A Clinical Trial to Evaluate Safety, Tolerability, and Immunogenicity of Adjuvanted HIV-1 Fusion Peptide Conjugate Vaccine Alone or in Prime-Boost Regimens With Adjuvanted HIV-1 Envelope Trimer 4571 and HIV-1 Trimer 6931 Vaccines in Healthy Adults

Phase 1

Completed

• Conditions: HIV
• Interventions: Biological: Trimer 6931 (100 mcg); Biological: FP conjugate vaccine (200 mcg); Biological: FP conjugate vaccine (25 mcg); Biological: Trimer 4571 (200 mcg); Biological: Trimer 6931 (200 mcg); Biological: Trimer 4571 (100 mcg)

• Registration Number: NCT05470400
• Lead Sponsor: National Institute of Allergy and Infectious Diseases (NIAID)

Brief Summary

This is an open-label, dose-escalation study to examine the safety, tolerability, and immunogenicity of adjuvanted Fusion Peptide Vaccine alone or in prime-boost regimens with adjuvanted Trimer 4571 and Trimer 6931 vaccines in healthy adults. The hypothesis is that the vaccines will be safe, and well tolerated when administered alone, and when co-administered with HIV-1 Trimer 4571, in prime-boost regimens, and will induce detectable immune response.

Detailed Description

This study has two parts. Part A will evaluate the safety, tolerability, and immunogenicity of single doses of the FP conjugate, Trimer 4571 and Trimer 6931 vaccines, in a dose-escalation design. Each product must be assessed as safe prior to use in Part B. Trimer 4571 with alum adjuvant has been previously evaluated in humans but will be tested in Part A with Adjuplex. Part B will evaluate the safety, tolerability, and immunogenicity of FP conjugate prime, Trimer 4571 prime, or an FP plus Trimer 4571 prime, all followed by subsequent doses of Trimer 4571, or Trimer 6931, or both alone and then both Trimers combined.

Total study duration is 36 months (includes enrollment, planned safety holds and follow-up).

Study Timeline

• Study First Submitted: 2022-06-29
• Study First Submitted QC: 2022-07-19
• Study First Posted: 2022-07-22
• Study Start: 2022-08-15
• Primary Completion: 2024-01-24
• Study Completion: 2024-01-24
• Results First Submitted: 2025-01-23
• Status Verified: 2025-02
• Results First Submitted QC: 2025-03-17
• Last Update Submitted: 2025-03-17
• Results First Posted: 2025-03-21
• Last Update Posted: 2025-03-21

Recruitment & Eligibility

• Status: COMPLETED
• Sex: All
• Target Recruitment: 44

Inclusion Criteria

1. Able and willing to complete the informed consent process, including an Assessment of Understanding (AoU): volunteer demonstrates understanding of this study, completes a questionnaire prior to first vaccination with verbal demonstration of understanding of all questionnaire items answered incorrectly.

2. 18-50 years old, inclusive, on day of enrollment.

3. Agrees to comply with planned study procedures and be available for clinic follow-up through the last clinic visit.

4. Agrees not to enroll in another study of an investigational agent during participation in the trial, including severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) investigational agents that may subsequently obtain emergency use authorization (EUA) or undergo licensure by the FDA. If a potential participant is already enrolled in a SARS-CoV-2 clinical trial, prior approvals from the SARS-COV-2 study sponsor and HVTN 303 PSRT are required prior to enrollment in HVTN 303.

5. In good general health without clinically significant medical history.

6. Physical examination and laboratory results without clinically significant findings that would interfere with assessment of safety or reactogenicity.

7. Body Mass Index (BMI) ≤ 40.

8. Assessed as low risk for HIV acquisition.

9. Suitable injection sites in the deltoid muscle of each arm, as assessed by a clinician.

10. White blood cells (WBCs) 2,500-12,000/mm3

11. WBC differential either within institutional normal range or approved by the Investigator of Record (IoR) as "not clinically significant."

12. Platelets = 125,000 - 500,000/mm3

13. 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

14. Serum creatinine ≤ 1.1 x upper limit of normal (ULN) based on the institutional normal range.

15. Alanine aminotransferase (ALT) ≤1.25 x ULN based on the institutional normal range.

16. Negative for HIV infection by an (US) Food and Drug Administration (FDA)-approved enzyme immunoassay (EIA) or chemiluminescent microparticle immunoassay (CMIA).

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

18. Negative for Hepatitis B surface antigen.

19. Agrees to use effective means of birth control from at least 21 days prior to enrollment through 12 weeks after the last product administration.

20. Negative β-HCG (beta human chorionic gonadotropin) pregnancy test (urine or serum) at screening and prior to each study product administration on the day of study product administration.

Exclusion Criteria

1. Active duty and reserve US military personnel.

2. Breast-feeding or planning to become pregnant from at least 21 days prior to enrollment through 12 weeks after the last product administration.

3. An investigational HIV vaccine (previous placebo recipients are not excluded).

4. Immunosuppressive medications received within 168 days before first vaccination (Not exclusionary: [1] corticosteroid nasal spray; [2] inhaled corticosteroids; [3] topical corticosteroids for mild, uncomplicated dermatologic condition; or [4] a single course of oral/parenteral prednisone or equivalent at doses ≤ 60 mg/day and length of therapy < 11 days with completion at least 30 days prior to enrollment).

5. Blood products within 60 days prior to enrollment

6. Monoclonal antibodies (mAbs), whether licensed or investigational. Exceptions may be made by the HVTN 303 PSRT on a case-by-case basis

7. Receipt of any of the following:

   • Within 4 weeks prior to enrollment:

     • Any licensed live, attenuated vaccine
     • Any adenoviral-vectored SARS-CoV-2 vaccine with FDA Emergency Use Authorization (EUA), FDA licensure or World Health Organization (WHO) Emergency Use Listing (EUL)

   • Within 2 weeks prior to enrollment:

     • Any licensed killed/subunit/inactivated vaccine
     • Any mRNA based or protein SARS-CoV-2 vaccines with FDA EUA, FDA licensure, or WHO EUL

8. 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.

9. Current allergen immunotherapy with antigen injections, unless on maintenance schedule.

10. Current anti-TB prophylaxis or therapy.

11. Serious adverse reactions to vaccines or vaccine components.

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

13. Hypertension that is not well controlled.

14. 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]); OR
    • 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.

15. Autoimmune disease, current or history, including psoriasis.

16. Clinically significant immunodeficiency.

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

18. History of generalized urticaria, angioedema, or anaphylaxis. (Not exclusionary: angioedema or anaphylaxis to a known trigger with at least 5 years since last reaction to demonstrate satisfactory avoidance of trigger.).

19. Diabetes mellitus type 1 or type 2.

20. Bleeding disorder diagnosed by a doctor (eg, factor deficiency, coagulopathy, or platelet disorder requiring special precautions) or significant bruising or bleeding difficulties with IM injections or blood draws.

21. Seizure disorder other than: 1) febrile seizures, 2) seizures secondary to alcohol withdrawal more than 3 years ago, or 3) seizures that have not required treatment within the last 3 years.

22. Asplenia or functional asplenia.

23. Malignancy (Not excluded from participation: Volunteer who has had malignancy excised surgically and who, in the investigator's estimation, has a reasonable assurance of sustained cure, or who is unlikely to experience recurrence of malignancy during the period of the study).

24. 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).

Study & Design

• Study Type: INTERVENTIONAL
• Study Design: SEQUENTIAL

Arm && Interventions

Group	Intervention	Description
Prime Boost Regimen - Group 6	Trimer 6931 (100 mcg)	Prime Boost Regimen will evaluate the safety, tolerability, and immunogenicity of adjuvanted vaccines: FP conjugate prime, Trimer 4571 prime, or an FP plus Trimer 4571 prime, all followed by subsequent doses of Trimer 4571, Trimer 6931 and both Trimers combined.
Prime Boost Regimen - Group 7	Trimer 6931 (200 mcg)	Prime Boost Regimen will evaluate the safety, tolerability, and immunogenicity of adjuvanted vaccines: FP conjugate prime, Trimer 4571 prime, or an FP plus Trimer 4571 prime, all followed by subsequent doses of Trimer 4571, Trimer 6931 and both Trimers combined.
Prime Boost Regimen - Group 6	Trimer 6931 (200 mcg)	Prime Boost Regimen will evaluate the safety, tolerability, and immunogenicity of adjuvanted vaccines: FP conjugate prime, Trimer 4571 prime, or an FP plus Trimer 4571 prime, all followed by subsequent doses of Trimer 4571, Trimer 6931 and both Trimers combined.
Prime Boost Regimen - Group 6	Trimer 4571 (100 mcg)	Prime Boost Regimen will evaluate the safety, tolerability, and immunogenicity of adjuvanted vaccines: FP conjugate prime, Trimer 4571 prime, or an FP plus Trimer 4571 prime, all followed by subsequent doses of Trimer 4571, Trimer 6931 and both Trimers combined.
Prime Boost Regimen - Group 7	FP conjugate vaccine (200 mcg)	Prime Boost Regimen will evaluate the safety, tolerability, and immunogenicity of adjuvanted vaccines: FP conjugate prime, Trimer 4571 prime, or an FP plus Trimer 4571 prime, all followed by subsequent doses of Trimer 4571, Trimer 6931 and both Trimers combined.
Prime Boost Regimen - Group 8	Trimer 4571 (100 mcg)	Prime Boost Regimen will evaluate the safety, tolerability, and immunogenicity of adjuvanted vaccines: FP conjugate prime, Trimer 4571 prime, or an FP plus Trimer 4571 prime, all followed by subsequent doses of Trimer 4571, Trimer 6931 and both Trimers combined.
Dose Escalation - Group 1	FP conjugate vaccine (25 mcg)	Dose Escalation will evaluate the safety, tolerability, and immunogenicity of single adjuvanted doses of the FP conjugate, Trimer 4571 or Trimer 6931 vaccines, in a dose-escalation design. Each product must be assessed as safe prior to use in Prime Boost Regimen.
Dose Escalation - Group 3	Trimer 6931 (100 mcg)	Dose Escalation will evaluate the safety, tolerability, and immunogenicity of single adjuvanted doses of the FP conjugate, Trimer 4571 or Trimer 6931 vaccines, in a dose-escalation design. Each product must be assessed as safe prior to use in Prime Boost Regimen.
Dose Escalation - Group 5	Trimer 4571 (200 mcg)	Dose Escalation will evaluate the safety, tolerability, and immunogenicity of single adjuvanted doses of the FP conjugate, Trimer 4571 or Trimer 6931 vaccines, in a dose-escalation design. Each product must be assessed as safe prior to use in Prime Boost Regimen.
Prime Boost Regimen - Group 6	Trimer 4571 (200 mcg)	Prime Boost Regimen will evaluate the safety, tolerability, and immunogenicity of adjuvanted vaccines: FP conjugate prime, Trimer 4571 prime, or an FP plus Trimer 4571 prime, all followed by subsequent doses of Trimer 4571, Trimer 6931 and both Trimers combined.
Prime Boost Regimen - Group 7	Trimer 4571 (200 mcg)	Prime Boost Regimen will evaluate the safety, tolerability, and immunogenicity of adjuvanted vaccines: FP conjugate prime, Trimer 4571 prime, or an FP plus Trimer 4571 prime, all followed by subsequent doses of Trimer 4571, Trimer 6931 and both Trimers combined.
Prime Boost Regimen - Group 8	Trimer 6931 (100 mcg)	Prime Boost Regimen will evaluate the safety, tolerability, and immunogenicity of adjuvanted vaccines: FP conjugate prime, Trimer 4571 prime, or an FP plus Trimer 4571 prime, all followed by subsequent doses of Trimer 4571, Trimer 6931 and both Trimers combined.
Prime Boost Regimen - Group 8	Trimer 4571 (200 mcg)	Prime Boost Regimen will evaluate the safety, tolerability, and immunogenicity of adjuvanted vaccines: FP conjugate prime, Trimer 4571 prime, or an FP plus Trimer 4571 prime, all followed by subsequent doses of Trimer 4571, Trimer 6931 and both Trimers combined.
Dose Escalation - Group 2	FP conjugate vaccine (200 mcg)	Dose Escalation will evaluate the safety, tolerability, and immunogenicity of single adjuvanted doses of the FP conjugate, Trimer 4571 or Trimer 6931 vaccines, in a dose-escalation design. Each product must be assessed as safe prior to use in Prime Boost Regimen.
Dose Escalation - Group 4	Trimer 6931 (200 mcg)	Dose Escalation will evaluate the safety, tolerability, and immunogenicity of single adjuvanted doses of the FP conjugate, Trimer 4571 or Trimer 6931 vaccines, in a dose-escalation design. Each product must be assessed as safe prior to use in Prime Boost Regimen.
Prime Boost Regimen - Group 7	Trimer 4571 (100 mcg)	Prime Boost Regimen will evaluate the safety, tolerability, and immunogenicity of adjuvanted vaccines: FP conjugate prime, Trimer 4571 prime, or an FP plus Trimer 4571 prime, all followed by subsequent doses of Trimer 4571, Trimer 6931 and both Trimers combined.
Prime Boost Regimen - Group 7	Trimer 6931 (100 mcg)	Prime Boost Regimen will evaluate the safety, tolerability, and immunogenicity of adjuvanted vaccines: FP conjugate prime, Trimer 4571 prime, or an FP plus Trimer 4571 prime, all followed by subsequent doses of Trimer 4571, Trimer 6931 and both Trimers combined.
Prime Boost Regimen - Group 8	FP conjugate vaccine (200 mcg)	Prime Boost Regimen will evaluate the safety, tolerability, and immunogenicity of adjuvanted vaccines: FP conjugate prime, Trimer 4571 prime, or an FP plus Trimer 4571 prime, all followed by subsequent doses of Trimer 4571, Trimer 6931 and both Trimers combined.
Prime Boost Regimen - Group 8	Trimer 6931 (200 mcg)	Prime Boost Regimen will evaluate the safety, tolerability, and immunogenicity of adjuvanted vaccines: FP conjugate prime, Trimer 4571 prime, or an FP plus Trimer 4571 prime, all followed by subsequent doses of Trimer 4571, Trimer 6931 and both Trimers combined.

Primary Outcome Measures

Name	Time	Method
Number of Participants Reporting Local Reactogenicity Signs and Symptoms: Pain and/or Tenderness	Measured through 7 days after each vaccine dose (7 days after the first dose at Week 0 in all Groups, and 7 days after the second dose at Week 4 in Groups 7 and 8 for participants who received the second dose).	Graded according to the Division of AIDS (DAIDS) Table for Grading the Severity of Adult and Pediatric Adverse Events, Version 2.1 \[July 2017\]. The maximum grade observed for each symptom over the time frame is presented
Number of Participants Reporting Local Reactogenicity Signs and Symptoms: Erythema and/or Induration	Measured through 7 days after each vaccine dose (7 days after the first dose at Week 0 in all Groups, and 7 days after the second dose at Week 4 in Groups 7 and 8 for participants who received the second dose).	Graded according to the Division of AIDS (DAIDS) Table for Grading the Severity of Adult and Pediatric Adverse Events, Version 2.1 \[July 2017\]. The maximum grade observed for each symptom over the time frame is presented
Number of Participants Reporting Systemic Reactogenicity Signs and Symptoms	Measured through 7 days after each vaccine dose (7 days after the first dose at Week 0 in all Groups, and 7 days after the second dose at Week 4 in Groups 7 and 8 for participants who received the second dose).	Graded according to the Division of AIDS (DAIDS) Table for Grading the Severity of Adult and Pediatric Adverse Events, Version 2.1 \[July 2017\]. The following symptoms are considered as systemic reactogenicity if the onset date was within the periods of assessment specified in the protocol: malaise a
Number (Percentage) of Participants With Local Laboratory Values Recorded as Meeting Grade 1 AE Criteria or Above as Specified in the Division of AIDS Table.	T1-T5: Screening, Days 0,7,14,28; T6: Screening, Days 0,7,14,84,91,98,168,175,182,252,259; T7: Screening, Days 0,7,14,28,35,42,56,63,70,84,91,98,168,175,252,259; T8: Screening, Days 0,7,14,28,35,42,56,63,70,140,147,154,231,238,252	The number (percentage) of participants with local laboratory values recorded as meeting Grade 1 AE criteria or above as specified in the Division of AIDS Table for Grading the Severity of Adult and Pediatric Adverse Events for alanine aminotransferase (ALT), creatinine, hemoglobin, lymphocyte count, neutrophil count, platelets, white blood cells (WBC) was summarized by treatment arm for each post vaccination time point.
Number of Participants Reporting Adverse Events (AEs), by Severity Grade	28 days after each vaccine dose (28 days after the first dose at Week 0 in all Groups, and 28 days after the second dose at Week 4 in Groups 7 and 8 for participants who received the second dose).	Graded according to the Division of AIDS (DAIDS) Table for Grading the Severity of Adult and Pediatric Adverse Events, Corrected Version 2.1, July 2017 (exceptions apply)
Number of Participants Reporting Adverse Events (AEs), by Relationship to Study Product	28 days after each vaccine dose (28 days after the first dose at Week 0 in all Groups, and 28 days after the second dose at Week 4 in Groups 7 and 8 for participants who received the second dose).	Graded according to the Division of AIDS (DAIDS) Table for Grading the Severity of Adult and Pediatric Adverse Events, Corrected Version 2.1, July 2017 (exceptions apply).
Number of Participants Reporting Serious Adverse Events (SAEs)	12 months after each vaccine dose (12 months after the first dose at Week 0 in all Groups, and 12 months after the second dose at Week 4 in Groups 7 and 8 for participants who received the second dose).	Graded according to the Division of AIDS (DAIDS) Table for Grading the Severity of Adult and Pediatric Adverse Events, Corrected Version 2.1, July 2017 (exceptions apply)
Number of Participants Reporting Medically Attended Adverse Events (MAAEs)	12 months after each vaccine dose (12 months after the first dose at Week 0 in all Groups, and 12 months after the second dose at Week 4 in Groups 7 and 8 for participants who received the second dose).	Graded according to the Division of AIDS (DAIDS) Table for Grading the Severity of Adult and Pediatric Adverse Events, Corrected Version 2.1, July 2017 (exceptions apply)
Number of Participants Reporting Adverse Events of Special Interest (AESIs)	12 months after each vaccine dose (12 months after the first dose at Week 0 in all Groups, and 12 months after the second dose at Week 4 in Groups 7 and 8 for participants who received the second dose).	Graded according to the Division of AIDS (DAIDS) Table for Grading the Severity of Adult and Pediatric Adverse Events, Corrected Version 2.1, July 2017 (exceptions apply)
Number of Participants With Study Product Discontinuation Associated With an AE or Reactogenicity	12 months after each vaccine dose (12 months after the first dose at Week 0 in all Groups, and 12 months after the second dose at Week 4 in Groups 7 and 8 for participants who received the second dose).	Graded according to the Division of AIDS (DAIDS) Table for Grading the Severity of Adult and Pediatric Adverse Events, Corrected Version 2.1, July 2017 (exceptions apply)
Number of Participants With Early Study Termination Associated With an AE or Reactogenicity	12 months after each vaccine dose (12 months after the first dose at Week 0 in all Groups, and 12 months after the second dose at Week 4 in Groups 7 and 8 for participants who received the second dose).	Graded according to the Division of AIDS (DAIDS) Table for Grading the Severity of Adult and Pediatric Adverse Events, Corrected Version 2.1, July 2017 (exceptions apply)
Response Rate of Serum Antibody Binding of FP and Envelope Trimer Antigens as Measured by the MSD Assay 2 Weeks After the Last Vaccination.	Measured at week 2, 2 weeks after the 1st vaccination, for Groups T5+T6, T7, and T8 and week 6, 2 weeks after the 2nd vaccination for Groups T7 and T8.	Meso Scale Discovery Immunogenicity Assay (MSD) was used to measure the IgG binding antibody responses to fusion protein (FP), Trimer 4571, and Trimer 6931 based on two distinct positivity call methods: Method 1, known for its liberal approach, and Method 2, acknowledged for its conservative nature. Method 1 is using the cutoffs from the lab based on the 80 naïve samples (the 95th percentile). Method 2 is using the cutoffs (mean + 3\*SD of AUC to each analyte) based on the 80 naïve samples after filtering out %CV\>= 30% plus the baseline values from this study. The readout was the area under the curve (AUC) that were calculated from 8 serial dilutions (8-fold) for each sample. Group 5 and Group 6 were combined in the summary of IgG response rate.
Magnitude of Serum Antibody Binding of FP and Envelope Trimer Antigens as Measured by the MSD Assay 2 Weeks After the Last Vaccination.	Measured at week 2, 2 weeks after the 1st vaccination, for Groups T5+T6, T7, and T8 and week 6, 2 weeks after the 2nd vaccination for Groups T7 and T8.	Meso Scale Discovery Immunogenicity Assay (MSD) was used to measure the IgG binding antibody responses to fusion protein (FP), Trimer 4571, and Trimer 6931 based on two distinct positivity call methods: Method 1, known for its liberal approach, and Method 2, acknowledged for its conservative nature. Method 1 is using the cutoffs from the lab based on the 80 naïve samples (the 95th percentile). Method 2 is using the cutoffs (mean + 3\*SD of AUC to each analyte) based on the 80 naïve samples after filtering out %CV\>= 30% plus the baseline values from this study. The readout was the area under the curve (AUC) that were calculated from 8 serial dilutions (8-fold) for each sample. The Unit of Measure is expressed as Mean Electrochemiluminescence Signal\*1/dilution to reflect the AUC of responses across serial dilutions. Group 5 and Group 6 were combined in the summary of IgG magnitudes.

Trial Locations

Locations (6)

BIDMC Vcrs [32077]; 🇺🇸 Boston, Massachusetts, United States

New York Blood Center CRS [31801]; 🇺🇸 New York, New York, United States

Atlanta - Hope Clinic; 🇺🇸 Atlanta, Georgia, United States

University of Rochester Vaccines to Prevent HIV Infection CRS [31467]; 🇺🇸 Rochester, New York, United States

Columbia P&S CRS [30329]; 🇺🇸 New York, New York, United States

University of Pittsburgh CRS [1001]; 🇺🇸 Pittsburgh, Pennsylvania, United States