The purpose of the study is to evaluate the safety, tolerability, and immunogenicity of polyvalent env (A,B,C,A/E)/gag (C) DNA prime and gp120 (A,B,C,A/E) protein HIV-1 vaccines boost (PDPHV) with either Alhydrogel or GLA-SE in healthy, HIV-uninfected adults.

Volunteers will receive either the PDPHV or the placebo (normal saline) by intramuscular injections. Some volunteers will receive Alhydrogel and others will receive GLA-SE as part of the protein boost.

Participants will be enrolled in Group 1 to group 5. Within each group, participants will be randomly assigned to either Treatment or Placebo Control.

Group 1 (Sentinel group) will be enrolled first to test the safety of the protein vaccines mixed with the Alhydrogel adjuvant. Participants in Group 1 (Treatment) will receive polyvalent gp120 (A, B, C, A/E) protein vaccines mixed with Alhydrogel in the non-dominant arm at months 0, and 3. Participants in Group 1 (Control) will receive placebo at months 0, and 3.

The Safety Monitoring Board (SMB) will evaluate the safety profile of volunteers in Group 1 in two weeks after the 2nd dose. The Alhydrogel adjuvanted Protein Vaccines boosts in group 2 and group 4 can only proceed after SMB reviews the safety data from Group 1 and approves to the use of Alhydrogel in these studies.

Participants in Group 2 (Treatment) will receive env (A, B, C, A/E)/gag (C) DNA Vaccines in the dominant arm at months 0, and 1, followed by gp120 (A, B, C, A/E) Protein Vaccines mixed with Alhydrogel boosts in the non-dominant arm at Months 3, and 6. Participants in Group 2 (Control) will receive placebo at Months 0, 1, 3, and 6.

Participants in Group 3 (Treatment) will receive env (A, B, C, A/E)/gag (C) DNA Vaccines in the dominant arm at months 0, and 1, followed by gp120 (A, B, C, A/E) Protein Vaccines mixed with GLA-SE boosts in the non-dominant arm at Months 3, and 6. Participants in Group 3 (Control) will receive placebo at Months 0, 1, 3, and 6.

Participants in Group 4 (Treatment) will receive env (A, B, C, A/E)/gag (C) DNA Vaccines in the dominant arm at months 0, and 1, followed by gp120 (A, B, C, A/E) Protein Vaccines mixed with Alhydrogel boosts in the non-dominant arm AND env (A, B, C, A/E)/gag (C) DNA Vaccines in the dominant arm at Months 3, and 6. Participants in Group 4 (Control) will receive placebo at Months 0, 1, 3, and 6.

Participants in Group 5 (Treatment) will receive env (A, B, C, A/E)/gag (C) DNA Vaccines in the dominant arm at months 0, and 1, followed by gp120 (A, B, C, A/E) Protein Vaccines mixed with GLA-SE boosts in the non-dominant arm AND env (A, B, C, A/E)/gag (C) DNA Vaccines in the dominant arm at Months 3, and 6. Participants in Group 5 (Control) will receive placebo at Months 0, 1, 3, and 6.

Study visits for participants in Group 1 will occur at Months 0, 0.5, 3, 3.5, 6, 9, and 15. Study visits for participants in Group 2 to Group 5 will occur at Monthes 0, 0.5, 1, 1.5, 3, 3.5, 6, 6.5, 12 and 18. Visits may include physical examination, blood and urine collection, HIV testing, risk reduction counselling, and questionnaires.

Inclusion Criteria:

1. Age of 18 to 55 years

2. Access to a trial site and willingness to be followed for the planned duration of the study.

3. Ability and willingness to provide informed consent

4. Demonstrates an understanding of the study

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

6. Good general health as shown by medical history, physical exam, and screening laboratory tests

7. Willingness to receive HIV test results

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

9. Assessed by the clinic staff as being at "low risk" for HIV infection and committed to maintaining behavior consistent with low risk of HIV exposure through the last required protocol clinic visit.

10. Hemoglobin ≥ 11.0 g/dL for volunteers who were born female, ≥ 12.0 g/dL for volunteers who were born male

11. White blood cell count = 3,000 to 12,000 cells/mm3

12. Total lymphocyte count > 800 cells/mm3

13. Remaining differential either within institutional normal range or with site physician approval

14. Platelets = 125,000 to 450,000/mm3

15. Chemistry panel: ALT< 1.25 times the institutional upper limit of normal; creatinine < 1.1 times institutional upper limit of normal.

16. Negative HIV-1 and -2 blood test

17. Negative Hepatitis B surface antigen (HBsAg)

18. Negative anti-Hepatitis C virus antibodies (anti-HCV)

19. Urinalysis

    • Negative or trace urine glucose, and
    • Negative or trace urine protein, and
    • Negative, trace, or 1+ urine hemoglobin (if 1+ hemoglobin is present on dipstick in the absence of menstruation, a microscopic urinalysis with red blood cells morphology within institutional normal range)

20. Volunteers who were born female: negative serum or urine beta human chorionic gonadotropin (β HCG) pregnancy test performed prior to vaccination on the day of initial vaccination.

21. Reproductive status: A volunteer who was born female must:

    • Agree to consistently use effective contraception for sexual activity that could lead to pregnancy from at least 21 days prior to enrollment until at least 3 months after last vaccination.;
    • Or not be of reproductive potential, such as having reached menopause (no menses for 1 year) or having undergone hysterectomy, bilateral oophorectomy, or tubal ligation (verified by medical records where available, or based on the judgement of the local investigator);
    • Or have no male sexual partner.

22. Volunteers who were born female must also agree not to seek pregnancy through alternative methods, such as artificial insemination, or in vitro fertilization until at least 3 months after last vaccination.

Exclusion 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.

4. Intent to participate in another study of an investigational research agent or any other study that requires HIV antibody testing.

5. Pregnant or breastfeeding.

6. Active duty and reserve US military personnel.

7. HIV vaccine(s) received in a prior HIV vaccine trial.

8. Non-HIV experimental vaccine(s) received within the last 1 year in a prior vaccine trial unless the vaccine subsequently received regulatory approval or emergency authorization.

9. Live attenuated vaccines, other than the influenza vaccine, received within 30 days before first vaccination or scheduled within 14 days after injection.

10. Any vaccines that are not live attenuated vaccines and were received within 14 days prior to first vaccination.

11. Allergy treatment with antigen injections within 30 days before the first vaccination or those that are scheduled within 14 days after the first vaccination

12. Immunosuppressive medications received within 168 days before the first vaccination.

13. Serious adverse reactions to vaccines or to vaccine components, including a history of anaphylaxis and related symptoms such as hives, respiratory difficulty, angioedema, and/or abdominal pain.

14. Immunoglobulin received within 60 days before the first vaccination.

15. Autoimmune disease, connective tissue disease, or history of vasculitis. A volunteer with a history of a potential immune-mediated medical condition (PIMMC), 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 or other mild, uncomplicated, localized or dermatologic condition that does not require ongoing systemic treatment; (3) remote history (>10 years ago) of Kawasaki disease without sequelae; and (4) celiac disease well controlled for 6 months with diet only.

16. Immunodeficiency.

17. Clinically significant medical condition, physical examination findings, clinically significant abnormal laboratory results, or past medical history with clinically significant implications for current health as per the investigator's judgement.

18. Any medical, psychiatric, occupational, or other condition that, in the judgment of the investigator, would interfere with, or serve as a contraindication to, protocol adherence, assessment of safety or reactogenicity, or a volunteer's ability to give informed consent.

19. Psychiatric condition that precludes compliance with the protocol. Specifically excluded are persons with psychoses within the past 3 years, ongoing risk for suicide, or history of suicide attempt or gesture within the past 3 years.

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

21. Asthma other than mild, well-controlled asthma

22. Diabetes mellitus type 1 or type 2, including cases controlled with diet alone. (Not excluded: history of isolated gestational diabetes.)

23. Uncontrolled thyroid disease, recent thyroidectomy, or new onset hypothyroidism or hyperthyroidism, defined as new or changing doses of thyroid medication within the last 12 months.

24. Hypertension

    • If a person has been found to have elevated blood pressure or hypertension during screening or previously, exclude for blood pressure that is not well controlled (defined as ≥ 90 mmHg diastolic or ≥ 140 mmHg systolic after 10 minutes' rest).
    • If a person has NOT been found to have elevated blood pressure or hypertension during screening or previously, exclude for systolic blood pressure ≥ 140 mm Hg at enrollment or diastolic blood pressure ≥ 90 mm Hg at enrollment. One repeat attempt at measurement on a different date is allowed.

25. Bleeding disorder diagnosed by a doctor.

26. Malignancy.

27. Seizure disorder: History of seizure(s) within past three years.

28. Asplenia: any condition resulting in the absence of a functional spleen.

29. History of hereditary angioedema, acquired angioedema, or idiopathic angioedema.

Data obtained through this study may be provided to qualified researchers with academic interest. Data will be deidentified, and access requires approval of a research proposal, execution of a Data Sharing Agreement, and IRB approval. Requests can be submitted starting 9 months after publication and will be available for up to 24 months.