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
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Brief Summary
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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

Detailed Description
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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.

Official Title
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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

Conditions
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HIV Infections

Intervention / Treatment
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* Biological: HIVIS DNA/MVA-CMDR
* Biological: HIVIS DNA + Cervarix and MVA-CMDR
* Biological: Cervarix


Participation Criteria
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Eligibility Criteria
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Inclusion criteria: HIV perinatally infected Know their HIV+ status Initiated ART prior to 6 months of age Male and female ≥ 9 years old In generally good health Plasma viral load < 200 copies/ml on ART at screening CD4 count above 400 cells/mm3 at screening Participants of childbearing potential who are sexually active must be willing to practice effective contraception during the study Negative urine β-HCG (human chorionic gonadotropin) pregnancy test for any female of childbearing age (post-menarche) Availability for follow-up for planned duration of the study 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. 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. 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: Participants who experienced virological failure necessitating ART modifications Participants who had ART interruption that lasted >2 weeks Prior or current pancreatitis or history of alcohol abuse. Systemic cortisone treatment within the past 30 days Participants coinfected with chronic hepatitis B (Hepatitis B surface antigen, HBsAg+) or hepatitis C (Hepatitis C antibody, HCV Ab+) at screening Participants with signs of autoimmune diseases Participants with history of myocarditis Participants on any immune modulating or investigational drug Pregnant or breastfeeding female

Ages Eligible for Study
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Minimum Age: 9 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

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


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Arm 1 (n=10): HIVIS DNA / MVA-CMDR<br>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<br>* 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.<br>|
| Experimental: Arm 2 (n=10): HIVIS DNA + Cervarix/ / MVA-CMDR<br>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<br>* 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.<br>|
| Experimental: Arm 3 (n=5): Cervarix<br>Arm 3 (n=5) will receive 0.5 ml of Cervarix by IM needle injection at weeks 0, 4 and 24. | Biological: Cervarix<br>* Cervarix by IM needle injection at weeks 0, 4 and 24.<br>|

What is the study measuring?
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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 | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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HIV reservoir, Perinatally HIV Infected Children, Vaccine