Evaluation of Safety, Immunogenicity and Efficacy of a Triple Immune Regimen in Adults Initiated on ART During Acute HIV-1

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

The purpose of this study is to evaluate the safety, tolerability, and efficacy of therapeutic vaccination with chimpanzee adenovirus (ChAdV)- 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).

Study Overview

• Status: Recruiting
• Conditions: HIV-1-infection
• Intervention / Treatment: Biological: ChAdOx1.tHIVconsv1; Biological: ChAdOx1.HIVconsv62; Biological: MVA.tHIVconsv3; Biological: MVA.tHIVconsv4; Drug: Vesatolimod (VES); Drug: GS-5423; Drug: GS-2872; Biological: MVA.tHIVconsv4; Biological: Placebo

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 (ChAdV)- 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 with continued virologic control for 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).

• Study Type: Interventional
• Enrollment (Estimated): 45
• Phase: Phase 2; Phase 1

Contacts and Locations

Study Locations

• Brazil
  • Rio De Janeiro, Brazil
    • Not yet recruiting
    • Instituto de Pesquisa Clinica Evandro Chagas (IPEC) CRS
    • Contact: Brenda Hoagland, MD; Phone Number: 55-21-38659122; Email: brenda.hoagland@ipec.fiocruz.br
• United States
  • California
    • San Diego, California, United States, 92103
      • Recruiting
      • University of California, San Diego AntiViral Research Center CRS
      • Contact: Steven Hendrickx, BSN; Phone Number: 619-543-6968; Email: smhendrickx@health.ucsd.edu
  • Georgia
    • Atlanta, Georgia, United States, 30308
      • Recruiting
      • Ponce de Leon Center CRS
      • Contact: Ericka Patrick, RN, MSN; Phone Number: 404-616-6313; Email: erpatri@emory.edu
  • Illinois
    • Chicago, Illinois, United States, 60611
      • Recruiting
      • Northwestern University CRS
      • Contact: Baiba Berzins, MPH; Phone Number: 312-695-5012; Email: baiba@northwestern.edu
  • Massachusetts
    • Boston, Massachusetts, United States, 02114
      • Not yet recruiting
      • Massachusetts General Hospital CRS (MGH CRS)
      • Contact: Amy Sbrolla, ACRN, BSN; Phone Number: 617-726-5598; Email: asbrolla@mgh.harvard.edu
  • Missouri
    • Saint Louis, Missouri, United States, 63110
      • Recruiting
      • Washington University Therapeutics CRS
      • Contact: Michael Klebert, RN, NP-C, PhD; Phone Number: 314-747-1098; Email: mklebert@wustl.edu
  • New York
    • New York, New York, United States, 10032
      • Recruiting
      • Columbia Physicians & Surgeons CRS
      • Contact: Mascha Elskamp; Phone Number: 212-305-2201; Email: me2500@cumc.columbia.edu
  • North Carolina
    • Chapel Hill, North Carolina, United States, 27599
      • Recruiting
      • Chapel Hill CRS
      • Contact: Erin Hoffman, BS; Phone Number: 919-843-0720; Email: erin_hoffman@med.unc.edu
    • Greensboro, North Carolina, United States, 27401
      • Not yet recruiting
      • Greensboro CRS
      • Contact: Kim Epperson, RN, BSN, CCRC; Phone Number: 336-832-3262; Email: kim.epperson@conehealth.com
      • Contact: Kelly Phillips, PAC, MPAS; Phone Number: 336-832-7297; Email: kelly.phillips@conehealth.com
  • Ohio
    • Cincinnati, Ohio, United States, 45267
      • Not yet recruiting
      • Cincinnati CRS
      • Contact: Michelle Saemann, RN; Phone Number: 513-584-2245; Email: saemanmd@ucmail.uc.edu
    • Columbus, Ohio, United States, 43210
      • Recruiting
      • Ohio State University CRS
      • Contact: Lindsay Summers, MPH; Phone Number: 614-293-8529; Email: Lindsay.Summers@osumc.edu
  • Pennsylvania
    • Philadelphia, Pennsylvania, United States, 19104
      • Recruiting
      • Penn Therapeutics CRS
      • Contact: Jamie Doyle; Phone Number: 215-615-2316; Email: jamie.doyle1@pennmedicine.upenn.edu
  • Texas
    • Houston, Texas, United States, 77004
      • Recruiting
      • Houston AIDS Research Team CRS
      • Contact: Maria Martinez, BS; Phone Number: 713-500-6718; Email: maria.l.martinez@uth.tmc.edu

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: Adult; Older Adult
• Accepts Healthy Volunteers: No

Description

Inclusion Criteria

• Provision of written informed consent.
• History of Initiation of combination ART within 28 days of acute HIV diagnosis
• No known ART interruption >14 consecutive days since initiation of ART.
• 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 ≤115 kg at Screening.
• CD4 cell count ≥500 cells/mm3 obtained within 60 days prior to study Entry.
• HIV-1 RNA <50 copies/mL since initial viral suppression on ART and for at least 1 year and within 60 days prior to study Entry.
• Select laboratory results within 60 days of study entry
• For cisgender women and transgender men of reproductive potential, negative urine or serum pregnancy test within 48 hours prior to or at study Entry.
• Participants who are able to become pregnant and who are engaging in sexual activity that could lead to pregnancy must agree to use two methods of contraception, one of which must be a highly effective methods for contraception. Barrier methods of contraception are required for the second method of contraception.
• Availability of results of HLA typing (required for randomization).
• Completion of pre-entry leukapheresis or LVBD.

Exclusion Criteria

• Currently pregnant or breastfeeding or planning to become pregnant during study participation.
• Prior receipt of monoclonal antibody therapy (except for COVID treatment).
• 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 entry.
• Prior receipt of any simian adenovirus-vectored vaccine (e.g., anti-COVID-19 AZD1222).
• 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).
• Significant drug sensitivity or drug allergy (such as anaphylaxis or hepatoxicity).
• Any history of anaphylaxis and related symptoms such as hives, respiratory difficulty, or angioedema.
• Previous or current history of bleeding factor deficiency, coagulopathy or platelet disorder or on chronic anticoagulation.
• History of inflammatory neurologic diseases.
• History of pregnancy, head trauma or major surgery within 90 days prior to study Entry.
• History of use of any immunomodulatory medications within the 6 months prior to study entry.
• Significant serious skin disease, such as but not limited to active rash, eczema, psoriasis, or urticaria.
• Autoimmune disease (e.g., lupus, multiple sclerosis, and others) requiring ongoing immunosuppression.
• Known history of CDC Stage 3 opportunistic infection (OI).
• Any history of an HIV-associated malignancy.
• Known or suspected active or untreated latent Mycobacterium tuberculosis infection.
• Active or recent non-HIV-associated malignancy.
• Serious illness requiring systemic treatment and/or hospitalization within 90 days prior to study entry.
• Known resistance to one or more drugs in two or more ARV drug classes.
• History of or current clinical atherosclerotic cardiovascular disease
• Current advanced liver disease.
• Use of complementary or alternative medicines within 14 days prior study entry.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Double

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Arm A: Active ChAdV and MVA vaccines, vesatolimod and bnAbs	Biological: ChAdOx1.tHIVconsv1; Administered as 0.4 mL intramuscularly (IM) at Week 0; Biological: ChAdOx1.HIVconsv62; Administered as 0.3 mL IM at Week 0; Biological: MVA.tHIVconsv3; Administered as 0.3 mL IM at Week 4; Biological: MVA.tHIVconsv4; Administered as 0.5 mL IM at week 4; Drug: Vesatolimod (VES); 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.; Drug: GS-5423; Administered via intravenous (IV) infusion at week 7; Other Names: 3BNC117-LS; Drug: GS-2872; Administered via IV infusion at week 7; Other Names: 10-1074-LS; Biological: MVA.tHIVconsv4; Administered 0.5 mL IM at week 60
Placebo Comparator: Arm B: Placebos for vaccines, vesatolimod and bnAbs	Biological: Placebo; Placebos for vaccines, VES, and bnAbs

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Time Frame
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, VES, GS-5423 or GS-2872	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.	Week 0 to Week 16 on Step 2

Secondary Outcome Measures

Outcome Measure	Time Frame
Change in cell-associated HIV-1 RNA and DNA levels	Weeks 0 to Week 24 on Step 2
Change in plasma HIV-1 RNA viral load as measured by single copy assay (SCA)	Weeks 0 to Week 24 on Step 2
Change in intact proviral DNA levels (IPDA)	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 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
Time to first HIV-1 RNA ≥1000 copies/mL after ATI.	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.	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
Occurrence of Adverse Events of Special Interest (AESIs)	Week 0 on Step 1 to 12 months following the last dose of study vaccination

Collaborators and Investigators

• Sponsor: National Institute of Allergy and Infectious Diseases (NIAID)
• Collaborators: Gilead Sciences; University of Oxford
• Investigators: Study Chair: Sharon Riddler, MD, MPH, University of Pittsburgh

Study record dates

Study Major Dates

• Study Start (Actual): April 1, 2024
• Primary Completion (Estimated): April 29, 2026
• Study Completion (Estimated): April 29, 2026

Study Registration Dates

• First Submitted: September 5, 2023
• First Submitted That Met QC Criteria: October 4, 2023
• First Posted (Actual): October 6, 2023

Study Record Updates

• Last Update Posted (Actual): April 9, 2024
• Last Update Submitted That Met QC Criteria: April 8, 2024
• Last Verified: April 1, 2024

More Information

Terms related to this study

• Keywords: HIV; Antibodies; Therapeutic vaccine; HIV vaccine; Broadly neutralizing antibody; TLR7; Suppressive Antiretroviral Therapy; Acute HIV-1; Toll-like receptor 7 agonist; HIV vaccines; HIV antibody; HIV Broadly neutralizing antibody
• Additional Relevant MeSH Terms: Anti-Infective Agents; Antiviral Agents; Vesatolimod
• Other Study ID Numbers: A5374; 12025 (Other Identifier: DAIDS-ES ID); HIV-CORE 009 (Other Identifier: University of Oxford clinical program for developing T-cell vaccines for conserved HIV protein regions)

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: YES
• IPD Sharing Time Frame: Beginning 3 months following publication and available throughout period of funding of the AIDS Clinical Trials Group by NIH.
• IPD Sharing Access Criteria: With whom? Researchers who provide a methodologically sound proposal for use of the data that is approved by the AIDS Clinical Trials Group.; For what types of analyses? To achieve aims in the proposal approved by the AIDS Clinical Trials Group.; By what mechanism will data be made available? Researchers may submit a request for access to data using the AIDS Clinical Trials Group "Data Request" form at: https://actgnetwork.org/submit-a-proposal/. Researchers of approved proposals will need to sign an AIDS Clinical Trials Group Data Use Agreement before receiving the data.
• IPD Sharing Supporting Information Type: STUDY_PROTOCOL; SAP

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No