Safety and immunogenicity of the ChAdOx1-MVA-vectored conserved mosaic HIVconsvX candidate T-cell vaccines in HIV-CORE 005.2, an open-label, dose-escalation, first-in-human, phase 1 trial in adults living without HIV-1 in the UK.

BACKGROUND: An HIV-1 vaccine is long overdue. Although vaccine research focuses on the induction of broadly neutralising antibodies, challenging infections such as HIV-1 could require parallel induction of protective T cells. It is important to recognise that not all T cells contribute to protection equally. Previously, we developed a T-cell immunogen-based bivalent mosaic vaccine, HIVconsvX, delivered by vaccine vectors ChAdOx1 and modified vaccinia Ankara. In this study, we tested the HIVconsvX vaccine regimen for the first time in humans. Other ongoing trials will assess the contribution of the vaccine-induced killer T cells to the control of HIV-1. METHODS: HIV-CORE 005.2 was an open-label, dose-escalation, first-in-human, phase 1 trial done at the Centre for Clinical Vaccinology and Tropical Medicine, University of Oxford, Oxford, UK. Eligible participants were healthy volunteers aged 18-65 years living without HIV-1 and at a low likelihood of acquiring it. Because it was the first administration of ChAdOx1.tHIVconsv1 (C1) to humans, participants were assigned stepwise to two groups. Volunteer group 1 received a low dose of C1 on enrolment. Following a satisfactory safety review 7 days after vaccination, volunteer group 2 received a full dose of C1 boosted by vaccines MVA.tHIVconsv3 (M3) and MVA.tHIVconsv4 (M4) 4 weeks later in regimen C1-M3M4 and were followed up until day 140. Focusing on the full vaccine doses in group 2, the primary outcome was the local and systemic safety of the vaccine. The secondary outcome was the frequency and breadth of epitope recognition by vaccine-induced T cells determined by IFN-γ ELISPOT assay using peripheral blood mononuclear cells (PBMC) at peak (1 and 2 weeks after the M3M4 boost) and at the end of the study, assessed against volunteer's pre-vaccination levels. The HIV-CORE 005.2 trial is registered at ClinicalTrials.gov (NCT04586673) and is closed. FINDINGS: Between July 3, 2021, and Aug 3, 2022, 13 participants were recruited and assigned to group 1 (n=3) and group 2 (n=10). Low-dose C1 was safe and well tolerated in group 1, and all three vaccine components were well tolerated in volunteer group 2. There were no serious adverse events. Local and systemic reactogenicities were consistent with intramuscular needle administration of immunogenic substances. All volunteers responded, and their vaccine-elicited T-cell frequencies peaked at a median of 4433 (IQR 2750-5820) IFN-γ spot-forming units per 106 PBMC and recognised a median of 9 (IQR 9-10) peptide pools out of 10, indicating that the responses were broadly specific and each vaccine recipient targeted at least nine epitopes on HIV-1. These frequencies were 7·4 times lower by day 140 (ie, 3 months later). T cells proliferated upon antigen re-exposure and displayed multiple effector functions, recognised variant epitopes, and inhibited HIV-1 from the four major global clades A, B, C, and D. INTERPRETATION: These results inform and support a programme of clinical evaluations of the HIVconsvX T-cell vaccines together with other cutting-edge tools for HIV-1 cure and prevention such as latency reactivating agents, passively infused combinations of broadly neutralising antibodies, and active Env-based vaccines or immunomodulators. FUNDING: EU Horizon 2020 Research and Innovation programme, Medical Research Council and Foreign Commonwealth and Development Office Concordat agreement, European and Developing Countries Clinical Trials Partnership, National Institute for Health Research Oxford Biomedical Research Centre, and IAVI.