Triple immune regimen combining T-cell vaccines, a TLR7 agonist, and two broadly neutralizing antibodies for adults who began 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

This trial tests whether giving conserved-mosaic T-cell vaccines plus the TLR7 drug vesatolimod and two broadly neutralizing antibodies can help people who started ART during acute HIV stay controlled off daily therapy.

Quick facts

• Phase: Phase1; Phase2
• Study type: Interventional
• Enrollment: 36 (estimated)
• Ages: 18 Years and up
• Sex: All
• Sponsor: National Institute of Allergy and Infectious Diseases (NIAID) (NIH)
• Locations: 12 sites (San Diego, California and 11 other locations)
• Trial ID: NCT06071767 on ClinicalTrials.gov

What this trial studies

A5374 is a randomized, double-blind, placebo-controlled Phase 1/2a trial that enrolls adults who began suppressive ART during acute HIV-1 and randomizes them 2:1 to receive an active combination regimen or matched placebo. The active regimen uses sequential chimpanzee adenovirus (ChAdOx1) and MVA-vectored conserved mosaic T-cell vaccines, repeated dosing of the TLR7 agonist vesatolimod, and two broadly neutralizing antibodies targeting the CD4 binding site and V3-loop base. Participants complete a multi-step protocol including ~67 weeks of interventions, an analytical treatment interruption (up to 24 weeks), monitored ART restart if viral rebound occurs, and possible extended ATI, with total participation up to ~110 weeks. The primary focus is safety, tolerability, immunogenicity, and whether the combination can induce control of HIV during ATI compared with placebo.

Who should consider this trial

Good fit: Adults who initiated combination ART within 90 days of acute HIV diagnosis, have been virologically suppressed on ART for at least one year, have CD4 counts ≥500 cells/mm3, meet weight and lab criteria, and are willing to undergo and adhere to an analytic treatment interruption are ideal candidates.

Not a fit: People who started ART in chronic infection, who are not virologically suppressed, have low CD4 counts, are pregnant or unwilling to stop ART or attend frequent visits are unlikely to benefit from this protocol.

Why it matters

Potential benefit: If successful, the regimen could enable durable immune control of HIV off antiretroviral therapy for people treated during acute infection, reducing dependence on daily ART.

How similar studies have performed: Prior animal studies and early human trials of individual components (bNAbs, TLR7 agonists, or therapeutic vaccines) have shown mixed or limited success and combination approaches remain promising but largely unproven in humans.

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
* 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 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).
* 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 Step 1 Study Entry.
* History of use of any immunomodulatory medications within the 6 months prior to Step 1 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.

Where this trial is running

San Diego, California and 11 other locations

• University of California, San Diego AntiViral Research Center CRS — San Diego, California, United States (Recruiting)
• Ponce de Leon Center CRS — Atlanta, Georgia, United States (Recruiting)
• Northwestern University CRS — Chicago, Illinois, United States (Recruiting)
• Massachusetts General Hospital CRS (MGH CRS) — Boston, Massachusetts, United States (Not_yet_recruiting)
• Washington University Therapeutics CRS — St Louis, Missouri, United States (Recruiting)
• Columbia Physicians & Surgeons CRS — New York, New York, United States (Recruiting)
• Chapel Hill CRS — Chapel Hill, North Carolina, United States (Recruiting)
• Ohio State University CRS — Columbus, Ohio, United States (Recruiting)
• Penn Therapeutics CRS — Philadelphia, Pennsylvania, United States (Recruiting)
• Houston AIDS Research Team CRS — Houston, Texas, United States (Recruiting)
• Instituto de Pesquisas em AIDS do Rio Grande do Sul - IPARGS CRS — Porto Alegre, Rio Grande do Sul, Brazil (Recruiting)
• Instituto de Pesquisa Clinica Evandro Chagas (IPEC) CRS — Rio de Janeiro, Brazil (Not_yet_recruiting)

Conditions HIV-1-infection; Suppressive Antiretroviral Therapy; HIV; Acute HIV-1; HIV vaccine; T-cell vaccine; Therapeutic T-cell vaccine; ChAdOx1