurement within 48weeks prior to the screening visit and another viral load from the screening priorto enrollment visit must be available for review. Two "blips" (ie, plasma HIV-1 RNA > LLOQ and < 400 copies/mL) are allowed if each blip is preceded and followed byvalues < LLOQ and if the blip(s) occur(s) more than 24 weeks prior to enrollment.

6. CD4+ cell count > 450 cells/mm3 and CD4+ cell % ≥ 15% obtained within 40 days priorto enrollment.

7. Available for clinic follow-up through the last clinic visit, willing to undergoleukapheresis, and willing to be contacted 12 months after the last study-productadministration.

8. 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 807 PSRTare required prior to enrollment into HVTN 807.

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

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

11. Total serum calcium of ≥ 8.5 mg/dL.

12. Hemoglobin (Hgb):

• ≥ 10.0 g/dL for volunteers who were assigned female sex at birth (AFAB)

• ≥ 11.0 g/dL for cisgender volunteers who were assigned male sex at birth (AMAB)and for transgender men who have been on hormone therapy for more than 6consecutive months

• ≥ 11.0 g/dL for transgender women who have been on hormone therapy for morethan 6 consecutive months

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

13. Absolute neutrophil count (ANC) ≥ 750/mm3

.

14. Platelets ≥ 100,000/mm3

.

15. Alanine aminotransferase (ALT) < 2.5 x upper limit of normal (ULN) based on theinstitutional normal range and direct bilirubin within the institutional range ofnormal.

16. Estimated glomerular filtration rate (eGFR) ≥ 60 mL/min/1.73m2 as calculated usingthe Chronic Kidney Disease Epidemiology Collaboration (CKD-Epi) equation.

17. For Group 1 volunteers: must agree to consistently use condoms from study week 14through until viral load post-ATI is undetectable (at a minimum 20 weeks on study,at a maximum 64 weeks on study).

18. For Group 1 volunteers

• Persons of pregnancy potential

• Must have a negative beta human chorionic gonadotropin (β-HCG) pregnancytest (urine or serum) on day of enrollment.

• Must agree to use effective means of contraception from at least 21 daysprior to enrollment until at least 8 weeks post last vaccination and viralload post-ATI is undetectable (at a minimum 20 weeks on study, at amaximum 64 weeks on study).

• Volunteers who are AFAB or intersex at birth must agree to not seek pregnancythrough alternative methods, such as oocyte retrieval, artificial insemination,or in vitro fertilization from at least 21 days prior to enrollment throughuntil viral load post-ATI is undetectable (at a minimum 20 weeks on study, at amaximum 64 weeks on study).

19. For Group 2 volunteers

• Persons of pregnancy potential:

• Must have a negative β-HCG pregnancy test (urine or serum) on day ofenrollment.

• Must agree to use effective means of contraception from at least 21 daysprior to enrollment until 8 weeks after their last scheduled vaccination (study week 20).

• Volunteers who are AFAB or intersex at birth must agree to not seek pregnancythrough alternative methods, such as oocyte retrieval, artificial insemination,or in vitro fertilization from at least 21 days prior to enrollment through 8weeks after their last scheduled vaccination timepoint.

Exclusion Criteria:

1. Current receipt of ART other than nucleoside reverse transcriptase inhibitor andintegrase inhibitor.

2. Receipt of long-acting ART within 3 months of enrollment.

3. Documented history of resistance to any components of the current ARV regimen.

4. Known resistance to 1 or more drugs in 2 or more ARV drug classes. NOTE: M184V/I isan exception and should not be considered when assessing this criterion. Prior HIVresistance testing is not required.

5. ART initiation during acute HIV-1 infection (defined as within 1 year of HIV-1acquisition, if known).

6. History of an HIV-associated malignancy (including Kaposi's sarcoma), and any typeof lymphoma or virus-associated cancers.

7. History of HIV-associated neurocognitive disease or progressive multifocalleukoencephalopathy.

8. History of HIV-related illness under US Centers for Disease Control (CDC) Category C (except for recurrent pneumonia) within 10 years prior to screening, based onavailable medical history and assessed by the Investigator for clinical relevance.Anyone with a history of CD4 < 200 cells/mm3 on one or more occasions, based onavailable medical history and assessed by the Investigator for clinical relevance.Documentation of every case with history of CD4 < 200 cells/mm3 must be provided tothe Sponsor and PSRT, who will determine eligibility on a case-by-case basis. NOTE:History of treated and resolved pulmonary tuberculosis (TB) will not beexclusionary.

9. Active or recent non-HIV-associated malignancy requiring systemic chemotherapy orsurgery within 36 months prior to enrollment or for whom such therapies are expectedin the subsequent 12 months. NOTE: Minor surgical removal of localized skin cancers (squamous cell carcinoma, basal cell carcinoma) is not exclusionary.

10. Hepatitis B or C infection as indicated by the presence of Hepatitis B surfaceantigen (HBsAg), hepatitis C antibody without documented history of prior treatmentand clearance, or hepatitis C virus RNA (HCV-RNA) in blood.

11. Diagnosis of cirrhosis.

12. Current untreated or incompletely treated active TB disease or untreated latent TBinfection. NOTE: Individuals who are on treatment for latent TB with at least 4weeks of treatment completed are not excluded.

13. Volunteer who is breastfeeding or pregnant.

14. 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.

15. 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

16. History of or current clinical atherosclerotic cardiovascular disease (ASCVD), asdefined by 2013 American College of Cardiology/American Heart Association (ACC/AHA)guidelines, including a previous diagnosis of any of the following:

• Acute myocardial infarction

• Acute coronary syndromes

• Stable or unstable angina

• Coronary or other arterial revascularization

• Stroke

• Transient ischemic attack

• Peripheral arterial disease presumed to be of atherosclerotic origin

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

18. Receipt of non-HIV experimental 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.

19. Congenital or acquired immunodeficiency, including systemic medication use likely toimpair immune response to vaccine in the opinion of the site investigator, such ashistory of systemic corticosteroids (long-term use), immunosuppressive anti-canceror other immunosuppressive agents, interleukins, systemic interferons, systemicchemotherapy, or other medications considered significant by the investigator withinthe 24 weeks prior. Note: HIV is not exclusionary.

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

21. Previous receipt of any anti-HIV monoclonal antibody.

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

• Live replicating vaccines

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

• ACAM2000 vaccine > 30 days prior with a vaccination scab still present.

23. Receipt of any vaccines that are not covered in #22 above within 14 days prior toenrollment. Please note this includes replication incompetent vaccines such as theJynneos vaccine for the prevention of mpox (formerly known as monkeypox) disease.

24. Initiation of antigen-based immunotherapy (AIT) for allergies within the previousyear (stable immunotherapy is not exclusionary); inclusion of participants whoinitiated immunotherapy within the previous year requires PSRT approval. Note: AnyAIT should be scheduled at least 14 days prior to enrollment.

25. 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 greater than 7 days (or unknownhalf-life) within the past year, PSRT approval is required for enrollment.

26. History of serious reaction (eg, hypersensitivity, anaphylaxis) to any vaccine orcomponent of the study vaccine, including imidazoquinolone (eg, imiquimod).

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

28. Idiopathic urticaria within the past year.

29. Bleeding disorder diagnosed by a clinician which would make study procedures acontraindication (eg, factor deficiency, coagulopathy, platelet disorder requiringspecial precautions).

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

31. Asplenia or functional asplenia.

32. Active duty and reserve US military personnel.

33. Any other chronic or clinically significant condition that, in the clinical judgmentof the investigator, would jeopardize the safety or rights of the study participant,including but not limited to: clinically significant forms of substance use oralcohol use disorder(s), serious psychiatric disorders, persons with any suicideattempt within the past 1 year (if between 1 and 2 years, consult PSRT forapproval), or cancer that, in the clinical judgement of the site investigator, haspotential for recurrence (excluding basal cell carcinoma).

34. A participant with a history of a potential immune-mediated medical condition (PIMMC), either active or remote. Specific examples are listed in Appendix I (AESIIndex). Not exclusionary: 1) Remote history of Bell's palsy (> 2 years ago) notassociated with other neurologic symptoms and 2) mild psoriasis that does notrequire ongoing systemic treatment.

35. Investigator concern for difficulty with venous access based on clinical history andphysical examination. For example, persons with a history of intravenous drug use orsubstantial difficulty with previous blood draws.