A Phase I/IIa Clinical Trial of HIV-1 Vaccines pSG2.HIVconsv DNA, MVA.HIVconsv and Ad35-GRIN in Combined Regimens in Healthy HIV-1/2-negative Adults in Nairobi.

The study is part of a long-term aim to develop an effective HIV-1 vaccine and will evaluate safety and immunogenicity of vaccines focusing T cell responses on the conserved region of the HIV-1 proteome. The vaccines used are pSG2.HIVconsv DNA (D), MVA.HIVconsv (M) and Ad35-GRIN (A), delivered in regimens AM, DDDAM and DeDeDeAM, where e indicates electroporation.

Start Date01 Mar 2014

Sponsor / Collaborator

University of Oxford

[+4]

NCT02425241 / CompletedPhase 1/2IIT

A Randomised Double-blind, Placebo-controlled Phase I/IIa Trial to Investigate the Effect of Depletion of Serum Amyloid P Component (SAP) on the Immune Response to DNA Vaccination in Healthy Male Volunteers

This is a clinical proof-of-concept (PoC) study of DNA vaccination after SAP depletion. The investigators will measure the immune responses to DNA vaccination against HIV-1 in healthy adult male volunteers, comparing a group in whom SAP has been completely depleted at the time of DNA vaccination and a control group vaccinated without SAP depletion.

Start Date01 Oct 2013

Sponsor / Collaborator

University College London

[+3]

100 Clinical Results associated with pSG2.HIVconsv(University of Oxford)

100 Translational Medicine associated with pSG2.HIVconsv(University of Oxford)

100 Patents (Medical) associated with pSG2.HIVconsv(University of Oxford)

Literatures (Medical) associated with pSG2.HIVconsv(University of Oxford)

01 Mar 2020·The LancetQ1 · MEDICINE

Antiretroviral therapy alone versus antiretroviral therapy with a kick and kill approach, on measures of the HIV reservoir in participants with recent HIV infection (the RIVER trial): a phase 2, randomised trial

Q1 · MEDICINE

Article

Author: Kelly, Damian ; Collins, Simon ; Fitzpatrick, Colin ; O'Rourke, Patrick ; Wills, Mark ; Topping, Katie ; Babiker, Abdel ; Hague, Dominic ; Kinloch-de Loes, Sabine ; Merle, Simon ; Gleig, Rebecca ; Finnerty, Fiounnuala ; Lever, Andrew ; Cuthbertson, Zoe ; Howell, Bonnie ; Ngwu, Nnenna ; Anderson, Jane ; Murray, Tammy ; Robinson, Nicola ; Erlwein, Otto ; Fisher, Martin ; Weller, Ian ; Crook, Alison ; Adams, Tanya ; Trevitt, Vittorio ; Fedele, Serge ; Jendrulek, Isabel ; Box, Hanna ; Markham, Alex ; Sasieni, Peter ; Nwokolo, Nneka ; Thomas, Lervina ; McClure, Myra ; Brown, Helen ; Lukha, Hinal ; Darbyshire, Janet ; Schoolmeesters, Alexandra ; Nightingale, Alice ; Hudson, Fleur ; Johnson, Margaret ; Sandström, Eric ; Rowlands, Jane ; Pace, Matt ; Post, Frank ; Olejniczak, Natalia ; Conlon, Christopher ; Uzu, Hiromi ; Kingsley, Cherry ; Peto, Timothy ; Pace, Matthew ; Gregory, Adam ; Cerrone, Maddalena ; Weaver, Christine ; Shidfar, Shaadi ; Khan, Maryam ; Jones, Martin ; Frater, John ; Lwanga, Julianne ; Taylor, Mark ; Kaye, Steven ; Pett, Sarah ; Lewis, Heather ; Thunder, Orla ; Kuldanek, Kristin ; Wu, Guoxin ; Sy, Aminata ; Sowunmi, Yinka ; Barnard, Richard ; Russell, Charlotte ; Higgs, Christopher ; Wood, Gemma ; Fidler, Sarah ; Clarke, Amanda ; Castrillo Martinez, Nadia ; Miller, Veronica ; Bennett, Rachel ; Hanke, Tomáš ; Bandara, Mikaila ; Fiorino, Marzia ; Tiraboschi, Juan Manuel ; Lawrenson, Gaynor ; Fun, Axel ; Bracchi, Margherita ; Fernandez, Tina ; Lovell, Andrew ; Thornhill, John ; Gabrielle, Michelle ; Fox, Julie ; ZarkoFlynn, Taras ; Bourke, Peter ; Stöhr, Wolfgang ; Yang, Hongbing ; Lee, Ming ; Maini, Mala ; Kopycinski, Jakub ; Byrne, Patrick ; Kaye, Steve ; Nelson, Mark ; Rauchenberger, Mary ; Dorrell, Lucy ; Barber, Tristan

BACKGROUNDAntiretroviral therapy (ART) cannot cure HIV infection because of a persistent reservoir of latently infected cells. Approaches that force HIV transcription from these cells, making them susceptible to killing-termed kick and kill regimens-have been explored as a strategy towards an HIV cure. RIVER is the first randomised trial to determine the effect of ART-only versus ART plus kick and kill on markers of the HIV reservoir.METHODSThis phase 2, open-label, multicentre, randomised, controlled trial was undertaken at six clinical sites in the UK. Patients aged 18-60 years who were confirmed as HIV-positive within a maximum of the past 6 months and started ART within 1 month from confirmed diagnosis were randomly assigned by a computer generated randomisation list to receive ART-only (control) or ART plus the histone deacetylase inhibitor vorinostat (the kick) and replication-deficient viral vector T-cell inducing vaccines encoding conserved HIV sequences ChAdV63. HIVconsv-prime and MVA.HIVconsv-boost (the kill; ART + V + V; intervention). The primary endpoint was total HIV DNA isolated from peripheral blood CD4⁺ T-cells at weeks 16 and 18 after randomisation. Analysis was by intention to treat. This trial is registered with ClinicalTrials.gov, NCT02336074.FINDINGSBetween June 14, 2015 and Jul 11, 2017, 60 men with HIV were randomly assigned to receive either an ART-only (n=30) or an ART + V + V (n=30) regimen; all 60 participants completed the study, with no loss-to-follow-up. Mean total HIV DNA at weeks 16 and 18 after randomisation was 3·02 log₁₀ copies HIV DNA per 10⁶ CD4⁺ T-cells in the ART-only group versus 3·06 log₁₀ copies HIV DNA per 10⁶ CD4⁺ T-cells in ART + V + V group, with no statistically significant difference between the two groups (mean difference of 0·04 log₁₀ copies HIV DNA per 10⁶ CD4⁺ T-cells [95% CI -0·03 to 0·11; p=0·26]). There were no intervention-related serious adverse events.INTERPRETATIONThis kick and kill approach conferred no significant benefit compared with ART alone on measures of the HIV reservoir. Although this does not disprove the efficacy kick and kill strategy, for future trials enhancement of both kick and kill agents will be required.FUNDINGMedical Research Council (MR/L00528X/1).

03 Oct 2019·Expert Review of VaccinesQ2 · MEDICINE

Aiming for protective T-cell responses: a focus on the first generation conserved-region HIVconsv vaccines in preventive and therapeutic clinical trials

Q2 · MEDICINE

Review

Author: Hanke, Tomáš

Introduction: Despite life-saving antiretroviral drugs, an effective HIV-1 vaccine is the best solution and likely a necessary component of any strategy for halting the AIDS epidemic. The currently prevailing aim is to pursue antibody-mediated vaccine protection. With ample evidence for the ability of T cells to control HIV-1 replication, their protective potential should be also harnessed by vaccination. The challenge is to elicit not just any, but protective T cells.Areas covered: This article reviews the clinical experience with the first-generation conserved-region immunogen HIVconsv delivered by combinations of plasmid DNA, simian adenovirus, and poxvirus MVA. The aim of our strategy is to induce strong and broad T cells targeting functionally important parts of HIV-1 proteins common to global variants. These vaccines were tested in eight phase 1/2 preventive and therapeutic clinical trials in Europe and Africa, and induced high frequencies of broadly specific CD8⁺ T cells capable of in vitro inhibition of four major HIV-1 clades A, B, C and D, and in combination with latency-reactivating agent provided a signal of drug-free virological control in early treated patients.Expert opinion: A number of critical T-cell traits have to come together at the same time to achieve control over HIV-1.

01 May 2019·EClinicalMedicine

Therapeutic Vaccination Refocuses T-cell Responses Towards Conserved Regions of HIV-1 in Early Treated Individuals (BCN 01 study)

Article

Author: Rosas-Umbert, Miriam ; Crook, Alison ; Escrig, Roser ; Perez-Alvarez, Núria ; Dorrell, Lucy ; Yang, Hongbing ; Coll, Pep ; Rovira, Cristina ; Puertas, Maria C ; Ruiz, Irene ; Meulbroek, Michael ; Wee, Edmund G ; Mothe, Beatriz ; Hanke, Tomáš ; Manzardo, Christian ; Miró, Jose M ; Clotet, Bonaventura ; Sanchez-Bernabeu, Alvaro ; Brander, Christian ; Borthwick, Nicola ; Cobarsi, Patricia ; Martinez-Picado, Javier ; Morón-López, Sara

BACKGROUNDStrong and broad antiviral T-cell responses targeting vulnerable sites of HIV-1 will likely be a critical component for any effective cure strategy.METHODSBCN01 trial was a phase I, open-label, non-randomized, multicenter study in HIV-1-positive individuals diagnosed and treated during early HIV-1 infection to evaluate two vaccination regimen arms, which differed in the time (8 versus 24 week) between the ChAdV63.HIVconsv prime and MVA.HIVconsv boost vaccinations. The primary outcome was safety. Secondary endpoints included frequencies of vaccine-induced IFN-γ⁺ CD8⁺ T cells, in vitro virus-inhibitory capacity, plasma HIV-1 RNA and total CD4⁺ T-cells associated HIV-1 DNA. (NCT01712425).FINDINGSNo differences in safety, peak magnitude or durability of vaccine-induced responses were observed between long and short interval vaccination arms. Grade 1/2 local and systemic post-vaccination events occurred in 22/24 individuals and resolved within 3 days. Weak responses to conserved HIV-1 regions were detected in 50% of the individuals before cART initiation, representing median of less than 10% of their total HIV-1-specific T cells. All participants significantly elevated these subdominant T-cell responses, which after MVA.HIVconsv peaked at median (range) of 938 (73-6,805) IFN-γ SFU/10⁶ PBMC, representing on average 58% of their total anti-HIV-1 T cells. The decay in the size of the HIV-1 reservoir was consistent with the first year of early cART initiation in both arms.INTERPRETATIONHeterologous prime-boost vaccination with ChAdV63-MVA/HIVconsv was well-tolerated and refocused pre-cART T-cell responses towards more protective epitopes, in which immune escape is frequently associated with reduced HIV-1 replicative fitness and which are common to most global HIV-1 variants.FUNDINGHIVACAT Catalan research program for an HIV vaccine and Fundació Gloria Soler. Vaccine manufacture was jointly funded by the Medical Research Council (MRC) UK and the UK Department for International Development (DFID) under the MRC/DFID Concordat agreements (G0701669.RESEARCH IN CONTEXTEvidence Before this Study: T cells play an important role in the control of HIV infection and may be particularly useful for HIV-1 cure by killing cells with reactivated HIV-1. Evidence is emerging that not all T-cell responses are protective and mainly only those targeting conserved regions of HIV-1 proteins are effective, but typically immunologically subdominant, while those recognizing hypervariable, easy-to-escape immunodominant 'decoys' do not control viremia and do not protect from a loss of CD4 T cells. We pioneered a vaccine strategy focusing T-cell responses on the most conserved regions of the HIV-1 proteome using an immunogen designated HIVconsv. T cells elicited by the HIVconsv vaccines in HIV-uninfected UK and Kenyan adults inhibited in vitro replication of HIV-1 isolates from 4 major global clades A, B, C and D.Added Value of this Study: The present study demonstrated the concept that epitopes subdominant in natural infection, when taken out of the context of the whole HIV-1 proteome and presented to the immune system by a potent simian adenovirus prime-poxvirus MVA boost regimen, can induce strong responses in patients on antiretroviral treatment and efficiently refocus HIV-1-specific T-cells to the protective epitopes delivered by the vaccine.Implications of all the Available Evidence: Nearly all HIV-1 vaccine strategies currently emphasize induction of broadly neutralizing Abs. The HIVconsv vaccine is one of a very few approaches focussing exclusively on elicitation of T cells and, therefore, can complement antibody induction for better prevention and cure. Given the cross-clade reach on the HIVconsv immunogen design, if efficient, the HIVconsv vaccines could be deployed globally. Effective vaccines will likely be a necessary component in combination with other available preventive measures for halting the HIV-1/AIDS epidemic.

100 Deals associated with pSG2.HIVconsv(University of Oxford)

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Indication	Highest Phase	Country/Location	Organization	Date
HIV Infections	Phase 1	UG	University of Oxford	30 Jan 2022
HIV Infections	Phase 1	KE	University of Oxford	30 Jan 2022
HIV Infections	Phase 1	ZM	University of Oxford	30 Jan 2022

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