Safety and Effects of Using Prime-boost HIVIS DNA and MVA-CMDR Vaccine Regimens With or Without Toll-like Receptor 4 Agonist on HIV Reservoirs in Perinatally HIV Infected Children and Youth (HVRRICANE)

Phase I, Proof of Concept, Open-Label, Randomized Clinical Trial to Evaluate the Safety and Effects of Using Prime-boost HIVIS DNA and MVA-CMDR Vaccine Regimens With or Without Toll-like Receptor 4 Agonist on HIV Reservoirs in Perinatally HIV Infected Children and Youth

Phase I, Proof of Concept, Open-Label, Randomized Clinical Trial to Evaluate the Safety and Effects of Using Prime-boost HIVIS DNA and MVA-CMDR Vaccine Regimens with or without Toll-like Receptor 4 Agonist on HIV Reservoirs in Perinatally HIV Infected Children and Youth

Study Overview

• Status: Active, not recruiting
• Conditions: HIV Infections
• Intervention / Treatment: Biological: HIVIS DNA/MVA-CMDR; Biological: HIVIS DNA + Cervarix and MVA-CMDR; Biological: Cervarix

Detailed Description

HIVIS DNA and MVA-CMDR vaccines induce immune responses important for clearing infected cells: broad HIV-specific CD8+ cytotoxic T cells, potent antibodydependent cellular cytotoxicity (ADCC), and binding antibody (Ab) and neutralizing antibody (NAb). The study include early treated children because of their healthy immunity and small HIV reservoirs. Giving licensed vaccine, Cervarix®, against human papilloma virus (HPV) that contains toll-like receptor (TLR) 4 agonist with HIVIS DNA could increase DNA antigen loading on dendritic cells and promote adaptive immune responses to the HIV vaccine.

• Study Type: Interventional
• Enrollment (Estimated): 25
• Phase: Phase 1

Contacts and Locations

Study Locations

• South Africa
  • Cape Town
    • Tygerberg Hills, Cape Town, South Africa, 7505
      • Stellenbosch University

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 9 years and older (Child, Adult, Older Adult)
• Accepts Healthy Volunteers: No

Description

Inclusion criteria:

1. HIV perinatally infected
2. Know their HIV+ status
3. Initiated ART prior to 6 months of age
4. Male and female ≥ 9 years old
5. In generally good health
6. Plasma viral load < 200 copies/ml on ART at screening
7. CD4 count above 400 cells/mm3 at screening
8. Participants of childbearing potential who are sexually active must be willing to practice effective contraception during the study
9. Negative urine β-HCG (human chorionic gonadotropin) pregnancy test for any female of childbearing age (post-menarche)
10. Availability for follow-up for planned duration of the study
11. Passing a test of understanding is required for participants ≥ 18 years old or the parent(s)/legal representative of participants < 18 years old before consent.
12. Written informed consent from participants ≥ 18 years old or parent(s)/legal representative of participants < 18 years old. Assent by participants aged 9-17 years old will also be required.

13. Laboratory criteria within 8 weeks prior to enrollment

    • Hb >11.0 g/dl
    • White blood cell count >3000 cells/mm3
    • Platelets >125,000/ mm3
    • ALT <1.5 x upper limit of normal
    • Creatinine <1.5 x upper limit of normal

Exclusion criteria:

1. Participants who experienced virological failure necessitating ART modifications
2. Participants who had ART interruption that lasted >2 weeks
3. Prior or current pancreatitis or history of alcohol abuse.
4. Systemic cortisone treatment within the past 30 days
5. Participants coinfected with chronic hepatitis B (Hepatitis B surface antigen, HBsAg+) or hepatitis C (Hepatitis C antibody, HCV Ab+) at screening
6. Participants with signs of autoimmune diseases
7. Participants with history of myocarditis
8. Participants on any immune modulating or investigational drug
9. Pregnant or breastfeeding female

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: None (Open Label)

Number of Arms

3

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Arm 1 (n=10): HIVIS DNA / MVA-CMDR; Arm 1 (n=10) will receive 1500 micrograms (0.5ml) HIVIS DNA IM by needle-free injection at weeks 0 and 4 followed by intramuscular (IM) needle injection of 1 X 108 IU/mL (1ml) MVA-CMDR at weeks 24 and 36 in the same arm as HIVIS DNA. Participants who have been randomized to receive HIVIS DNA and MVA-CMDR alone (ARM 1) will be administered Cervarix after week 72, the last study follow-up visit, if required.	Biological: HIVIS DNA/MVA-CMDR; HIVIS DNA IM by needle-free injection at weeks 0 and 4 followed by intramuscular (IM) needle injection of 1 X 108 IU/mL (1ml) MVA-CMDR at weeks 24 and 36 in the same arm as HIVIS DNA.
Experimental: Arm 2 (n=10): HIVIS DNA + Cervarix/ / MVA-CMDR; Arm 2 (n=10) will receive 0.5 ml of Cervarix IM by needle injection followed by 1500 micrograms (0.5ml) per injection of HIVIS DNA IM by a needle-free injection device in the skin above (proximal to) the Cervarix injection (within 1.5 cm). They will receive 1 X 108 IU/mL (1ml) MVA-CMDR IM by needle injection at weeks 24 and 36 in the same arm as HIVIS DNA. They will also receive 0.5 ml Cervarix at the time of the first MVACMDR injection in the opposite arm from the MVA injection at week 24.	Biological: HIVIS DNA + Cervarix and MVA-CMDR; Cervarix IM by needle injection followed by 1500 micrograms (0.5ml) per injection of HIVIS DNA IM by a needle-free injection device in the skin above (proximal to) the Cervarix injection (within 1.5 cm). They will receive 1 X 108 IU/mL (1ml) MVA-CMDR IM by needle injection at weeks 24 and 36 in the same arm as HIVIS DNA. They will also receive 0.5 ml Cervarix at the time of the first MVACMDR injection in the opposite arm from the MVA injection at week 24.
Experimental: Arm 3 (n=5): Cervarix; Arm 3 (n=5) will receive 0.5 ml of Cervarix by IM needle injection at weeks 0, 4 and 24.	Biological: Cervarix; Cervarix by IM needle injection at weeks 0, 4 and 24.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Solicited and unsolicited serious adverse events	Safety	through study completion, an average of 1 year
Frequencies of CD4+ T cells that produce Tat/Rev transcription (tat/rev RNA+ cells/106 CD4+ T cells)	Efficacy	Change from Baseline at week 24, 36, 48, 60, 72
HIV DNA (copies/106 CD4+ T cells)	Efficacy	Change from Baseline at week 28, 48

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Solicited and unsolicited non-serious adverse events	Safety	through study completion, an average of 1 year
Unspliced and multiply-spliced RNA+ cells/1000 ng cellular RNA	Efficacy	Week 24, 36, 48, 60, 72
IUPM from total CD4+ T cells in blood by QVOA	Efficacy	Week 24, 36, 48, 60, 72
Plasma HIV RNA by SCA	Efficacy	Week 24, 36, 48, 60, 72
HIV-specific CD8+ and CD4+ T cells	Immunogicity	Week 28, 48
ADCC	Immunogicity	Week 28, 48
Binding and neutralizing Ab	Immunogicity	Week 28, 48
Global gene expression on PBMCs by RNA seq	immune response	Week 28, 48
Gene expression on HIV-specific CD8+ and CD4+ T cells	immune response	Week 28, 48

Collaborators and Investigators

• Sponsor: Henry M. Jackson Foundation for the Advancement of Military Medicine
• Collaborators: Johns Hopkins University; Karolinska Institutet; University of Miami; Chulalongkorn University; University of Padova; Bambino Gesù Hospital and Research Institute; Walter Reed Army Institute of Research (WRAIR); Case Western Reserve University; PENTA Foundation; Armed Forces Research Institute of Medical Sciences, Thailand; Leidos Biomedical Research, Inc.
• Investigators: Study Chair: Merlin Robb, MD, Henry M. Jackson Foundation for the Advancement of Military Medicine

Study record dates

Study Major Dates

• Study Start (Actual): February 18, 2022
• Primary Completion (Actual): October 16, 2023
• Study Completion (Estimated): February 28, 2025

Study Registration Dates

• First Submitted: March 2, 2020
• First Submitted That Met QC Criteria: March 5, 2020
• First Posted (Actual): March 10, 2020

Study Record Updates

• Last Update Posted (Actual): May 3, 2024
• Last Update Submitted That Met QC Criteria: May 2, 2024
• Last Verified: May 1, 2024

More Information

Terms related to this study

• Keywords: Vaccine; HIV reservoir; Perinatally HIV Infected Children
• Additional Relevant MeSH Terms: RNA Virus Infections; Virus Diseases; Infections; Blood-Borne Infections; Communicable Diseases; Sexually Transmitted Diseases, Viral; Sexually Transmitted Diseases; Lentivirus Infections; Retroviridae Infections; Immunologic Deficiency Syndromes; Immune System Diseases; Urogenital Diseases; Genital Diseases; HIV Infections
• Other Study ID Numbers: RV534

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No