A Phase I/IIa Randomized, Placebo-Controlled Trial of Conserved-Mosaic T-cell Vaccine in a Regimen With Vesatolimod and Broadly Neutralizing Antibodies in Adults Initiated on Suppressive Antiretroviral Therapy During Acute HIV-1
Overview
- Phase
- Phase 1
- Intervention
- ChAdOx1.tHIVconsv1
- Conditions
- HIV-1-infection
- Sponsor
- National Institute of Allergy and Infectious Diseases (NIAID)
- Enrollment
- 36
- Locations
- 12
- Primary Endpoint
- Occurrence of any serious adverse event (AE), Grade 3 or higher AE, or AE that leads to permanent discontinuation of study treatment regardless of grade, that is related to ChAdOx1-MVA/HIVconsvX vaccines, vesatolimod, GS-5423 or GS-2872
- Status
- Recruiting
- Last Updated
- 2 months ago
Overview
Brief Summary
The purpose of this study is to evaluate the safety, tolerability, and efficacy of therapeutic vaccination with chimpanzee adenovirus ChAdOx1- and poxvirus modified vaccinia Ankara (MVA)-vectored conserved mosaic T-cell vaccines in a sequential regimen with the toll-like receptor 7 (TLR7) agonist vesatolimod (VES) and two broadly neutralizing antibodies (bNAbs) compared to placebo, to induce HIV-1 control during analytic treatment interruption (ATI).
Detailed Description
A5374 is a phase I/IIa randomized, two-arm, double-blind placebo-controlled, multi-step strategy trial to evaluate safety and efficacy of therapeutic vaccination with chimpanzee adenovirus ChAdOx1- and poxvirus modified vaccinia Ankara (MVA)-vectored conserved mosaic T-cell vaccines in a sequential regimen with the toll-like receptor 7 (TLR7) agonist vesatolimod (VES) and two broadly neutralizing antibodies (bNAbs) of the CD4 binding site and V3-loop base classes in individuals with HIV-1 who started suppressive antiretroviral therapy (ART) during acute HIV-1. Participants will be screened for eligibility and have a pre-entry visit. After determination of eligibility, participants will be randomized prior to entry to either the active intervention arm (Arm A) or the placebo arm (Arm B) in a 2:1 ratio. The study consists of four steps including an analytical treatment interruption (ATI). * Step 1: Study Intervention and ART (67 weeks) * Step 2: Analytic Treatment Interruption (up to 24 weeks) * Step 3: ART Restart (24 weeks) * Step 4: Continuation of ATI (up to 24 weeks) Each participant will complete Step 1 and Step 2. At the end of Step 2, participants who have experienced virologic rebound will enter Step 3 and resume ART. Participants who did not meet ART restart criteria after 24 weeks in Step 2 will enter Step 4 for an extended ATI. Each participant will be enrolled for up to approximately 110 weeks. The total time on study for each participant is dependent on the time spent in the treatment interruption steps (Step 2 and 4).
Investigators
Eligibility Criteria
Inclusion Criteria
- •Provision of written informed consent.
- •History of Initiation of combination ART within 90 days of acute HIV diagnosis
- •On ART for at least 12 months with no known ART interruption \>28 consecutive days within 12 months prior to Step 1 Study Entry
- •ART with an integrase inhibitor-based regimen with two NRTIs or dolutegravir/lamivudine regimen for at least 6 weeks prior to Study Entry.
- •Willingness to participate in the ATI and willingness to restart ART according to study guidelines.
- •Willingness to adhere to protocol therapy and complete all study visits.
- •Weight ≥50 kg and ≤150 kg at Screening.
- •CD4 cell count ≥500 cells/mm3 obtained within 60 days prior to Study Entry.
- •HIV-1 RNA \<50 copies/mL (or below the assay limit of quantification if local assay lower limit of quantification is \>50 copies/mL) for at least 1 year and within 60 days prior to Study Entry.
- •Select laboratory results within 60 days of study entry
Exclusion Criteria
- •Currently pregnant or breastfeeding or planning to become pregnant during study participation.
- •Prior receipt of anti-HIV broadly neutralizing antibody therapy.
- •Receipt of any non-HIV monoclonal antibody therapy within 1 year prior to study entry.
- •Prior receipt of a latency-reversing agent (LRA).
- •Receipt of HIV-1 or other investigational vaccines within 6 months prior to Study Entry.
- •Receipt of a live-virus vaccine within 60 days or any vaccination within 14 days prior to Study Entry.
- •Receipt of any simian adenovirus-vectored vaccine (e.g., anti-COVID-19 AZD1222) within 12 months prior to Step 1 Study Entry.
- •Known allergy/sensitivity or any hypersensitivity to components of study treatments or their formulations.
- •Known severe chicken egg allergy.
- •Known history of a severe reaction or anaphylaxis to prior vaccinations or antibody preparations (e.g., intravenous immunoglobulin).
Arms & Interventions
Arm A: Active ChAdOx1 and MVA/HIVconsvX vaccines, vesatolimod and bnAbs
Intervention: ChAdOx1.tHIVconsv1
Arm A: Active ChAdOx1 and MVA/HIVconsvX vaccines, vesatolimod and bnAbs
Intervention: ChAdOx1.HIVconsv62
Arm A: Active ChAdOx1 and MVA/HIVconsvX vaccines, vesatolimod and bnAbs
Intervention: MVA.tHIVconsv3
Arm A: Active ChAdOx1 and MVA/HIVconsvX vaccines, vesatolimod and bnAbs
Intervention: MVA.tHIVconsv4
Arm A: Active ChAdOx1 and MVA/HIVconsvX vaccines, vesatolimod and bnAbs
Intervention: Vesatolimod (VES)
Arm A: Active ChAdOx1 and MVA/HIVconsvX vaccines, vesatolimod and bnAbs
Intervention: GS-5423
Arm A: Active ChAdOx1 and MVA/HIVconsvX vaccines, vesatolimod and bnAbs
Intervention: GS-2872
Arm B: Placebos for vaccines, vesatolimod and bnAbs
Intervention: Placebo
Outcomes
Primary Outcomes
Occurrence of any serious adverse event (AE), Grade 3 or higher AE, or AE that leads to permanent discontinuation of study treatment regardless of grade, that is related to ChAdOx1-MVA/HIVconsvX vaccines, vesatolimod, GS-5423 or GS-2872
Time Frame: Week 0 to Week 64
Proportion of participants with viral control during an ATI defined as remaining off ART with HIV-1 RNA <1,000 copies/mL at Week 16 following ATI.
Time Frame: Week 0 to Week 16 on Step 2
Secondary Outcomes
- Change in plasma HIV-1 RNA viral load as measured by single copy assay (SCA)(Weeks 0 to Week 24 on Step 2)
- HIV-1-specific T-cell responses to the conserved regions present in the vaccines as measured by IFN-γ ELISPOT - total frequency and breadth (number of recognized peptide pools out of 10).(Week 0 to Week 24 on Step 2)
- Change in cell-associated HIV-1 RNA and DNA levels(Weeks 0 to Week 24 on Step 2)
- Change in intact proviral DNA levels (IPDA)(Weeks 0 to Week 24 on Step 2)
- Change in soluble markers of systemic inflammation and immune activation: sCD163 (pg/mL)(Weeks 0 to Week 24 on Step 2)
- Change in soluble markers of systemic inflammation and immune activation: sCD14 (pg/mL)(Weeks 0 to Week 24 on Step 2)
- Change in soluble markers of systemic inflammation and immune activation: IL-6 (pg/mL)(Weeks 0 to Week 24 on Step 2)
- Change in soluble markers of systemic inflammation and immune activation: sTNFαR (pg/mL)(Weeks 0 to Week 24 on Step 2)
- Changes in soluble markers of systemic inflammation and immune activation: hsCRP (pg/mL)(Weeks 0 to Week 24 on Step 2)
- Change in HIV-specific CD8+ T-cell-mediated viral inhibition as measured by in vitro virus inhibition assay (VIA) using representative viruses from major HIV-1 clades of group M.(Weeks 0 to Week 24 on Step 2)
- Occurrence of Medically Attended Adverse Events (MAAEs)(Week 0 on Step 1 to 12 months following the last dose of study vaccination)
- Time to first HIV-1 RNA ≥1000 copies/mL after ATI.(Week 0 to Week 24 on Step 2)
- Occurrence of Adverse Events of Special Interest (AESIs)(Week 0 on Step 1 to 12 months following the last dose of study vaccination)