A Phase I Pilot Study to Evaluate the Safety and Immunogenicity of the HIV-1 Vaccines MVA.tHIVconsv3 (M3) and MVA.tHIVconsv4 (M4) Given Alone or In Combination in HIV-1-Infected Adults Suppressed on Antiretroviral Therapy - The M&M Study
Overview
- Phase
- Phase 1
- Intervention
- Not specified
- Conditions
- HIV-1 Infection
- Sponsor
- University of North Carolina, Chapel Hill
- Enrollment
- 26
- Locations
- 1
- Primary Endpoint
- Percent of Participants With a Grade 3 or Higher Treatment-Related Adverse Event (AE)
- Status
- Completed
- Last Updated
- 3 years ago
Overview
Brief Summary
This is a double blind, randomized, placebo-controlled, parallel design, study in which 24 HIV-infected participants with durable viral suppression will be randomly assigned to receive vaccination with MVA.tHIVconsv3 (M3), MVA.tHIVconsv4 (M4), M3+M4 combined, or placebo. Participants will be randomized 7:7:7:3 to one of four study arms, and receive study treatment or placebo at Day 0. Each enrolled participant will complete the study in approximately 33.5 weeks (8.4 months).
The purpose of this study is to find out:
- If it is safe for people to receive injections of two investigational HIV vaccines, called MVAtHIVconsv3 and MVAtHIVconsv4 alone or in combination.
- If giving participants these vaccine doses will increase their immune system's ability to kill HIV virus.
Detailed Description
This is a Phase 1, single site, pilot study to evaluate the safety and immunogenicity of the M3 and M4 vaccines administered alone or in combination in HIV-infected participants suppressed on ART. This is a double blind, randomized, placebo-controlled, parallel design study to evaluate the safety and immunogenicity of viral-vector, MVA, expressing immunogens, tHIVconsv3 (M3) and tHIVconsv4 (M4), derived from conserved yet immunogenic regions of HIV-1. The participant population is HIV-1 infected adults suppressed on ART with plasma HIV-1 RNA \<50 copies/mL. Hypotheses: The administration of M3 or M4 or M3+M4 together will be safe in HIV-1-infected participants suppressed on ART. The simultaneous administration of M3 with M4 (M3+M4) will result in both an increase in total magnitude of HIV-1-specific T cell responses and increase the breadth of T cells targeting conserved regions of HIV-1 compared with either M3 or M4 vaccination alone. The vaccine and placebo doses will be administered to all participants as an IM (intramuscular) injection in the deltoid muscle of the non-dominant arm, unless a participant requests vaccination in their dominant arm. Participants continue their baseline ART regimen throughout the study. Randomized assignment 7:7:7:3 occurs at Day 0 to one of four arms as provided below: Arm 1 - 7 participants - Treatment: M3 - Dose (pfu): 2x10-8 - Route: IM; Arm 2 - 7 participants - Treatment: M4 - Dose (pfu): 2x10-8 - Route: IM; Arm 3 - 7 participants - Treatment: M3+M4 - Dose (pfu): 1x10-8, each vaccine - Route: IM; Arm 4 - 3 participants - Treatment: Placebo/saline - Dose: N/A - Route: IM; M3 = MVA.tHIVconsv3; M4 = MVA.tHIVconsv4; pfu = plaque forming units; IM = intramuscular The primary safety outcome is the occurrence of at least one ≥ Grade 3 Adverse Event (AE) including signs/symptoms, lab toxicities, and/or clinical events that are possibly, probably, or definitely related to study treatment through 28 days following vaccination. The primary safety analysis will be blinded through Day 28 after the last dose of vaccine/placebo and the second leukapheresis is completed by the last participant. Screening, Enrollment, and Leukapheresis. The participant reviews and signs the informed consent (ICF). Participants meeting eligibility requirements enroll and undergo one leukapheresis procedure between Day -60 and Day 0. The leukapheresis procedure collects white blood cells allowing for completion of detailed immunologic and virologic assays with minimal blood loss. Participants have the option to consent to a lymph node FNA; participants choosing this option will complete the pre-vaccine FNA between Day -60 and Day 0 and a post-vaccine FNA between Day 7 and Day 21. The post-vaccine FNA should be collected even if the pre-vaccine collection attempt is unsuccessful. Randomization, Study Treatment, Follow-up Assessment, and Leukapheresis. Randomization occurs at Day 0 when a randomization identification number (RID) will be assigned. All participants receive a vaccine or placebo dose as an IM injection. Post vaccination safety assessments occur via clinical evaluations, and lab testing/evaluations. The study will collect research assays at designated visits. At Day 28, all participants will undergo their 2nd leukapheresis. This procedure can be completed between Day 21 through Day 35. The leukapheresis product will be used for immunologic and virologic research assays post vaccine/placebo. Participants will be followed for immunogenicity assessments through Day 70 and safety assessments through Day 168 (Week 24) following the administration of vaccine/placebo at Day 0. Note: The post-vaccine leukapheresis must be done as close to Day 28 as possible. There may be a rare situation where the completion of the procedure in the 2-week visit window will not be possible. As soon as the study coordinator becomes aware of this scenario, the study coordinator should notify the study PI (or designee) to schedule the procedure outside the study window, preferably earlier (between Days 14 and 28). If the procedure can only be done after Day 35, participants should complete the Day 28 visit with collection of a 42.5 mL ACD sample at that visit.
Investigators
Eligibility Criteria
Inclusion Criteria
- •HIV 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, plasma HIV-1 RNA viral assay.
- •A reactive initial rapid test should be confirmed by either another type of rapid assay or an E/CIA that is based on a different antigen preparation and/or different test principle (e.g., indirect versus competitive), or a Western blot or a plasma HIV-1 RNA viral load.
- •WHO (World Health Organization) and CDC (Centers for Disease Control and Prevention) guidelines mandate that confirmation of the initial test result must use a test that is different from the one used for the initial assessment.
- •Ages ≥ 18 to ≤ 65 years old
- •Able and willing to give written informed consent.
- •Able and willing to provide adequate locator information.
- •Able and willing to comply with time requirements for protocol-specified visits and evaluations.
- •Able and willing to commit to all study visits including follow-up through Day 168 (Week 24).
- •Continuous ART prior to screening, defined as not missing more than 9 total days and never more than 4 consecutive days in the last 3 months.
- •On a stable ART regimen defined as no changes in any ART medication within the 30 days prior to screening.
Exclusion Criteria
- •If the HIV provider or study investigator is unable, as assessed by the study PI or protocol team, to construct a fully active alternative regimen based on previous resistance testing and/or treatment history.
- •Women of childbearing age/potential must not be breast feeding, pregnant, or planning pregnancy any time from enrollment to 4 months after vaccination at Day
- •Body Mass Index (BMI) ≥40 kg/m2
- •Untreated syphilis infection (defined as a positive rapid plasma reagin (RPR) without clear documentation of treatment).
- •NOTE: In cases of untreated syphilis, participant may rescreen following documentation of adequate treatment of syphilis.
- •Current treatment for HCV with antiviral therapy or participants who have received HCV treatment within 6 months prior to screening.
- •HIV RNA ≥150 copies/mL in the 6 months prior to screening.
- •Received any infusion blood product, immune globulin, or hematopoetic growth factors within 6 months prior to screening.
- •Use of any of the following within 90 days prior to screening: immunomodulatory, cytokine, or growth stimulating factors such as systemic cytotoxic chemotherapy, , immune globulin, interferon, cyclosporine, methotrexate, azathioprine, anti-CD25 antibody, IFN, interleukins, interleukin-2 (IL-2), hydroxyurea, thalidomide, sargramostim (granulocyte macrophage-colony stimulating factor \[GM-CSF\]), growth factors, dinitrochlorobenzene (DNCB), thymosin alpha, thymopentin, inosiplex, polyribonucleoside, or diticarb sodium, coumadin, warfarin, or other Coumadin derivative anticoagulants.
- •Intent to use immunomodulators (e.g., IL-2, IL-12, interferons or TNF modifiers) during the course of the study.
Outcomes
Primary Outcomes
Percent of Participants With a Grade 3 or Higher Treatment-Related Adverse Event (AE)
Time Frame: First day of study treatment through 28 days following vaccination
The DAIDS Table for Grading the Severity of Adult and Pediatric Adverse Events (DAIDS AE Grading Table), corrected Version 2.1, July 2017 will be used to measure safety where Grade 3 is defined as severe and Grade 4 is defined as potentially life-threatening. Treatment-Related AEs will be assessments that are considered related to study product as possible, probable, or definite as defined in the protocol.
Secondary Outcomes
- Percent of Participants With a Grade 1 or Higher Treatment-Related Adverse Event (AE)(First day of study treatment through Day 168 (Week 24) following vaccination)