Therapeutic Vaccination in Treated HIV Disease

NCT ID: NCT03606213

Last Updated: 2023-05-31

Basic Information

• Recruitment Status: COMPLETED
• Clinical Phase: PHASE1/PHASE2
• Total Enrollment: 56 participants
• Study Classification: INTERVENTIONAL
• Study Start Date: 2018-08-01
• Study Completion Date: 2021-05-17

Brief Summary

The central premise of our program is that durable control of HIV in the absence of antiretroviral therapy ("remission") will require the generation of de novo potent and sustained HIV-specific CD8+ cell responses that target evolutionarily conserved epitopes. Our program is inspired by the recent success of VGX-3100 (Inovio), a DNA therapeutic vaccine for HPV that leads to histopathologic regression of pre-malignant lesions in people and is associated with a potent, sustained boost to HPV-specific CD8+ T cell populations. A closely related multi-clade gag/pol/env DNA vaccine administered with an IL-12 DNA plasmid (PENNVAX, Inovio) has been studied for HIV prevention and is known to be both safe and highly immunogenic. In a randomized placebo-controlled study we will compare the immunogenicity and anti-reservoir activities of gag/pol DNA versus gag/pol/env DNA (both administered with IL-12). We will determine for the first time in established HIV disease whether presence of env in a DNA vaccine blunts T cell responses to more conserved Gag-specific and Pol-specific epitopes. We will also determine if Env-specific responses (which will presumably be mediated by antibodies and antibody-dependent cellular cytotoxicity, or ADCC) have a measurable effect on reservoir.

Conditions

HIV-1-infection

Study Design

• Allocation Method: RANDOMIZED
• Intervention Model: PARALLEL
• Primary Study Purpose: TREATMENT
• Blinding Strategy: SINGLE

Study Groups

Cohort A - Arm 1

Placebo will be administered by electoporation at Day 0 and Weeks 4, 8 and 12

Group Type: PLACEBO_COMPARATOR

CELLECTRA® 2000

Intervention Type: DEVICE

Electroporation (EP) is a technology in which an electrical field is applied to increase the permeability of cell membranes and thereby enhance the uptake of drugs, vaccines, or other agents into target cells. This technology has been used in the last decade in both therapeutics and vaccinations. EP is currently being used to deliver cancer vaccines and therapeutics as well as in gene therapy. The expression levels are increased by as much as 3 orders of magnitude over plasmid injection alone.

Cohort A - Arm 2

Active gag/pol, env and IL-12 plasmids (PENNVAX-GP and INO-9102)) administered by electoporation (CELLECTRA-2000) at Day 0 and Weeks 4, 8 and 12.

Group Type: ACTIVE_COMPARATOR

PENNVAX-GP

Intervention Type: BIOLOGICAL

PENNVAX®-GP is a circular, double stranded, deoxyribonucleic acid consisting of expression plasmids that encode synthetic HIV-1 multiclade consensus Gag, Pol and Env proteins.

INO-9012

Intervention Type: BIOLOGICAL

The IL-12 DNA adjuvant (INO-9012) consists of a single plasmid containing a dual promoter system for expression of both the IL-12 p35 and p40 genes necessary for production of the active heterodimeric (p70) IL-12 protein.

CELLECTRA® 2000

Intervention Type: DEVICE

Electroporation (EP) is a technology in which an electrical field is applied to increase the permeability of cell membranes and thereby enhance the uptake of drugs, vaccines, or other agents into target cells. This technology has been used in the last decade in both therapeutics and vaccinations. EP is currently being used to deliver cancer vaccines and therapeutics as well as in gene therapy. The expression levels are increased by as much as 3 orders of magnitude over plasmid injection alone.

Cohort A - Arm 3

Active gag/pol and IL-12 plasmids (INO-6145 INO-9012) will be administered by electroporation (CELLECTRA-2000) at Day 0 and Weeks 4, 8 and 12.

Group Type: ACTIVE_COMPARATOR

INO-6145

Intervention Type: BIOLOGICAL

INO-6145 is a circular, double stranded, deoxyribonucleic acid consisting of expression plasmids that encode synthetic HIV-1 multiclade consensus Gag and Pol proteins.

INO-9012

Intervention Type: BIOLOGICAL

The IL-12 DNA adjuvant (INO-9012) consists of a single plasmid containing a dual promoter system for expression of both the IL-12 p35 and p40 genes necessary for production of the active heterodimeric (p70) IL-12 protein.

CELLECTRA® 2000

Intervention Type: DEVICE

Electroporation (EP) is a technology in which an electrical field is applied to increase the permeability of cell membranes and thereby enhance the uptake of drugs, vaccines, or other agents into target cells. This technology has been used in the last decade in both therapeutics and vaccinations. EP is currently being used to deliver cancer vaccines and therapeutics as well as in gene therapy. The expression levels are increased by as much as 3 orders of magnitude over plasmid injection alone.

Cohort B - Arm 1

A single arm study of gag/pol/env/IL-12 DNA plasmids PENNVAX-GP and INO-9102) administered by electoporation (CELLECTRA-2000) will be performed in HIV-infected adults for whom ART was initiated during acute HIV infection.

Group Type: ACTIVE_COMPARATOR

PENNVAX-GP

Intervention Type: BIOLOGICAL

PENNVAX®-GP is a circular, double stranded, deoxyribonucleic acid consisting of expression plasmids that encode synthetic HIV-1 multiclade consensus Gag, Pol and Env proteins.

INO-9012

Intervention Type: BIOLOGICAL

The IL-12 DNA adjuvant (INO-9012) consists of a single plasmid containing a dual promoter system for expression of both the IL-12 p35 and p40 genes necessary for production of the active heterodimeric (p70) IL-12 protein.

CELLECTRA® 2000

Intervention Type: DEVICE

Electroporation (EP) is a technology in which an electrical field is applied to increase the permeability of cell membranes and thereby enhance the uptake of drugs, vaccines, or other agents into target cells. This technology has been used in the last decade in both therapeutics and vaccinations. EP is currently being used to deliver cancer vaccines and therapeutics as well as in gene therapy. The expression levels are increased by as much as 3 orders of magnitude over plasmid injection alone.

Interventions

PENNVAX-GP

PENNVAX®-GP is a circular, double stranded, deoxyribonucleic acid consisting of expression plasmids that encode synthetic HIV-1 multiclade consensus Gag, Pol and Env proteins.

Intervention Type: BIOLOGICAL

INO-6145

INO-6145 is a circular, double stranded, deoxyribonucleic acid consisting of expression plasmids that encode synthetic HIV-1 multiclade consensus Gag and Pol proteins.

Intervention Type: BIOLOGICAL

INO-9012

The IL-12 DNA adjuvant (INO-9012) consists of a single plasmid containing a dual promoter system for expression of both the IL-12 p35 and p40 genes necessary for production of the active heterodimeric (p70) IL-12 protein.

Intervention Type: BIOLOGICAL

CELLECTRA® 2000

Electroporation (EP) is a technology in which an electrical field is applied to increase the permeability of cell membranes and thereby enhance the uptake of drugs, vaccines, or other agents into target cells. This technology has been used in the last decade in both therapeutics and vaccinations. EP is currently being used to deliver cancer vaccines and therapeutics as well as in gene therapy. The expression levels are increased by as much as 3 orders of magnitude over plasmid injection alone.

Intervention Type: DEVICE

Other Intervention Names

HIV DNA vaccine; HIV DNA vaccine; IL-12 DNA adjuvant; Electroporation device

Eligibility Criteria

Inclusion Criteria

1. Willing and able to provide written informed consent

2. Male or female, age ≥ 18 and ≤ 65 years

3. HIV-1 infection, documented by any licensed rapid HIV test or HIV enzyme or chemiluminescence immunoassay (E/CIA) test kit at any time prior to study entry and confirmed by a licensed Western blot or a second antibody test by a method other than the initial rapid HIV and/or E/CIA, or by HIV-1 antigen or plasma HIV-1 RNA viral load.

4. For Cohort A participants, ART initiated during chronic infection (e.g., more than 6 months after estimated date of infection, or as determined by site investigator and/or available medical records).

5. For Cohort B participants, ART initiated during "hyperacute" HIV infection (Fiebig I/II) or early HIV infection (Fiebig III/IV).

6. On continuous antiretroviral therapy for at least 24 months without any interruptions of greater than 14 consecutive days, and on a stable regimen for at least 8 weeks, without plans to modify ART during the study period

7. Screening plasma HIV RNA levels < 40 copies/mL on all available determinations in past 24 months (isolated single values ≥ 40 but < 200 copies/mL will be allowed if they were preceded and followed by undetectable viral load determinations)

8. Screening CD4+ T-cell count ≥ 350 cells/mm3

9. Creatinine Clearance (CrCl) > 60 mL/min via Cockroft-Gault method at screening

10. The following laboratory criteria must be met at screening:

• Absolute neutrophil count (ANC) ≥ 1000 neutrophils/mm3
• Hemoglobin ≥ 10.0 g/dL
• Platelet count ≥ 100,000/uL
• Aspartate aminotransferase (AST) ≤ 2x upper limit of normal (ULN)
• Alanine aminotransferase (ALT) ≤ 2x ULN

Exclusion Criteria

1. Pregnant, breastfeeding, or unwilling to practice birth control during participation in the study

a. Acceptable birth control is defined as the following: i. For female participants of childbearing potential, two of the following forms of contraception are required, one of which must be a barrier method:

1. Condoms (male of female) with or without a spermicidal agent 2. Diaphragm or cervical cap with spermicide 3. Intrauterine device (IUD) with published data showing that expected failure rate is < 1% per year 4. Tubal ligation 5. Hormone-based contraceptive such as oral birth control pills ii. Male participants participating in sexual activity that could lead to pregnancy must agree to at least one reliable method of contraception of the above listed 2. Active malignancy requiring systemic chemotherapy or surgery in the preceding 3 months or for whom such therapies are expected in the subsequent 6 months 3. Active (untreated) HCV or HBV infection 4. Decompensated liver disease as defined by the presence of ascites, encephalopathy, esophageal or gastric varices, or persistent jaundice 5. Serious illness requiring systemic treatment and/or hospitalization in the 3 months prior to study enrollment 6. Concurrent treatment with immunomodulatory drugs, and/or exposure to any immunomodulatory drug in the 4 weeks prior to study enrollment (e.g. corticosteroid therapy equal to or exceeding a dose of 15 mg/day of prednisone for more than 10 days, IL-2, interferon-alpha, methotrexate, cancer chemotherapy). NOTE: use of inhaled or nasal steroid is not exclusionary.

7. Serious medical or psychiatric illness that, in the opinion of the site investigator, would interfere with the ability to adhere to study requirements or to give informed consent.

8. Active drug or alcohol use or dependence that, in the opinion of the site investigator, would interfere with adherence to study requirements or to give informed consent.

9. Unable to undergo leukapheresis procedure 10. Acute or chronic bleeding or clotting disorder that would contraindicate IM injections or use of blood thinners (e.g. anticoagulants or antiplatelet drugs) within 2 weeks of Day 0; 11. Less than two acceptable sites available for IM injection considering the deltoid and anterolateral quadriceps muscles; 12. Tattoos, keloids or hypertrophic scars located within 2 cm of intended treatment site; 13. Cardioverter-defibrillator or pacemaker (to prevent a life-threatening arrhythmia) that is located in ipsilateral deltoid injection site (unless deemed acceptable by a cardiologist); 14. Metal implants or implantable medical device within the intended treatment site (i.e. electroporation area)

• Minimum Eligible Age: 18 Years
• Maximum Eligible Age: 65 Years
• Eligible Sex: ALL
• Accepts Healthy Volunteers: No

Sponsors

National Institute of Allergy and Infectious Diseases (NIAID)

NIH

Sponsor Role: collaborator

University of California, Los Angeles

OTHER

Sponsor Role: collaborator

Inovio Pharmaceuticals

INDUSTRY

Sponsor Role: collaborator

Steven Deeks

OTHER

Sponsor Role: lead

Responsible Party

Steven Deeks

Professor

Responsibility Role: SPONSOR_INVESTIGATOR

Principal Investigators

Steven Deeks, MD

Role: PRINCIPAL_INVESTIGATOR

University of California, San Francisco

Locations

University of California, Los Angeles

Los Angeles, California, United States

Zuckerberg San Francisco General Hospital (ZSFG)

San Francisco, California, United States

Countries

United States

Provided Documents

Document Type: Study Protocol, Statistical Analysis Plan, and Informed Consent Form

View Document

Other Identifiers

U01AI131296

Identifier Type: NIH

Identifier Source: secondary_id

View Link

DAIDS-ES 38409

Identifier Type: -

Identifier Source: org_study_id