A Trial to Evaluate an HIV Envelope Trimer, N332-GT5 gp140, Adjuvanted With SMNP in Adult Participants Without HIV

Inclusion Criteria:

General and demographic criteria:

1. Age of 18 through 55 years

2. Access to a participating HVTN Clinical Research Site (CRS) and willingness to befollowed for the planned duration of the study

3. Ability and willingness to provide informed consent

4. Assessment of Understanding (AoU): Volunteer demonstrates understanding of thisstudy by completing a questionnaire prior to the first vaccination with verbaldemonstration of understanding of all questionnaire items answered incorrectly

5. Agrees not to enroll in another study of an investigational research agent untilcompletion of the study

6. Good general health as shown by medical history, physical exam, and screeninglaboratory tests HIV-related criteria:

7. Willingness to receive HIV test results

8. Willingness to discuss HIV risks and amenable to HIV risk-reduction counseling

9. Assessed by the clinic staff as having a low likelihood of acquiring HIV and iscommitted to avoiding behaviors associated with a higher likelihood of acquiring HIVthrough the last required protocol clinic visit Laboratory inclusion values Criteria:

10. Hemoglobin (Hgb)

• ≥ 11.0 g/dL for volunteers who were assigned female sex at birth (AFAB)

• ≥ 13.0 g/dL for volunteers who were assigned male sex at birth (AMAB) andtransgender men who have been on hormone therapy for more than 6 consecutivemonths

• ≥ 12.0 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

11. White blood cell (WBC) count = 2500 to 12000 cells/mm3 with normal differential, ordifferential approved by Investigator of Record (IoR) as not clinically significant

12. Total lymphocyte count ≥ 650 cells/mm3 with normal differential, or differentialapproved by IoR as not clinically significant

13. Remaining differential either within local lab reference range or with sitephysician approval

14. Platelets = 125000 to 550000 cells/mm3

15. Chemistry panel: Alanine aminotransferase (ALT) < 1.25 times the institutional upperlimit of normal (ULN); serum creatinine ≤ 1.1 x ULN based on the local lab referencerange.

16. Corrected total serum calcium level of ≥ 8.5 mg/dL

17. Negative HIV-1 and -2 blood test: US volunteers must have a negative FDA-approvedenzyme immunoassay (EIA) or chemiluminescent microparticle immunoassay (CMIA)

18. Negative Hepatitis B surface antigen (HBsAg)

19. Negative anti-Hepatitis C virus antibodies (anti-HCV), or negative HCV nucleic acidtest (NAT) if the anti-HCV is positive. Reproductive status criteria:

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

• Must agree to use effective means of contraception for sexual activity thatcould lead to pregnancy from at least 21 days prior to enrollment and 4 weeksafter their last scheduled vaccination timepoint.

• Must have a negative beta human chorionic gonadotropin (β-HCG) pregnancy test (urine or serum) at screening (ie, prior to randomization, if applicable) andprior to study-product administration on the day of study-productadministration. (Persons of pregnancy potential require a pregnancy test priorto injection 1 of the fractionated escalating dose series)

• Persons who are NOT of pregnancy potential due to having undergone hysterectomyor bilateral oophorectomy (verified by medical records) or having reachedmenopause (no menses for 1 year) are not required to undergo pregnancy testing.

21. AFAB volunteers or volunteers who were intersex at birth must also agree not to seekpregnancy through alternative methods, such as oocyte retrieval, artificialinsemination or in vitro fertilization until after the last required protocol clinicvisit.

Exclusion Criteria:

General criteria:

1. Blood products received within 120 days before first vaccination

2. Investigational research agents received within 30 days before first vaccination

3. Body mass index (BMI) ≥ 40, or BMI ≥ 35 with 2 or more of the following: Age > 45,systolic blood pressure > 140 mm Hg, diastolic blood pressure > 90 mm Hg, currentsmoker, known hyperlipidemia

4. Intent to participate in any other study that requires non-HVTN HIV Ab testingduring the planned duration of the HVTN 144 study

5. Pregnant or breastfeeding

6. Active duty and reserve US military personnel Vaccines and other injections criteria:

7. HIV vaccine(s) received in a prior HIV vaccine trial. For volunteers who havereceived control/placebo in an HIV vaccine trial, the HVTN 144 Protocol SafetyReview Team (PSRT) will determine eligibility on a case-by-case basis.

8. Previous receipt of monoclonal antibodies (mAbs), whether licensed orinvestigational. Exceptions may be made by the HVTN 144 PSRT on a case-by-casebasis.

9. Non-HIV experimental vaccine(s) received within the last 1 year in a prior vaccinetrial. Exceptions may be made by the HVTN 144 PSRT for vaccines that havesubsequently undergone licensure by the FDA. For volunteers who have receivedcontrol/placebo in an experimental vaccine trial, the HVTN 144 PSRT will determineeligibility on a case-by-case basis. For volunteers who have received anexperimental vaccine(s) more than 1 year ago, eligibility for enrollment will bedetermined by the HVTN 144 PSRT on a case-by-case basis.

10. Live attenuated vaccines received within 30 days before the first vaccination orscheduled within 28 days after injection (eg, measles, mumps, and rubella (MMR);oral polio vaccine (OPV); varicella; yellow fever; live attenuated influenzavaccine). ACAM2000 vaccine >28 days prior with a vaccination scab still present.

11. Any vaccines that are not live attenuated vaccines and were received within 14 daysprior to the first vaccination (eg, tetanus, pneumococcal, Hepatitis A or B). Pleasenote this includes incompetent vaccine such as the Jynneos vaccine for theprevention of mpox disease.

12. Allergy treatment with antigen injections within 30 days before the firstvaccination or that are scheduled within 14 days after the first vaccination Immune system criteria:

13. Immunosuppressive medications received within 168 days before first vaccination (notexclusionary: [1] corticosteroid nasal spray; [2] inhaled corticosteroids; [3]topical corticosteroids for mild, uncomplicated dermatologic condition; or [4] asingle course of oral/parenteral prednisone or equivalent at doses < 60 mg/day andlength of therapy < 11 days with completion at least 30 days prior to enrollment)

14. Serious adverse reactions to vaccines or to vaccine components such as AS01B ("Shingrix") or Matrix M (Novovax CoV2373), including history of anaphylaxis andrelated symptoms, such as hives, respiratory difficulty, angioedema, and/orabdominal pain (not exclusionary: a volunteer who had a nonanaphylactic adversereaction to pertussis vaccine as a child).

15. IgG received within 60 days before first vaccination (for mAbs, see criterion #8above)

16. Autoimmune disease, current or history (not exclusionary: mild, well-controlledpsoriasis)

17. AESIs: Volunteers who currently have, or have a history of, any condition that couldbe considered an AESI for the product(s) administered in this protocol.

18. Immunodeficiency Clinically significant medical conditions criteria:

19. Clinically significant medical condition, physical examination findings, clinicallysignificant abnormal laboratory results, or past medical history with clinicallysignificant implications for current health. A clinically significant condition orprocess includes but is not limited to:

• A process that would affect the immune response,

• A process that would require medication that affects the immune response,

• Any contraindication to repeated injections or blood draws,

• A condition that requires active medical intervention or monitoring to avertgrave danger to the volunteer's health or well-being during the study period,

• A condition or process for which signs or symptoms could be confused withreactions to vaccine, or

• Any condition specifically listed among the exclusion criteria below.

20. Any medical, occupational, or other condition that, in the judgment of theinvestigator, would interfere with, or serve as a contraindication to, protocoladherence, assessment of safety or reactogenicity, or a volunteer's ability to giveinformed consent

21. Psychiatric condition that precludes compliance with the protocol. Specificallyexcluded are persons with psychoses within the past 3 years, ongoing risk forsuicide, or history of suicide attempt or gesture within the past 3 years.

22. Current anti-tuberculosis (TB) prophylaxis or therapy

23. Asthma exclusion criteria: 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/week for acute asthmasymptoms (ie, not for preventive treatment prior to athletic activity); OR

• Uses medium- to high-dose inhaled corticosteroids (greater than 250 mcgfluticasone or therapeutic equivalent) or more than 1 medication formaintenance therapy daily. For example, potential participants takinglong-acting bronchodilator/inhaled corticosteroid combinations for dailymaintenance are excluded (note: maintenance monotherapy with cromolyn,leukotriene receptor antagonist, or theophylline is not exclusionary).

24. Diabetes mellitus type 1 or type 2 (not exclusionary: type 2 cases controlled withdiet alone or a history of isolated gestational diabetes)

25. Thyroidectomy, or thyroid disease requiring medication during the last 12 months (not exclusionary: well-controlled non-autoimmune thyroid disease)

26. Hypertension: The average systolic blood pressure between the screening visit andthe enrollment visit must be below 140 mmHg. The average diastolic blood pressurebetween the screening visit and the enrollment visit must be below 90 mmHg. A singlemeasurement greater than or equal to 160 mmHg systolic or 100 mmHg diastolic duringthe current study evaluation is exclusionary.

27. Bleeding disorder (eg, factor deficiency, coagulopathy, or platelet disorderrequiring special precautions)

28. Malignancy (not exclusionary: volunteer who has had malignancy excised surgicallyand who, in the investigator's estimation, has a reasonable assurance of sustainedcure, or who is unlikely to experience recurrence of malignancy during the period ofthe study)

29. Seizure disorder: History of seizure(s) within past 3 years. Also exclude ifvolunteer has used medications in order to prevent or treat seizure(s) at any timewithin the past 3 years.

30. Asplenia: Any condition resulting in the absence of a functional spleen

31. History of angioedema or anaphylaxis (not exclusionary: angioedema or anaphylaxiswith known trigger and no episodes within 5 years)

32. History of generalized urticaria within past 5 years