MVA.tHIVconsv3

Even within the context of antiretroviral treatment and prevention, an HIV-1 vaccine remains the best strategy for ending the HIV/AIDS epidemic. A vaccine is particularly needed in sub-Saharan Africa, where HIV-1 greatly affects people's lives and economy. Here, we aimed to assess the safety and immunogenicity of candidate T-cell vaccines in African populations.

HIV-CORE 006 was a double-blind, randomised, placebo-controlled phase 1 trial conducted across four clinical research centres in Uganda, Kenya, and Zambia. Eligible participants were not pregnant, were living without HIV-1 or HIV-2, had a low likelihood of acquiring HIV-1, were aged 18-50 years, fully comprehended the purpose and details of this study as outlined in the participant information sheet, and passed an assessment of understanding before providing written informed consent. Participants were randomly assigned (9:2) to receive either a vaccine regimen or a placebo. The vaccine was administered as ChAdOx1.tHIVconsv1 (C1) followed by MVA.tHIVconsv3 (M3) and MVA.tHIVconsv4 (M4) in regimen C1-M3M4. The first primary outcome was the vaccines' safety assessment, assessed in all participants who received at least one vaccine or placebo dose. The second primary outcome evaluated the C1-M3M4 regimen's induction of HIVconsvX-specific T-cell responses by assessing the proportion of vaccine recipients who responded to the vaccination, assessed in all participants who received all doses of vaccine or placebo as per protocol. This study is registered with ClinicalTrials.gov, NCT04553016, and the Pan-African Clinical Trials Registry PACTR202006495409011, and is now closed.

Between July 15, 2021, and Nov 2, 2022, 89 healthy adults living without HIV-1 were randomly assigned, with 88 receiving either the vaccine (n=72) or placebo (n=16). Of these 88 participants, 57 (65%) were male and 31 (35%) were female. The C1, M3, and M4 vaccine components were well tolerated and induced HIVconsvX-specific responses in 70 (99%) of the 71 participants who completed all vaccine doses. Vaccine-elicited T cells peaked at a median of 2310 (IQR 1080-4480) IFN-γ spot-forming units per 10⁶ peripheral blood mononuclear cells and recognised a median of eight (five to ten) of ten peptide pools spanning the HIVconsvX immunogen. The total frequencies of elicited T cells decreased 4·6 times over a 40-week follow-up period compared with the peak responses. Upon antigenic re-exposure, T cells proliferated, exhibited multiple effector functions, and inhibited HIV-1 representatives from clades A, B, C, and D.

Results from key sub-Saharan African populations supported the safety of the vaccine regimen previously shown in the first-in-human trial in the UK. The induction of T cells and their characteristics encourage vaccine integration into HIV-1 cure strategies, which could inform HIV-1 prevention efforts.

The European and Developing Countries Clinical Trials Partnership.

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.

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.

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.

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.

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.