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).
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 analytic treatment interruption (ATI) for all participants, and two subsequent optional steps including a second ATI for placebo participants. * 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) * Step 5 (optional): Study Intervention and ART (Placebo roll-over) * Step 6 (optional): Analytic Treatment Interruption 2 (ATI 2) Each participant will complete Step 1 and Step 2. At any time on Step 2\[mw1.1\]\[KM1.2\], participants on Arm A who meet criteria to restart ART will enter Step 3 and resume ART. Arm B (placebo) participants who have experienced virologic restart criteria may choose to enter Step 3 to resume ART or elect to enter Step 5 to resume ART and receive active study products. Participants who elect to enter Step 5 will undergo second ATI in Step 6. Participants who do 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). Eligible participants participating in for Steps 5 and 6 will have up to 110 additional weeks on study.
Study Type
INTERVENTIONAL
Allocation
RANDOMIZED
Purpose
TREATMENT
Masking
DOUBLE
Enrollment
36
Administered as 0.4 mL intramuscularly (IM) at Week 0
Administered as 0.3 mL IM at Week 0
Administered as 0.3 mL IM at Week 4
Administered as 0.5 mL IM at week 4
VES 6 mg administered orally once every 2 weeks for two doses, then VES 8 mg once every 2 weeks for 8 doses. Dose escalation may be held or the 8 mg dose may be reduced for intolerability for weeks 6 through 24.
Administered via intravenous (IV) infusion at week 7
Administered via IV infusion at week 7
Administered 0.5 mL IM at week 60
Placebos for vaccines, VES, and bnAbs
University of California, San Diego AntiViral Research Center CRS
San Diego, California, United States
Ponce de Leon Center CRS
Atlanta, Georgia, United States
Northwestern University CRS
Chicago, Illinois, United States
Massachusetts General Hospital CRS (MGH CRS)
Boston, Massachusetts, United States
Washington University Therapeutics CRS
St Louis, Missouri, United States
Chapel Hill CRS
Chapel Hill, North Carolina, United States
Ohio State University CRS
Columbus, Ohio, United States
Penn Therapeutics CRS
Philadelphia, Pennsylvania, United States
Houston AIDS Research Team CRS
Houston, Texas, United States
Instituto de Pesquisa Clinica Evandro Chagas (IPEC) CRS
Rio de Janeiro, Brazil, Brazil
...and 1 more locations
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
Change in cell-associated HIV-1 RNA and DNA levels
Time frame: Weeks 0 to Week 24 on Step 2
Change in plasma HIV-1 RNA viral load as measured by single copy assay (SCA)
Time frame: Weeks 0 to Week 24 on Step 2
Change in intact proviral DNA levels (IPDA)
Time frame: 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).
Time frame: Week 0 to Week 24 on Step 2
Change in soluble markers of systemic inflammation and immune activation: sCD163 (pg/mL)
Time frame: Weeks 0 to Week 24 on Step 2
Change in soluble markers of systemic inflammation and immune activation: sCD14 (pg/mL)
Time frame: Weeks 0 to Week 24 on Step 2
Change in soluble markers of systemic inflammation and immune activation: IL-6 (pg/mL)
Time frame: Weeks 0 to Week 24 on Step 2
Change in soluble markers of systemic inflammation and immune activation: sTNFαR (pg/mL)
Time frame: Weeks 0 to Week 24 on Step 2
Changes in soluble markers of systemic inflammation and immune activation: hsCRP (pg/mL)
Time frame: Weeks 0 to Week 24 on Step 2
Time to first HIV-1 RNA ≥1000 copies/mL after ATI.
Time frame: Week 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.
Time frame: Weeks 0 to Week 24 on Step 2
Occurrence of Medically Attended Adverse Events (MAAEs)
Time frame: Week 0 on Step 1 to 12 months following the last dose of study vaccination
Occurrence of Adverse Events of Special Interest (AESIs)
Time frame: Week 0 on Step 1 to 12 months following the last dose of study vaccination
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