A universal T cell vaccine for HIV-1

Lead Research Organisation: University of Oxford
Department Name: Central Admin - Research Services

Abstract

HIV infection and AIDS continues to spread in a virtually uncontrolled manner. The best and possibly only hope to change this alarming situation is a safe, effective, accessible protective vaccine. Arguably the biggest challenge in developing such a vaccine is enormous HIV variability, which dwarfs that of almost any other infection. However, all parts of the virus cannot easily change. To remain alive, HIV has to keep some smaller regions of its proteins more or less constant. We have taken an advantage of this and constructed a candidate vaccine designed specifically to overcome HIV variability by focusing the body defences on the conserved regions of the virus, i.e. the Achilles heel of HIV. Here, we are proposing to build on and extend our ongoing vaccine development effort and, if successful, assemble a strong case for further evaluation of this vaccination strategy in larger scale and expensive field efficacy studies.

Technical Summary

The best solution to the HIV/AIDS epidemic is development of an effective prophylactic vaccine. T cell stimulating vaccines offer a realistic alternative, or supplement to, antibody inducing vaccines. The latter are proving extremely difficult to generate and T cell stimulating vaccines, while not preventing infection, do ameliorate disease in monkey/SIV models. However, virus variability is a major problem resulting in poor recognition of infecting virus and easy escape of virus from early T cell control. These issues could be avoided by focusing vaccine-induced T cell responses on conserved regions of HIV-1. While most patients with chronic HIV-1 infection do make some T cell responses to conserved regions, these responses are usually weak (subdominant) and, like broadly neutralizing antibody responses, develop too late in the infection to provide real benefit. We have constructed immunogen HIVconsv, which is derived from the 14 least variable HIV-1 segments and contains over 200 epitopes, and have shown that it stimulates strong T cell responses in mice and in rhesus macaques. Phase I clinical trials in Oxford evaluating safety and immunogenicity of three HIVconsv vaccines delivered as plasmid DNA, recombinant MVA and recombinant chimpanzee adenovirus have started.
Here, we shall further refine the vaccine design to improve the prototype immunogen, vaccine vectors and their formulation. We shall test different vaccination regimens to maximize T cell induction and assess surrogate efficacy in inbred and outbred mice. We shall make a second ?mosaic? immunogen complementing HIVconsv, which will improve perfect matching of amino acids to HIV-1 variants from clades A,B,C and D from 72% to 90%. We shall study in depth vaccine-induced responses in humans, looking at how well the known conserved (but often subdominant in HIV-1 infection) epitopes are presented by antigen-presenting cells exposed to these constructs. We shall examine how efficiently the HIVconsv-specific T cells recognize and kill HIV-1-infected cells. We shall employ state-of-the-art proteomics (tandem MS/nanoflow RPLC) to obtain a comprehensive picture of conserved region peptide processing and presentation on the cell surface, and comparing epitope presentation from the HIVconsv vaccines and HIV-1. This will indicate whether the HIVconsv needs further optimization.
Results generated from this programme together with our complementing, separately funded components (non-human primate and human trials) will be key in assessing the suitability of conserved region T cell vaccines for efficacy trials in high-risk human cohort(s), either alone or with an antibody-based vaccine.

Organisations

Publications

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Abdul-Jawad S (2016) Increased Valency of Conserved-mosaic Vaccines Enhances the Breadth and Depth of Epitope Recognition. in Molecular therapy : the journal of the American Society of Gene Therapy

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Borthwick N (2014) Vaccine-elicited human T cells recognizing conserved protein regions inhibit HIV-1. in Molecular therapy : the journal of the American Society of Gene Therapy

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Broset E (2019) MTBVAC-Based TB-HIV Vaccine Is Safe, Elicits HIV-T Cell Responses, and Protects against in Mice. in Molecular therapy. Methods & clinical development

 
Description CHAVI-ID (Duke)
Amount $100,000 (USD)
Organisation National Institutes of Health (NIH) 
Sector Public
Country United States
Start 01/2016 
End 06/2017
 
Description EAVI2020
Amount € 22,900,000 (EUR)
Funding ID 681137 
Organisation European Commission 
Sector Public
Country European Union (EU)
Start 11/2015 
End 10/2021
 
Description EDCTP Strategic Primer
Amount € 800,000 (EUR)
Funding ID SP.2011.41304.002 
Organisation Sixth Framework Programme (FP6) 
Department European and Developing Countries Clinical Trials Partnership
Sector Public
Country Netherlands
Start 01/2012 
End 01/2015
 
Description FP7
Amount € 7,000,000 (EUR)
Funding ID 305632 
Organisation European Commission 
Sector Public
Country European Union (EU)
Start 10/2013 
End 09/2017
 
Description GMP manufacture
Amount $2,200,000 (USD)
Funding ID SOW4 and SOW5 
Organisation International AIDS Vaccine Initiative (IAVI) 
Sector Charity/Non Profit
Country Global
Start 01/2015 
End 12/2016
 
Description ISSF Wellcome Trust
Amount £50,000 (GBP)
Organisation Wellcome Trust 
Sector Charity/Non Profit
Country United Kingdom
Start 07/2012 
End 07/2014
 
Description MARTIN DELANEY COLLABORATORY TOWARDS HIV-1 CURE: The Collaboratory of AIDS Researchers for Eradication (CARE)
Amount £4,600,000 (GBP)
Funding ID 1 UM1AI126619-01 
Organisation National Institute of Allergy and Infectious Diseases (NIAID) 
Sector Public
Country United States
Start 07/2016 
End 06/2021
 
Description MRC DCS
Amount £1,031,751 (GBP)
Funding ID MR/J008605/1 
Organisation Medical Research Council (MRC) 
Sector Public
Country United Kingdom
Start 11/2012 
End 09/2015
 
Description MRC RIVER DCS
Amount £2,000,000 (GBP)
Funding ID MR/L00528X/1 
Organisation Medical Research Council (MRC) 
Sector Public
Country United Kingdom
Start 10/2014 
End 09/2017
 
Description Phase I therapeutic testing of viral-vectored vaccines that shift CD8+ T cell immunodominance to conserved regions of HIV-1
Amount $5,000,000 (USD)
Funding ID U01 AI131310-01 
Organisation National Institute of Allergy and Infectious Diseases (NIAID) 
Sector Public
Country United States
Start 07/2016 
End 06/2021
 
Title 3 GMP candidate HIV-1 vaccines 
Description Novel candidate HIV vaccines available for clinical testing 
Type Of Material Technology assay or reagent 
Year Produced 2009 
Provided To Others? Yes  
Impact Interest of peers, new collaborations, new grant submission 
 
Title EDCTP2 - Capacity building at 5 African sites 
Description Building capacity for a future efficacy trial by engaging already identified populations with documented high-risk to circulating HIV-1 from diverse clades despite preventive interventions 
Type Of Material Improvements to research infrastructure 
Year Produced 2016 
Provided To Others? No  
Impact Our work realizes capacity building projects, which take place at African Clinical Research Centers (CRC) with the aim of preparing them for participation in the proposed phase 2a vaccine trial and future HIV-1 vaccine efficacy trials. Thus, at CRCs in Kenya, Uganda and Zambia, and also in Tanzania through the Lake Victoria Consortium for Health Research, capacity building takes place with the following objectives: • To strengthen clinical capacity for the proposed phase 2a vaccine trial though the training of personnel, procuring equipment and updating infrastructure as needed. • To build a sustainable platform for future HIV-1 vaccine efficacy trials by expanding clinical and laboratory infrastructure and establishing field-based clinical and laboratory capacity. • To ensure the availability of diverse, well-characterized key populations and the ability to ethically engage them in a future HIV-1 vaccine efficacy trial through formative research, community outreach and enhanced community engagement models, which will ensure good participatory practice. 
 
Title Elution and analysis of HLA class I-associated peptidomes 
Description Methodology for identifying HLA class i-associated peptides derived from intracellular pathogens 
Type Of Material Technology assay or reagent 
Year Produced 2015 
Provided To Others? Yes  
Impact Mainly academic -methods established in UOXF for eluting and sequencing peptides from MHC class I molecules opened door for may follow up studies in many diseases including e.g. malaria, theileria, HLA-E elations 
 
Title GMP 2nd generation HIVconsv vaccines 
Description 2nd generation improved HIVconsv vaccines designed, constructed and tested in pre-clinical models Improved immunogens with increased global coverage of HIV variants 
Type Of Material Technology assay or reagent 
Year Produced 2014 
Provided To Others? Yes  
Impact 2nd generation improved HIVconsv vaccines available for clinical testing 
 
Title HIV vaccines inducing antibodies 
Description Vaccines aiming at induction of broadly neutralizing anti-HIV antibody Genes for modified BG505 Env immunogens were inserted into DNA, MVA and ChAdV 
Type Of Material Technology assay or reagent 
Year Produced 2014 
Provided To Others? Yes  
Impact Mainly academic: We demonstrated that ChAdOx1 and MVA vectors are useful delivery modalities for not only T-cell, but also antibody vaccine development. 
 
Title Mapping of subdominant HLA-class I and II-restricted T cell epitopes 
Description we define novel protective T-cell epitopes subdominant in natural HIV infection. 
Type Of Material Technology assay or reagent 
Year Produced 2017 
Provided To Others? Yes  
Impact Mainly academic - We contribute to the collection of CD8+ and CD4+ T-cell determinants in HIV-1, which will drive iterative vaccine improvements especially in the light of the increasingly recognized important roles of T cells in the generation of protective anti-HIV-1 responses. 
 
Title Romidespin + vaccine - signal of post-antiretroviral treatment control of rebound HIV 
Description BCN 02 was an open-label, single-arm, phase I clinical trial, which enrolled 15 early-treated HIV-1-infected individuals and tested the combination of histone-deacetylase inhibitor romidepsin, a latency-reversing agent, and the MVA.HIVconsv vaccine. 
Type Of Material Model of mechanisms or symptoms - human 
Year Produced 2020 
Provided To Others? Yes  
Impact Results from this pilot study show that the kick&kill intervention was safe and suggest a role for this strategy in achieving an immune-driven durable viremic control. 
 
Title Vaccine focus on conserved regions of microbes 
Description The biggest roadblock for many vaccines is the pathogens' variability. This is best tackled by focusing both antibodies and T cells on the functionally most conserved regions of proteins common to many variants including escape mutants. For vectored vaccines, these 'universal' subunit immunogens are most efficiently delivered using heterologous prime-boost regimens, which can be further optimized by adjuvantation and route of delivery. 
Type Of Material Model of mechanisms or symptoms - human 
Year Produced 2007 
Provided To Others? Yes  
Impact Selecting for vaccine immunogens conserved regions of microbes common to many variants - HIV, HCV, Flu, Dengue 
 
Title Vaccine recipients' samples in BioBank 
Description Cryopreserved PBMC samples from recipient of HIV conserved region vaccines expanding and revealing naturally subdominant responses 
Type Of Material Biological samples 
Year Produced 2015 
Provided To Others? Yes  
Impact Mainly academic - Improving early prediction of vaccine success/failure. 
 
Title Vorinostat in the first randomised, double blind trial of kick-and-kill HIV cure 
Description The first randomised, double blind trial of kick-and-kill HIV cure. Antiretroviral 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. 
Type Of Material Model of mechanisms or symptoms - human 
Year Produced 2020 
Provided To Others? Yes  
Impact This 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. 
 
Title Clinical trial data management 
Description Each clinical trial developed Data Management databases based on OpenClinical, REDCap or used EMMES 
Type Of Material Database/Collection of data 
Year Produced 2010 
Provided To Others? Yes  
Impact Mainly academic as a guidance for other/future trials 
 
Description Adjuvantation by PIV5 DI particles 
Organisation University of St Andrews
Country United Kingdom 
Sector Academic/University 
PI Contribution Adjuvantation by PIV5 DI particles will be evaluated in mice. We shall use our candidate HIVconsv vaccines and carry out the experiments.
Collaborator Contribution Provision of PIV5 DI particles
Impact Multidisciplinary, we shall aim to publish our results.
Start Year 2012
 
Description Advent vaccine Manufacturing project 
Organisation Advent S.r.l
Country Italy 
Sector Private 
PI Contribution Provision of starting material and guidance throughout the manufacturing process GMP manufacture of two simian (chimpanzee) adenovirus-vectored vaccines
Collaborator Contribution Pre-GMP development
Impact non yet
Start Year 2016
 
Description Analysis of T cell responses in antiretroviral treatment-naive patients 
Organisation University of Kumamoto
Country Japan 
Sector Academic/University 
PI Contribution Identification of conserved regions and provision of corresponding peptides Identification and mapping of conserved region vaccine elicited epitopes
Collaborator Contribution Measurements of T cell responses and HIV viral load in treatment-naive patients and correlation of magnitude and breadth of responses with viral load and CD4 cell counts Determination of HLA-restriction of mapped epitopes
Impact Multidisciplinary, publications out and in preparation
Start Year 2013
 
Description Analysis of T cell responses in antiretroviral treatment-naive patients 
Organisation University of Tokyo
Country Japan 
Sector Academic/University 
PI Contribution Identification of conserved regions and provision of corresponding peptides Identification and mapping of conserved region vaccine elicited epitopes
Collaborator Contribution Measurements of T cell responses and HIV viral load in treatment-naive patients and correlation of magnitude and breadth of responses with viral load and CD4 cell counts Determination of HLA-restriction of mapped epitopes
Impact Multidisciplinary, publications out and in preparation
Start Year 2013
 
Description Assessment of tHIVconsvX-specific responses in HIV-positive patients 
Organisation Imperial College London
Country United Kingdom 
Sector Academic/University 
PI Contribution Design and provision of tHIVconsvX peptides
Collaborator Contribution Testing of peptides in HIV-1-positive patients
Impact In progress
Start Year 2014
 
Description Clinical evaluation of ChAdV63.HIVconsv 
Organisation GlaxoSmithKline (GSK)
Country Global 
Sector Private 
PI Contribution GSK acquired Okairos, the developer of the ChAdV-63-based vector platform. We are testing the ChAdV63.HIVconsv in four clinical trials: RIVER, PEACHI 04, HIV-CORE 003 and BCN 01.
Collaborator Contribution The GSK partner added a very slow and cumbersome process of approving of the jointly owned candidate vaccine for use in clinical trials. GSK is not interested in an early stage development of HIV vaccines.
Impact In process.
Start Year 2013
 
Description Clinical trial HIV-CORE 003 in London 
Organisation University College London
Department National Amyloidosis Centre
Country United Kingdom 
Sector Academic/University 
PI Contribution This an MRC DCS award to Prof Sir Mark Pepys, to which we are contributing know-how, GMP vaccines, immunological reagents and evaluation of immunogenicity output.
Collaborator Contribution Execution of clinical the trial HIV-CORE003, serum amyloid component P-depleting drug CHPHC.
Impact Multidisciplinary collaboration, the anticipated start of recruitment is March 2013.
Start Year 2012
 
Description Clinical trial HIV-CORE 004 in Nairobi 
Organisation Kenya AIDS Vaccine Initiative (KAVI)
Country Kenya 
Sector Academic/University 
PI Contribution This is a EDCTP-funded clinical trial HIV-CORE 004. We are providing know-how, GMP vaccines and immunological reagents and help with data analysis.
Collaborator Contribution Running of the clinical trial and primary safety and immunogenicity evaluations.
Impact Multidisciplinary, recruitment is planned to commence in March 2013.
Start Year 2012
 
Description Construction and preclinical evaluation of ChAdOx1.HIVACAT-T vaccines 
Organisation AELIX Therapeutics
Country Spain 
Sector Private 
PI Contribution Design of a synthetic genes and construction of candidate HIV vaccine ChAdOx1.HIVACAT-T
Collaborator Contribution Design of the immunogen and pre-clinical testing
Impact In progress
Start Year 2013
 
Description Construction and preclinical evaluation of ChAdOx1.HIVACAT-T vaccines 
Organisation HIVACAT Program IrsiCaixa Institute for AIDS Research
Country Spain 
Sector Academic/University 
PI Contribution Design of a synthetic genes and construction of candidate HIV vaccine ChAdOx1.HIVACAT-T
Collaborator Contribution Design of the immunogen and pre-clinical testing
Impact In progress
Start Year 2013
 
Description Construction and testing of Retrovirus-vectored tHIVconsvX vaccines 
Organisation Immune Design
Country United States 
Sector Private 
PI Contribution Provision of 2 tHIVconsvX genes and preclinical testing of candidate vaccines.
Collaborator Contribution Construction of two candidate vaccines.
Impact In progress
Start Year 2013
 
Description Construction of CMV-vectored vaccines and pre-clinical studies 
Organisation Oregon Health and Science University
Country United States 
Sector Academic/University 
PI Contribution Design and provision of two synthetic genes coding for tSIVconsv239 and tSIVconsvE660 Construction of chimp Adenovirus and MAV vectored vaccines carrying the tSIVconsv genes
Collaborator Contribution Construction of CMV.tSIVconsv239 and CMV.tSIVconsvE660 and immunogenicty study in primates
Impact In progress
Start Year 2013
 
Description Construction of HAdV-4-vectored tHIVconsvX vaccines 
Organisation PaxVax, Inc.
Country United States 
Sector Private 
PI Contribution Provision of two tHIVconsvX genes and pre-clinical evaluation
Collaborator Contribution Construction of candidate vaccines
Impact In progress
Start Year 2013
 
Description Construction of ID-lentiviral vectors for delivery of conserved mosaic vaccines 
Organisation Immune Design
Country United States 
Sector Private 
PI Contribution We provided designed and provided genes coding forHIV-derived conserved mosaic immunogens and tested the ImmuneDesign-generated vaccines in mice
Collaborator Contribution Immune Design provided lentiviral vectors and inserted our conserved mosaic immunogens gene into them to construct two candidate vaccines
Impact Manuscript ready for submission
Start Year 2014
 
Description Construction of MVA.HIVACAT-T for pre-clinical and clinical testing 
Organisation AELIX Therapeutics
Country Spain 
Sector Private 
PI Contribution Construction of candidate HIV vaccine MVA.HIVACAT-T carrying a IRSICAIXA-designed T cell immunogen Advice on GMP manufacture
Collaborator Contribution Design of HIVACAT-T immunogen, preclinical testing in mice and monkeys. GMP manufacture
Impact Publication submitted
Start Year 2012
 
Description Construction of MVA.HIVACAT-T for pre-clinical and clinical testing 
Organisation HIVACAT Program IrsiCaixa Institute for AIDS Research
Country Spain 
Sector Academic/University 
PI Contribution Construction of candidate HIV vaccine MVA.HIVACAT-T carrying a IRSICAIXA-designed T cell immunogen Advice on GMP manufacture
Collaborator Contribution Design of HIVACAT-T immunogen, preclinical testing in mice and monkeys. GMP manufacture
Impact Publication submitted
Start Year 2012
 
Description Construction of rBCG for delivery of conserved mosaic vaccines 
Organisation Albert Einstein College of Medicine
Country United States 
Sector Academic/University 
PI Contribution We provide gene for conserved mosaic HIV vaccine and shall conduct pre-clinical immunogenicity studies in mice
Collaborator Contribution Construct rBCG and provide sufficient stocks for preclinical studies
Impact Work in progress
Start Year 2014
 
Description DC 04: Comparison of Dendri/c Cell-­Based Therapeu/c Vaccine Strategies for HIV Func/onal Cure 
Organisation University of Pittsburgh
Country United States 
Sector Academic/University 
PI Contribution Design of peptides used in the clinical trials, trial design and outcome analysis
Collaborator Contribution Run a clinical trial and the outcome assays
Impact no output yet
Start Year 2017
 
Description Design of 2nd generation conserved mosaic tHIVconsvX vaccines 
Organisation Los Alamos National Laboratory
Country United States 
Sector Public 
PI Contribution Computer design of the 2nd generation conserved mosaic T-cell immunogens (tHIVconsvX)
Collaborator Contribution Designed the 2 mosaics used and helped to select the conserved regions oh the HIV -1 proteome
Impact 2nd generation vaccine - so far pre-clinical grade constructed A joint Patent between UOXF/ISIS and LANL
Start Year 2013
 
Description Determination of binding affinities of peptides for HLA 
Organisation University of Southampton
Country United Kingdom 
Sector Academic/University 
PI Contribution Peptide identification and provision
Collaborator Contribution HLA affinity assay
Impact Manuscript in preparation
Start Year 2014
 
Description Development of RhCMV-vectored conserved region vaccines 
Organisation Oregon Health and Science University
Country United States 
Sector Academic/University 
PI Contribution We provided SIV equivalents of our human conserved region mosaic immunogen (SIVconsv239 and SIVconsvE660) genes and vaccines expressing the same immunogens from ChAdOx1 and MVA
Collaborator Contribution Louis PIcker and Scott Hansen constructed RhCMV-vectored vaccines expressing SIVconsv239 and SIVconsvE660, immunized 16 rhesus macaques and will challenge them with SIVmac239
Impact Work in progress
Start Year 2014
 
Description Development of a conserved mosaic protein as an immunogen 
Organisation Los Alamos National Laboratory
Country United States 
Sector Public 
PI Contribution We describe what immunogen we would like to design and LANL used their computational power to design this immunogen. We then construct it and develop it
Collaborator Contribution Providing an expertise in designing a vaccine immunogen
Impact Early days
Start Year 2010
 
Description European AIDS Vaccine Initiative 2020 (EAVI2020) 
Organisation European AIDS Vaccine Initiative 2020 (EAVI2020)
Country European Union (EU) 
Sector Charity/Non Profit 
PI Contribution We shall provided preclinical and Experimental Medicine research, our conserved mosaic HIV vaccines and our expertise
Collaborator Contribution Our partners will provided preclinical and Experimental Medicine research, their candidate HIV vaccines and their expertise
Impact It is work in progress www.eavi2020.eu Twitter www.twitter.com/eavi2020 Like us on Facebook: www.facebook.com/eavi2020 LinkedIn: www.linkedin.com/company/eavi2020 ResearchGate: https://www.researchgate.net/profile/Eavi_2020
Start Year 2015
 
Description GMP manufacture of ChAdOx1.tHIVconsv5 and ChAdOx1.tHIVconsv6 
Organisation International AIDS Vaccine Initiative (IAVI)
Country Global 
Sector Charity/Non Profit 
PI Contribution Manufacture of two experimental vaccines for clinical use
Collaborator Contribution CBF will manufacture the vaccine IAVI provided the funds for one vaccine
Impact Clinical batches of two vaccines will be produced
Start Year 2015
 
Description GMP manufacture of ChAdOx1.tHIVconsv5 and ChAdOx1.tHIVconsv6 
Organisation University of Oxford
Department The Clinical Biomanufacturing Facility
Country United Kingdom 
Sector Academic/University 
PI Contribution Manufacture of two experimental vaccines for clinical use
Collaborator Contribution CBF will manufacture the vaccine IAVI provided the funds for one vaccine
Impact Clinical batches of two vaccines will be produced
Start Year 2015
 
Description GMP manufacture of MVA.tHIVconsv3 and MVA.tHIVconsv4 
Organisation IDT Biologika GmbH
Country Germany 
Sector Private 
PI Contribution Manufacture of two vaccines for clinical trial use
Collaborator Contribution IDT is the manufacturing house IAVI paid for one rMVA
Impact When completed, clinical lots of two experimental vaccines
Start Year 2015
 
Description GMP manufacture of MVA.tHIVconsv3 and MVA.tHIVconsv4 
Organisation International AIDS Vaccine Initiative (IAVI)
Country Global 
Sector Charity/Non Profit 
PI Contribution Manufacture of two vaccines for clinical trial use
Collaborator Contribution IDT is the manufacturing house IAVI paid for one rMVA
Impact When completed, clinical lots of two experimental vaccines
Start Year 2015
 
Description HIV inhibition assays 
Organisation International AIDS Vaccine Initiative (IAVI)
Department Human Immunology Laboratory, ICL
Country United States 
Sector Charity/Non Profit 
PI Contribution We provide samples from clinical trial, a visiting DPhil student and contribute to the cost of the virus inhibition assay (VIA)
Collaborator Contribution International AIDS Vaccine Initiative provide the expertise in VIA, welcome our student and provided HIV virus stock of various clades
Impact Assays are in progress.
Start Year 2012
 
Description HLA associated peptidome characterization 
Organisation University of Oxford
Department Radcliffe Department of Medicine
Country United Kingdom 
Sector Academic/University 
PI Contribution Methodology for eluting and identifying HLA-associated peptidome
Collaborator Contribution expertise in rheumatilogy
Impact Multi-disciplinary collaboration resulting in a publication
Start Year 2012
 
Description IDT Vaccine manufacture 
Organisation IDT Biologika GmbH
Country Germany 
Sector Private 
PI Contribution Provision of starting materials for two vaccines
Collaborator Contribution Pre-GMP development, manufacture and fill finish of two vaccines
Impact Two GMP vaccines
Start Year 2016
 
Description Impact of mosaic design on T cell response cloncality 
Organisation Cardiff University
Country United Kingdom 
Sector Academic/University 
PI Contribution Vaccine construction, immunisation of mice and T cell assays, tetramer design
Collaborator Contribution Tetramer sorting of immune mouse splenocytes and T cell receptor analysis
Impact In progress
Start Year 2013
 
Description Impact of mosaic design on T cell response cloncality 
Organisation Los Alamos National Laboratory
Country United States 
Sector Public 
PI Contribution Vaccine construction, immunisation of mice and T cell assays, tetramer design
Collaborator Contribution Tetramer sorting of immune mouse splenocytes and T cell receptor analysis
Impact In progress
Start Year 2013
 
Description Impact of mosaic design on T cell response cloncality 
Organisation National Institutes of Health (NIH)
Country United States 
Sector Public 
PI Contribution Vaccine construction, immunisation of mice and T cell assays, tetramer design
Collaborator Contribution Tetramer sorting of immune mouse splenocytes and T cell receptor analysis
Impact In progress
Start Year 2013
 
Description Importance of vectors for induction of broadly neutralising anti-HIV antibodies 
Organisation Duke University
Department Duke Center for HIV/AIDS Vaccine Immunology and Immunogen Discovery (CHAVI-ID)
Country United States 
Sector Academic/University 
PI Contribution We shall determine the importance of virus vector delivery in heterologous prime-boost regimens for induction of HIV broadly neutralizing antibodies.
Collaborator Contribution CHAVI-ID/Barton Haynes (Duke University) provided HIV Envelope genes from sequential HIV isolates with the idea to guide the maturation of antibody affinity.
Impact Pubished
Start Year 2016
 
Description Induction of HIV neutralizing antibodies 
Organisation Cornell University
Department Weill Cornell Medicine
Country United States 
Sector Academic/University 
PI Contribution We are developing heterologous prime-boost immunisation regimen delivering a highly promising HIV Env BG505 uncleaved or as SOSIP for induction of HIV neutralising antibodies. Also we are developing regimens for efficient induction of T cell and B cell responses in parallel.
Collaborator Contribution WCMC - provision or trimeric gp140 BG505 SOSIP protein immunogen IAVI - proviion of gp120 HBG505 unlceaved immunogen Sir Willima Dunn Schol of Pathology - quality control and research assays for characterisation of vector-expressed Ev immunogen Meditox - rabbit immunization study
Impact Studies with BG505 uncleaved - Publication Studies with BG505 SOSIP - In progress
Start Year 2014
 
Description Induction of HIV neutralizing antibodies 
Organisation International AIDS Vaccine Initiative (IAVI)
Country Global 
Sector Charity/Non Profit 
PI Contribution We are developing heterologous prime-boost immunisation regimen delivering a highly promising HIV Env BG505 uncleaved or as SOSIP for induction of HIV neutralising antibodies. Also we are developing regimens for efficient induction of T cell and B cell responses in parallel.
Collaborator Contribution WCMC - provision or trimeric gp140 BG505 SOSIP protein immunogen IAVI - proviion of gp120 HBG505 unlceaved immunogen Sir Willima Dunn Schol of Pathology - quality control and research assays for characterisation of vector-expressed Ev immunogen Meditox - rabbit immunization study
Impact Studies with BG505 uncleaved - Publication Studies with BG505 SOSIP - In progress
Start Year 2014
 
Description Induction of HIV neutralizing antibodies 
Organisation MediTox s.r.o.
Country Czech Republic 
Sector Academic/University 
PI Contribution We are developing heterologous prime-boost immunisation regimen delivering a highly promising HIV Env BG505 uncleaved or as SOSIP for induction of HIV neutralising antibodies. Also we are developing regimens for efficient induction of T cell and B cell responses in parallel.
Collaborator Contribution WCMC - provision or trimeric gp140 BG505 SOSIP protein immunogen IAVI - proviion of gp120 HBG505 unlceaved immunogen Sir Willima Dunn Schol of Pathology - quality control and research assays for characterisation of vector-expressed Ev immunogen Meditox - rabbit immunization study
Impact Studies with BG505 uncleaved - Publication Studies with BG505 SOSIP - In progress
Start Year 2014
 
Description Induction of HIV neutralizing antibodies 
Organisation University of Oxford
Department Sir William Dunn School of Pathology
Country United Kingdom 
Sector Academic/University 
PI Contribution We are developing heterologous prime-boost immunisation regimen delivering a highly promising HIV Env BG505 uncleaved or as SOSIP for induction of HIV neutralising antibodies. Also we are developing regimens for efficient induction of T cell and B cell responses in parallel.
Collaborator Contribution WCMC - provision or trimeric gp140 BG505 SOSIP protein immunogen IAVI - proviion of gp120 HBG505 unlceaved immunogen Sir Willima Dunn Schol of Pathology - quality control and research assays for characterisation of vector-expressed Ev immunogen Meditox - rabbit immunization study
Impact Studies with BG505 uncleaved - Publication Studies with BG505 SOSIP - In progress
Start Year 2014
 
Description LC-MS/MS 
Organisation University of Oxford
Department Central Proteomic Facility
Country United Kingdom 
Sector Academic/University 
PI Contribution The aim is to analyze the HLA-associated peptidome on HIV or HIVconsv expressing cells. Post-doctoral scientist and some key reagents.
Collaborator Contribution Know-how and equipment.
Impact Multidisciplinary, ongoing, publications anticipated.
Start Year 2011
 
Description Optimizing delivery of HIV trimeric envelope immunogens 
Organisation Amsterdam Medical Center
Country Netherlands 
Sector Hospitals 
PI Contribution We design and construct virus-vectored vaccines delivering single-chain Env trimeric immunogens, test them in mice in combination withAMC proteins and Oxford T-cell vaccines. We also provide the recombinant virus vaccines to Amsterdam for rabbit studies. Part of EAVI2020
Collaborator Contribution Design Env trimer immunogens, produce protein vaccines and used combination regimens in rabbits
Impact in progress
Start Year 2019
 
Description Optimizing vaccines in the NHP models 
Organisation Gilead Sciences, Inc.
Country United States 
Sector Private 
PI Contribution Design, construction and preparation of Gilead-conceived vaccines for the NHP SIV0challenge model
Collaborator Contribution Design of vaccine strategy and immunogenicity
Impact Vaccines prepared, experiments ongoing
Start Year 2019
 
Description Partnership for HIV vaccine development 
Organisation Kumamoto University
Country Japan 
Sector Academic/University 
PI Contribution Providing samples from vaccine recipients
Collaborator Contribution Promotion of the world's highest level of research activities Fostering global academic network fostering personnel who can work globally
Impact On going
Start Year 2019
 
Description Partnership for developing a T-cell vaccine targeting conserved regions of HIV 
Organisation International AIDS Vaccine Initiative (IAVI)
Country Global 
Sector Charity/Non Profit 
PI Contribution Partnership for development of a strategy for T-cell vaccine against HIV targeting the conserved region of the HIV proteome
Collaborator Contribution Contribution towards running of trial HIV-CORE 004 1-year post-doc plus expenses
Impact Clinical trial, optimizing vaccine delivery pre-clinically
Start Year 2012
 
Description Phase I therapeutic testing of viral-vectored vaccines that shift CD8+ T-cell immunodominance to conserved regions of HIV-1 
Organisation University of North Carolina at Chapel Hill
Department Department of Microbiology and Immunology
Country United States 
Sector Academic/University 
PI Contribution Provision of two GMP vaccines, input into trial design and evaluation
Collaborator Contribution Running a vaccine trial in HIV-positive individuals
Impact none yet
Start Year 2017
 
Description Prevention and treatment of HIV-associated neurocognitive disorders 
Organisation Icahn School of Medicine at Mount Sinai
Department Developmental and Regenerative Biology
Country United States 
Sector Academic/University 
PI Contribution We provide candidate vaccines and T-cell expertise
Collaborator Contribution EcoHIV mouse model of HIV-1-associated neurocognitive disorder (HAND)
Impact in progress
Start Year 2019
 
Description RIVER - Research In Viral Eradication of HIV Reservoirs 
Organisation Imperial College London
Country United Kingdom 
Sector Academic/University 
PI Contribution Providing GMP vaccines, expertise and input on trial design and immunological analysis
Collaborator Contribution Lucy Dorrell will provide a cohort of HIV-1-infected patients and carry out clinical trial evaluating safety and immunogenicity the MVA.HIVconsv vaccine.
Impact Safety and immunogenicity data on the MVA.HIVconsv vaccine.
Start Year 2010
 
Description Sample evaluation at HVTN 
Organisation HIV Vaccine Trials Network, USA
Country United States 
Sector Charity/Non Profit 
PI Contribution We have provided samples from clinical trial HIV-CORE 002 and peptides.
Collaborator Contribution Know-how, evaluation of samples in standardized, reference assays.
Impact Comparative data with other vaccine strategies.
Start Year 2012
 
Description Sample evaluation in HIL reference laboratory 
Organisation International AIDS Vaccine Initiative (IAVI)
Department Human Immunology Laboratory, ICL
Country United States 
Sector Charity/Non Profit 
PI Contribution Frozen PBMC samples from clinical trial
Collaborator Contribution IFN-y ELISPOT assays comparative with other HIV vaccine candidates tested by IAVI and others
Impact The results will likely be part of publication describing immunogenicity of the HIVconsv vaccines tested in HIV-CORE trials. Comparative data with other vaccine strategies.
Start Year 2012
 
Description T-cell clonality in responses to mosaic vaccination 
Organisation University of Oxford
Department Department of Zoology
Country United Kingdom 
Sector Academic/University 
PI Contribution We conceived and designed the experiment, provided vaccines and animals, collected samples, analysis of TCR. We are technically guided for TCR PCR amplification by Arian Smith's laboratory
Collaborator Contribution Know-how for analysis of T cell clonality, TCR sequencing and analysis
Impact In progress
Start Year 2018
 
Description The BCN 02 Trial 
Organisation IrsiCaixa Institute for AIDS Research
Country Spain 
Sector Academic/University 
PI Contribution Provision of four GMP vaccines for a clinical trial in HIV-positive adults with monitored antiretroviral pause
Collaborator Contribution Run a clinical trials and outcome assays
Impact Submitted two publications
Start Year 2017
 
Description Vacc2020 Development of scalable manufacturing processing form ChAdV and MVA 
Organisation IDT Biologika GmbH
Country Germany 
Sector Private 
PI Contribution Application under review
Collaborator Contribution Application under review
Impact Application under review
Start Year 2014
 
Description Viral vector regimens for delivery of Env trimer vaccines 
Organisation Cornell University
Department Weill Cornell Medicine
Country United States 
Sector Academic/University 
PI Contribution Construction of new vaccines Pre-clinical immunogenicity Optimizing co-delivery
Collaborator Contribution Immunogen BG505 SOSIP Structural characterization of expressed proteins
Impact Vaccines under construction
Start Year 2013
 
Title Mosaic conserved region HIV immunogenic polypeptides 
Description Disclosed herein are mosaic conserved region HIV polypeptides that can elicit an immune response to HIV (such as cytotoxic T cell (CTL), helper T cell, and/or hum oral responses). Also disclosed herein are immunogenic polypeptides including one or more of the mosaic conserved region polypeptides. In some examples, two or more of the mosaic conserved region polypeptides are included in a fusion (or chimeric) immunogenic polypeptide. In some 30 embodiments, the disclosed immunogenic polypeptides are included in an immunogenic composition, such as a polyvalent immunogenic composition. Also disclosed herein are methods for treating or inhibiting HIV in a subject including administering one or more (such as two or more) of the disclosed immunogenic polypeptides orcompositions to a subject infected with HIV or at risk of HIV infection. Also disclosed are methods of inducing an immune response to HIV in a subject by administering to the subject at least one (such as two or more) of the immunogenic polypeptides or a nucleic acid encoding at least one of the immunogenic polypeptides disclosed herein. 
IP Reference WO2015048785 
Protection Patent application published
Year Protection Granted 2014
Licensed No
Impact N/A
 
Title BCN 01 
Description The first immunogenicity evaluation of ChAdV63.HIVconsv prime-MVA.HIVconsv boost vaccine regimen delivering conserved regions of the HIV-1 proteome in HIV-1-infected individuals early on HAART 
Type Therapeutic Intervention - Vaccines
Current Stage Of Development Early clinical assessment
Year Development Stage Completed 2015
Development Status On hold
Clinical Trial? Yes
Impact Background Strong and broad antiviral T-cell responses targeting vulnerable sites of HIV-1 will likely be a critical component for any effective cure strategy. Methods BCN 01 trial was a phase I, open-label, non-randomised, 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-?+ CD8+ T cells, in vitro virus-inhibitory capacity, plasma HIV-1 RNA and total CD4+ T cells associated HIV-1 DNA. (NCT01712425) Findings No differences in safety, peak magnitude or durability of vaccine-induced responses were observed between the 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-? 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. Interpretation Heterologous prime-boost vaccination with ChAdV63-MVA/HIVconsv was well-tolerated and refocuses 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. 
URL https://www.clinicaltrialsregister.eu/ctr-search/search?query=eudract_number:2011-000846-39
 
Title BCN 02 
Description The first generation HIVconsv vaccines in early treated individuals with romidepsin and monitored antiretroviral treatment pause ISCIII PI15/01188 grant, the HIVACAT Catalan research program for an HIV vaccine and the Fundació Gloria Soler. The vaccine GMP manufacture was jointly funded by the UK Medical Research Council and the UK Department for International Development (DFID) under the MRC/DFID Concordat agreements (MRC G0701669). Some sub-analyses were partly funded by the European Union's Horizon 2020 research and innovation program under grant agreement 681137-EAVI2020 and by NIH grant P01-AI131568. 
Type Therapeutic Intervention - Vaccines
Current Stage Of Development Initial development
Year Development Stage Completed 2017
Development Status On hold
Clinical Trial? Yes
Impact Background Kick&kill strategies, which combine drugs reactivating the viral reservoir with therapeutic vaccines inducing effective cytotoxic T-cell responses, hold potential to achieve a functional cure for HIV-1 infection. Methods BCN02 was an open-label, single-arm, phase I clinical trial, which enrolled 15 early-treated HIV-1-infected individuals and tested the combination of histone-deacetylase inhibitor romidepsin, a latency-reversing agent, and the MVA.HIVconsv vaccine. Findings Romidepsin treatment resulted in increased histone acetylation, cell-associated HIV-1 RNA and T-cell activation, which were associated with a marginally significant reduction of the viral reservoir. Vaccinations boosted robust and broad HIVconsv-specific T cells, which were strongly refocused towards conserved regions of the HIV-1 proteome. During a monitored ART-interruption phase using plasma viral load over 2,000 copies/ml as a criterium for ART resumption, 23% of individuals showed sustained suppression of viremia for planned 32 weeks without evidence for reseeding the viral reservoir. Interpretation Results from this pilot study show that the kick&kill intervention was safe and suggest a role for this strategy in achieving an immune-driven durable viremic control. 
URL http://www.croiconference.org/sessions/viral-control-induced-hivconsv-vaccines-romidepsin-early-trea...
 
Title DC 04 
Description Dendritic cell (DC)-based therapeutic vaccines have shown the most promise for controlling HIV replication without antiretroviral therapy (ART). Although two seminal clinical trials demonstrated significant decreases in plasma viremia without ART that were associated with vaccine-induced HIV-specific immune responses, other DC-based vaccine studies have shown equivocal or no virologic efficacy. The disconnect between a DC-based vaccine's theoretical capability, supported by strong in vitro evidence of priming of effector T-cells, and the variable results of clinical trials, highlight important gaps in understanding the determinants of DC vaccine efficacy in vivo. We therefore propose a comparative analysis to confirm prior efficacy of DC vaccines and to test new, innovative DC vaccines with the dual goals of improving virological efficacy and identifying key determinants of DC vaccine efficacy. Specifically, we will conduct an initial phase I/II, randomized, double-blind, pilot study to compare safety and anti-HIV efficacy of four different DC-based vaccines and two corresponding placebos. The trial will evaluate two DC maturation techniques (the prostaglandin E2-matured DCs, which were partially effective in the two seminal clinical trials, and the alpha-type-1 DCs, which have shown improved antigen-presenting and T-cell priming function ex vivo), two HIV immunogens (whole, inactivated, autologous HIV that was partially effective in the two trials, and a pool of HIV peptides covering the most highly-conserved regions in Gag and Pol combined with epitopes known to be associated with control of viremia in untreated HIV-infected individuals), and two dosing strategies (3 vs 6 doses). The primary efficacy outcome will be change in the inducible HIV reservoir from pre-vaccination to 2 weeks after the final vaccine dose. We will also further evaluate the in vivo anti-HIV efficacy of the DC vaccines by performing an extensive analysis of vaccine-induced changes in virologic and immunologic parameters with the secondary goal of identifying immune correlates of vaccine-induced virologic responses. The parameters measured will include residual plasma viremia, the number and transcriptional activity of HIV-infected cells, CD8+ T-cell inhibition of autologous virus replication, the magnitude, breadth, and polyfunctionality of immune responses, and immunoregulatory responses including regulatory T-cells and myeloid-derived suppressor cells. We propose a second clinical trial to assess reproducibility of initial findings from the first trial and to assess the impact of further refinements of DC vaccine designs on efficacy. We have developed pre-specified Go/No-Go criteria for moving forward to a second trial. The decision whether a specific DC vaccine will be evaluated in the second trial will be based on the primary and secondary virologic and immunologic endpoints of the first trial. This innovative, sequential, and iterative approach will evaluate multiple DC vaccines, elucidate determinants of vaccine efficacy, identify immune correlates of vaccine-induced reductions in HIV reservoirs, and provide new insights into the potential for DC vaccines to achieve durable HIV remission without ART. 
Type Therapeutic Intervention - Vaccines
Current Stage Of Development Refinement. Clinical
Year Development Stage Completed 2020
Development Status Under active development/distribution
Clinical Trial? Yes
Impact On going 
 
Title HIV CORE 0052 
Description A phase 1 dose escalation open label trial to assess safety and immunogenicity of candidate ChAdOx1- and MVA-vectored conserved mosaic HIV-1 vaccines, given sequentially to healthy HIV-1/2-negative adult volunteers in Oxford, UK MVA-based vaccines The two MVA-vectored vaccines are called MVA.tHIVconsv3 and MVA.tHIVconsv4. Both were manufactured, labeled and technically released by IDT Biologika GmbH in Dessau-Rosslau, Germany. MVA is an efficient single-round expression vaccine vector that is itself incapable of replication and spread in mammals. Both MVA.tHIVconsv3 and MVA.tHIVconsv4 contain a transgene (insert) coding for 6 conserved HIV regions that are fused together to form a chimeric protein immunogen. These 6 regions are arranged in different unique orders, MVA.tHIVconsv3 as 3-6-2-5-1-4 and MVA.tHIVconsv4 as 4-1-5-2-6-3. Chimpanzee Adenovirus-based vaccine The Chimpanzee Adenovirus-vectored vaccine is called ChAdOx1.tHIVconsv1. It was manufactured, labeled and technically released by Advent S.r.l. in Rome, Italy. The ChAdOx1 vaccine vector is an engineered, non-replicating vector derived from simian adenovirus. ChAdOx1.tHIVconsv1 contains a transgene (insert) coding for 6 conserved HIV regions that are fused together to form chimeric protein immunogen in the region order of 1-2-3-4-5-6. 
Type Therapeutic Intervention - Vaccines
Current Stage Of Development Initial development
Year Development Stage Completed 2020
Development Status Under active development/distribution
Clinical Trial? Yes
Impact Seeking approvals 
 
Title HIV CORE 007 
Description A Phase I/II Randomized, Placebo-Controlled Trial of ChAdOx1.tHIVconsvX prime - MVA.tHIVconsvX Boost Vaccination Regimen in Early-treated durably-controlling HIV-1 positive Adults. MVA-based vaccines The two MVA-vectored vaccines are called MVA.tHIVconsv3 and MVA.tHIVconsv4. Both were manufactured, labeled and technically released by IDT Biologika GmbH in Dessau-Rosslau, Germany. MVA is an efficient single-round expression vaccine vector that is itself incapable of replication and spread in mammals. Both MVA.tHIVconsv3 and MVA.tHIVconsv4 contain a transgene (insert) coding for 6 conserved HIV regions that are fused together to form a chimeric protein immunogen. These 6 regions are arranged in different unique orders, MVA.tHIVconsv3 as 3-6-2-5-1-4 and MVA.tHIVconsv4 as 4-1-5-2-6-3. Chimpanzee Adenovirus-based vaccine The Chimpanzee Adenovirus-vectored vaccine is called ChAdOx1.tHIVconsv1. It was manufactured, labeled and technically released by Advent S.r.l. in Rome, Italy. The ChAdOx1 vaccine vector is an engineered, non-replicating vector derived from simian adenovirus. ChAdOx1.tHIVconsv1 contains a transgene (insert) coding for 6 conserved HIV regions that are fused together to form chimeric protein immunogen in the region order of 1-2-3-4-5-6. 
Type Therapeutic Intervention - Vaccines
Current Stage Of Development Early clinical assessment
Year Development Stage Completed 2020
Development Status Under active development/distribution
Clinical Trial? Yes
Impact Seeking approvals 
 
Title HIV CORE-0051 
Description A phase 1/2a open label trial to assess safety and immunogenicity of candidate T-cell vaccines ChAdOx1.HTI and MVA.HTI given sequentially to healthy HIV-1/2 negative adult volunteers in Oxford, UK 
Type Therapeutic Intervention - Vaccines
Current Stage Of Development Early clinical assessment
Year Development Stage Completed 2020
Development Status Under active development/distribution
Clinical Trial? Yes
UKCRN/ISCTN Identifier EudraCT Number: 2019-000621-47
Impact Seeking MHRA approval 
 
Title HIV-CORE 001 
Description The first use of conserved region vaccine MVA.HIVconsv in HIV-infected individuals in UK 
Type Therapeutic Intervention - Vaccines
Current Stage Of Development Early clinical assessment
Year Development Stage Completed 2013
Development Status On hold
Clinical Trial? Yes
Impact Background Vaccines may be key components of a curative strategy for HIV-1. We investigated whether a novel immunogen, HIVconsv, designed to re-direct T-cell responses to conserved regions of the viral proteome , could impact the HIV-1 reservoir in chronic antiretroviral therapy (ART)-treated subjects when delivered by modified vaccinia virus Ankara (MVA). Methods Nineteen virologically suppressed individuals were randomised to receive three intramuscular injections of MVA.HIVconsv at two doses, 5.5x107plaque-forming units (PFU) (n = 8), 2.2x108 PFU (n = 7) or placebo (n = 4) at 0, 4 and 12 weeks. Magnitude, breadth and antiviral function of vaccine-induced T cells and cell-associated HIV-1 DNA in circulating CD4+ T cells were measured before and after vaccination. Results 90% of subjects completed the vaccine regimen; there were no serious vaccine-related adverse events. CD8+ T-cell viral-inhibitory capacity was low in all groups at baseline and a post-vaccination increase occurred only in the high-dose group (p = 0.004). Total HIV-1 DNA did not change significantly from baseline in any group. Conclusions MVA.HIVconsv was safe in HIV-1-positive ART-treated subjects and without a heterologous vaccine prime induced a modest increase in CD8+ T-cell antiviral activity, but did not significantly change the size of the viral reservoir. 
URL https://www.clinicaltrialsregister.eu/ctr-search/search?query=eudract_number:2009-012662-31
 
Title HIV-CORE 002 
Description HIVconsv is a universal T cell immunogen focusing T cells responses on the conserved, i.e. common regions of the HIV-1 proteome. HIVconsv was delivered by DNA, modified vaccinia virua Ankara (MVA) and chimpanzee adenovirus serotype 63 (ChAdV-63) to healthy uninfected individual in UK. It is prophylactic, not therapeutic vaccine. 
Type Therapeutic Intervention - Vaccines
Current Stage Of Development Refinement. Clinical
Year Development Stage Completed 2012
Development Status On hold
Clinical Trial? Yes
Impact Virus diversity and escape from immune responses are the biggest challenges to the development of an effective vaccine against HIV-1. We hypothesized that T-cell vaccines targeting the most conserved regions of the HIV-1 proteome, which are common to most variants and bear fitness costs when mutated, will generate effectors that efficiently recognize and kill virus-infected cells early enough after transmission to potentially impact on HIV-1 replication and will do so more efficiently than whole protein-based T-cell vaccines. Here, we describe the first-ever administration of conserved immunogen vaccines vectored using prime-boost regimens of DNA, simian adenovirus and modified vaccinia virus Ankara to uninfected UK volunteers. The vaccine induced high levels of effector T cells that recognized virus-infected autologous CD4+ cells and inhibited HIV-1 replication by up to 5.79 log10. The virus inhibition was mediated by both Gag- and Pol- specific effector CD8+ T cells targeting epitopes that are typically subdominant in natural infection. These results provide proof of concept for using a vaccine to target T cells at conserved epitopes, showing that these T cells can control HIV-1 replication in vitro. 
URL https://www.clinicaltrialsregister.eu/ctr-search/search?query=eudract_number:2010-018439-16
 
Title HIV-CORE 003 
Description Background The failure of DNA vaccination in humans, in contrast to its efficacy in some species, is unexplained. Observational and interventional experimental evidence suggests that DNA immunogenicity may be prevented by binding of human serum amyloid P component (SAP). SAP is the single normal DNA binding protein in human plasma. The drug (R)-1-[6-[(R)-2-carboxypyrrolidin-1-yl]-6-oxo-hexanoyl]pyrrolidine-2-carboxylic acid (CPHPC, miridesap), developed for treatment of systemic amyloidosis and Alzheimer's disease, depletes circulating SAP by 95-99%. The proof-of-concept HIV-CORE 003 clinical trial tested whether SAP depletion by CPHPC would enhance the immune response in human volunteers to DNA vaccination delivering the HIVconsv immunogen derived from conserved sub-protein regions of HIV-1. Methods Human volunteers received 3 intramuscular immunizations with an experimental DNA vaccine (DDD) expressing HIV-1-derived immunogen HIVconsv, with or without prior depletion of SAP by CPHPC. All subjects were subsequently boosted by simian (chimpanzee) adenovirus (C)- and poxvirus MVA (M)-vectored vaccines delivering the same immunogen. After administration of each vaccine modality, the peak total magnitudes, kinetics, functionality and memory subsets of the T-cell responses to HIVconsv were thoroughly characterized. Results No differences were observed between the CPHPC treated and control groups in any of the multiple quantitative and qualitative parameters of the T-cell responses to HIVconsv, except that after SAP depletion, there was a statistically significantly greater breadth of T-cell specificities, that is the number of recognized epitopes, following the DDDC vaccination. Conclusions The protocol used here for SAP depletion by CPHPC prior to DNA vaccination produced only a very modest suggestion of enhanced immunogenicity. Further studies will be required to determine whether SAP depletion might have a practical value in DNA vaccination for other plasmid backbones and/or immunogens. 
Type Therapeutic Intervention - Vaccines
Current Stage Of Development Early clinical assessment
Year Development Stage Completed 2015
Development Status On hold
Clinical Trial? Yes
Impact Proof of concept trial 
URL https://www.clinicaltrialsregister.eu/ctr-search/search?query=eudract_number:2012-004052-11
 
Title HIV-CORE 004 
Description The first evaluation of the conserved region vaccines delivered by DNA (electroporated), MVA and HAdV-35 in healthy HIV-uninfected adults in Nairobi, Kenya Prophylactic, not therapeutic vaccine Trial is in not completed Mainly supported by EDCTP award 
Type Therapeutic Intervention - Vaccines
Current Stage Of Development Refinement. Clinical
Year Development Stage Completed 2015
Development Status On hold
Clinical Trial? Yes
UKCRN/ISCTN Identifier Ref no. PPB/ECCT/13/07/01/2013/(100) (Kenya regulator)
Impact We are developing a pan-clade HIV-1 T-cell vaccine HIVconsv, which could complement Env vaccines for prophylaxis and be key to HIV cure. Our strategy focuses vaccine-elicited effector T-cells on functionally and structurally conserved regions (not full-length proteins and not epitopes) of the HIV-1 proteome, which are common to most global variants and which, if mutated, cause a replicative fitness loss. Our first clinical trial in low risk HIV-1-negative adults in Oxford demonstrated the principle that mostly naturally subdominant epitopes, when taken out of the context of full-length proteins/virus and delivered by potent regimens involving combinations of simian adenovirus and poxvirus MVA, can induce robust CD8+ T cells of broad specificities and functions capable of inhibiting in vitro HIV-1 replication. Here and for the first time, we tested this strategy in low risk HIV-1-negative adults in Africa. We showed that the vaccines were well tolerated and induced high frequencies of broadly HIVconsv-specific plurifunctional T cells, which inhibited in vitro viruses from four major clades A, B, C and D. Because sub-Saharan Africa is globally the region most affected by HIV-1/AIDS, trial HIV-CORE 004 represents an important stage in the path towards efficacy evaluation of this highly rational and promising vaccine strategy. 
URL https://clinicaltrials.gov/show/NCT02099994
 
Title HIV-CORE 006 
Description A Phase 1 Trial of ChAdOx1- and MVA-vectored Conserved Mosaic HIV-1 Vaccines in Healthy, Adult HIV-1-negative Volunteers in Eastern and Southern Africa. MVA-based vaccines The two MVA-vectored vaccines are called MVA.tHIVconsv3 and MVA.tHIVconsv4. Both were manufactured, labeled and technically released by IDT Biologika GmbH in Dessau-Rosslau, Germany. MVA is an efficient single-round expression vaccine vector that is itself incapable of replication and spread in mammals. Both MVA.tHIVconsv3 and MVA.tHIVconsv4 contain a transgene (insert) coding for 6 conserved HIV regions that are fused together to form a chimeric protein immunogen. These 6 regions are arranged in different unique orders, MVA.tHIVconsv3 as 3-6-2-5-1-4 and MVA.tHIVconsv4 as 4-1-5-2-6-3. Chimpanzee Adenovirus-based vaccine The Chimpanzee Adenovirus-vectored vaccine is called ChAdOx1.tHIVconsv1. It was manufactured, labeled and technically released by Advent S.r.l. in Rome, Italy. The ChAdOx1 vaccine vector is an engineered, non-replicating vector derived from simian adenovirus. ChAdOx1.tHIVconsv1 contains a transgene (insert) coding for 6 conserved HIV regions that are fused together to form chimeric protein immunogen in the region order of 1-2-3-4-5-6. 
Type Therapeutic Intervention - Vaccines
Current Stage Of Development Early clinical assessment
Year Development Stage Completed 2020
Development Status Under active development/distribution
Clinical Trial? Yes
Impact Seeking approvals 
 
Title M&M Study 
Description A Phase I Pilot Study to Evaluate the Safety and Immunogenicity of the HIV-1 Vaccines MVA.tHIVconsv3 (M3) and MVA.tHIVconsv4 (M4) Given Alone or In Combination in HIV-1Infected Adults Suppressed on Antiretroviral Therapy - The M&M Study 
Type Therapeutic Intervention - Vaccines
Current Stage Of Development Initial development
Year Development Stage Completed 2020
Development Status Under active development/distribution
Clinical Trial? Yes
UKCRN/ISCTN Identifier IGHID 11810
Impact On going 
 
Title PEACHI 04 
Description We shall test novel potent T cell vaccines delivered in combination to safely induce anti-HCV and anti-HIV T cell immunity simultaneously in a single host. 
Type Therapeutic Intervention - Vaccines
Current Stage Of Development Early clinical assessment
Year Development Stage Completed 2016
Development Status On hold
Clinical Trial? Yes
Impact Background: Nearly 3 million people worldwide are coinfected with HIV and HCV. Affordable strategies for prevention are needed. We developed a novel vaccination regimen involving replication-defective and serologically distinct chimpanzee adenovirus (ChAd3, ChAd63) vector priming followed by modified vaccinia Ankara (MVA) boosts, for simultaneous delivery of HCV non-structural (NSmut) and HIV-1 conserved (HIVconsv) region immunogens. Methods: We conducted a phase I trial in which 33 healthy volunteers were sequentially enrolled and vaccinated via the intramuscular route as follows: 9 received ChAd3-NSmut [2.5 × 1010 vp] and MVA-NSmut [2 × 108 pfu] at weeks 0 and 8, respectively; 8 received ChAdV63.HIVconsv [5 × 1010 vp] and MVA.HIVconsv [2 × 108 pfu] at the same interval; 16 were co-primed with ChAd3-NSmut [2.5 × 1010 vp] and ChAdV63.HIVconsv [5 × 1010 vp] followed at week 8 by MVA-NSmut and MVA.HIVconsv [both 1 × 108 pfu]. Immunogenicity was assessed using peptide pools in ex vivo ELISpot and intracellular cytokine assays. Vaccine-induced whole blood transcriptome changes were assessed by microarray analysis. Results: All vaccines were well tolerated and no vaccine-related serious adverse events occurred. Co-administration of the prime-boost vaccine regimens induced high magnitude and broad T cell responses that were similar to those observed following immunization with either regimen alone.Median (interquartile range, IQR) peak responses to NSmut were 3,480 (2,728-4,464) and 3,405 (2,307-7,804) spot-forming cells (SFC)/106 PBMC for single and combined HCV vaccinations, respectively (p = 0.8). Median (IQR) peak responses to HIVconsv were 1,305 (1,095-4,967) and 1,005 (169-2,482) SFC/106 PBMC for single and combined HIV-1 vaccinations, respectively (p = 0.5). Responses were maintained above baseline to 34 weeks post-vaccination. Intracellular cytokine analysis indicated that the responding populations comprised polyfunctional CD4+ and CD8+ T cells. Canonical pathway analysis showed that in the single and combined vaccination groups, pathways associated with antiviral and innate immune responses were enriched for upregulated interferon-stimulated genes 24 h after priming and boosting vaccinations. Conclusions: Serologically distinct adenoviral vectors encoding HCV and HIV-1 immunogens can be safely co-administered without reducing the immunogenicity of either vaccine. This provides a novel strategy for targeting these viruses simultaneously and for other pathogens that affect the same populations. 
 
Title RIVER 
Description Assessment of decreasing latent HIV pool by reactivation and vaccination the first randomised, double blind study of kick and kill using vorinostat 
Type Therapeutic Intervention - Vaccines
Current Stage Of Development Early clinical assessment
Year Development Stage Completed 2018
Development Status On hold
Clinical Trial? Yes
Impact Background: Antiretroviral 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' - have been explored as a strategy towards an HIV cure. RIVER is the first randomized trial to determine the impact of ART alone versus ART plus 'kick-and-kill' on markers of the HIV reservoir. Methods: RIVER (Trial registration: NCT02336074) was an open-label, multicenter, 1:1 randomized controlled trial of ART-only (control) versus ART plus the histone deacetylase inhibitor vorinostat (the 'kick') and replication-deficient viral vector vaccines encoding conserved HIV sequences ChAdV63.HIVconsv-prime, MVA.HIVconsv-boost T-cell vaccination (the 'kill') (ART+V+V; intervention) in HIV-positive adults treated in recent HIV-infection. The primary endpoint was total HIV DNA in peripheral blood CD4+ T-cells at weeks 16 and 18 post-randomization. Secondary endpoints included safety, alternative measures of the HIV reservoir including quantitative viral outgrowth, HIV-specific T-cell frequencies, and CD8+ T-cell mediated viral inhibition. Findings: Between December 2015 and November 2017, 60 HIV-positive male participants were randomized (computer-based and stratified by time since diagnosis; 30 participants in each trial arm) and completed the study interventions, with no loss-to-follow-up. There were no intervention-related serious adverse events. Mean total HIV DNA at weeks 16 and 18 was 3.02 log10 copies HIV DNA/106 CD4+ T-cells in the control and 3.06 log10 copies HIV DNA/106 CD4+ T-cells in the intervention arm, with no statistically significant difference (mean difference of 0.04 (95%CI -0.03, 0.11) log10 total HIV DNA copies/106 CD4+ T-cells (p=0.26)). Interpretation: This 'kick-and-kill' approach conferred no significant benefit compared to ART alone on measures of the HIV reservoir. Although this does not disprove the 'kick and kill' strategy, for future trials significant enhancement of both 'kick' and 'kill' agents will be required. 
 
Description Adjacent Governmant article 
Form Of Engagement Activity A magazine, newsletter or online publication
Part Of Official Scheme? Yes
Geographic Reach International
Primary Audience Policymakers/politicians
Results and Impact Articles describing the importance of our research

Invitations to do more
Year(s) Of Engagement Activity 2014
 
Description EDCTP2 award of the GREAT Grant 
Form Of Engagement Activity A press release, press conference or response to a media enquiry/interview
Part Of Official Scheme? No
Geographic Reach International
Primary Audience Media (as a channel to the public)
Results and Impact Announcement of a grant award
Year(s) Of Engagement Activity 2017
 
Description International Innovation Article 
Form Of Engagement Activity A magazine, newsletter or online publication
Part Of Official Scheme? Yes
Geographic Reach International
Primary Audience Public/other audiences
Results and Impact Dissemination of science, research and technology

Many more requests from similar journals
Year(s) Of Engagement Activity 2014
 
Description NDM Podcast 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach Local
Primary Audience Other academic audiences (collaborators, peers etc.)
Results and Impact The podcast is available on the Univesity wensite.

Public understading.
Year(s) Of Engagement Activity 2012
 
Description Preliminary results of therapeutic trial BCN 02 
Form Of Engagement Activity A press release, press conference or response to a media enquiry/interview
Part Of Official Scheme? No
Geographic Reach International
Primary Audience Media (as a channel to the public)
Results and Impact Announcement of a partial/initial success in controlling the HIV virus during discontinuation of ART following vaccination
Year(s) Of Engagement Activity 2017
 
Description Race for Life 
Form Of Engagement Activity Participation in an activity, workshop or similar
Part Of Official Scheme? Yes
Type Of Presentation Workshop Facilitator
Geographic Reach Regional
Primary Audience Public/other audiences
Results and Impact Team building exercise
Websites:
http://www.ccmp.ox.ac.uk/public-engagement
http://www.raceforlifesponsorme.org/kessler-group/eurl.axd/289728e11b02e2478608452b80d5ec5e

Raising awareness for sport as a way to increase health
Year(s) Of Engagement Activity 2012