Definition and induction of broadly protective responses against HIV-1

Lead Research Organisation: University of Oxford
Department Name: The Jenner Institute

Abstract

Despite remarkable progress achieved in decreasing HIV transmission and AIDS-related deaths in the last decade due to development of over 30 antiretroviral drugs, HIV continues to spread in a virtually uncontrolled manner. An effective HIV vaccine remains one of the priorities of HIV/AIDS research and will always be the best solution and likely key to any strategy for halting the AIDS epidemic. The biggest challenge in developing such a vaccine is the enormous HIV variability, which dwarfs that of any other virus except hepatitis C virus. However, all parts of HIV cannot easily change; to remain alive, HIV has to keep some smaller regions of its proteins more or less constant to maintain function. Our vaccine strategy takes advantage of this and focuses the body defenses on these conserved parts of HIV, its Achilles heel. Because conserved regions are common to most of the global HIV variants, the vaccine, if successful, could be used in Africa, Asia, Europe, America and Australia: it would be universal. The 1st generation conserved-region vaccine was very safe and induced strong immune responses in adult volunteers in the UK and Africa. In 2014, the pharmaceutical company GSK acquired a small biotech company, which developed one of the benign viruses we used for vaccine delivery, and unilaterally decided that we could no longer use the jointly owned vaccine in high risk people. Thus we needed to switch to an alternative vaccine virus and this provided an opportunity to also substantially improve the 1st generation vaccine. These modifications are based on our experience from human vaccine testing and other developments in the HIV vaccine field over the last 10 years since its original design. Thus, the 2nd generation vaccine was born, using a new vaccine virus (ChAdOx1) owned by Oxford University and combining conserved regions with computer-designed proteins (mosaics), which significantly increase the vaccine match to global HIV variants. (Note that even the highly conserved regions are still somewhat variable.) Vaccines should match circulating HIVs as much as possible to stop them efficiently. The 2nd generation vaccines have been constructed, shown to induce strong immune responses in animal models and are now bound for testing in human volunteers. The requested funds will allow to us see how well the 2nd generation vaccine works in trying to get rid of HIV from already infected individuals and for larger scale testing in HIV-1 negative healthy volunteers in Africa. The latter study will aim first evidence that the vaccine can stop HIV from infecting healthy people. The funding will also allow clinical testing of the vaccine enabling further improvements including some new aimed at keeping ahead of HIV.

Technical Summary

Development of an effective vaccine against HIV/AIDS remains one of the top global health priorities even in the context of broader prevention landscape. It is generally accepted that development of HIV vaccine is a gradual iterative process that will take many years. It is very positive that significant inroads have been made into identifying what constitutes both protective T cells and broadly neutralizing Abs (bnAb) for this most difficult of vaccines.

The biggest challenges for vaccines are HIV variability and escape. Compelling evidence for an important role of CD8 T cells in controlling HIV has accumulated over the last 30 years. My group is taking a multipronged approach to HIV T-cell vaccine development combining our experimental data with novel vaccine strategies. The hypothesis we pursue is that focusing T cells on the functionally conserved regions of HIV proteins will enable early control or elimination of the transmitted/reactivated viruses. To achieve this, the vaccines must match as much as possible all HIV variants and the T cells must be robust enough to stay strong when facing natural infection, altering the natural immunodominance.

This PG Renewal will support a team of scientists led by Tomas Hanke, who are at the heart of a highly rational and promising T-cell vaccine approach. We demonstrated the concept of the conserved region strategy in European and African HIV seronegative adults and also in infected patients on ART. We are now adding a new element to the vaccine, the mosaic concept and are moving towards testing this much improved 2nd generation vaccine for HIV cure and small efficacy trials. The aim for the latter will be to complement induction of Abs when bnAb vaccines remain suboptimal. In the next 5 years, we will develop next generation of vaccine vectors and immunogens; evaluate the induction and role of non-canonical CD8 T cells for human vaccine use; asses the role of conserved T-cell responses in HIV cure and prevention.

Planned Impact

Who will benefit from this research?

Since the first report of AIDS in 1981, an estimated 60,000,000 people have become infected with HIV-1, of whom some 25,000,000 have died. Over 90% of new infections take place in countries with limited resources. Globally the rate of new infections has decreased by 33% since year 2001. Nevertheless in 2013, still 240,000 children became newly infected with HIV-1 and 50 young women became infected every hour, thus a control of the HIV-1 epidemic remains one of the global health priorities.
Effective preventive vaccine against HIV-1 can avert millions of new infections, empower women, protect children, circumvent the stigma facing men-who-have-sex-with-men, and help many other beyond the reach of today's HIV-1 treatment and prevention options. Millions of already infected people around the word will benefit from HIV cure, either functional (drug-free control of HIV-1) or sterile (complete elimination of the virus from the body).

How will they benefit from this research?

ART has revolutionized survival, but is far from an ideal solution, because antiretroviral drugs are not available on a regular reliable basis in many resource-poor settings, they have long-term side effects, their effective use requires rigorous daily compliance and the circulating and/or transmitted viruses develop resistance. In any case, ART alone is unable to eradicate the virus because of an inaccessible pool of HIV-1-infected cells, in which the virus is dormant (the proviral reservoir). Thus, with or without reactivation by latency reverting agents, effective T-cell vaccine will be a key to HIV cure. The gained understanding and approach stimulating CD8+ T cells specific for conserved regions, would be greatly preferable to simply reactivating the pre-antiretroviral treatment T-cell responses that had failed to control the virus. Similarly, efficient and early recognition of transmitted/founder viruses will control the virus spread and prevent damage to the immune system in healthy exposed individual. Our strategy is applicable to other immunological problems where variability is a major roadblock in developing effective preventive or therapeutic tools.
The MRC Programme Grant Renewal proposes science on the forefront of the biotechnology engineering and HIV-1 vaccine development, thus strengthening the UK's world-class excellence in science, fostering industrial leadership to support business including innovation by small and medium-sized enterprises (Immune Design (US), Clinical Biomanufacturing Facility) and even big Pharma will become re-engagement if a real promise is observed in an efficacy trial. Bioengineering is a proven driver of a long-term sustainability and economic growth, we shall demonstrate the feasibility and functional validation of novel designs and biotechnologies developed by academia and manufactured by industries, spur scientific innovation across a broad sector of public and animal health and contribute to educated societal debates on issues associated with novel biotechnologies.
Ultimately, vaccine research will provide a basis for clinical decision making and policy-making for governments, policy-makers and advocates to develop evidence-based policies and advocacy aiming at prioritizing investments in HIV-1 research (clinical and basic science), allowing for an efficient use of limited funds, supporting research that has a greater potential to deliver results at population level.

Organisations

Publications

10 25 50
publication icon
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

publication icon
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

publication icon
Hannoun Z (2018) Identification of novel HIV-1-derived HLA-E-binding peptides. in Immunology letters

 
Description Evidence before
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 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
Under the present award, we 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 emphasise 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.
Exploitation Route Depending on the data from each stage of testing, the vaccine strategy is being taken toward assessment of preventive and therapeutic efficacy.
Sectors Healthcare

URL https://www.ncbi.nlm.nih.gov/sites/myncbi/1xIGqrtdUVlkf/bibliography/48269782/public/?sort=date&direction=ascending
 
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 EDCTP2 SRIA2015
Amount € 7,100,000 (EUR)
Funding ID SRIA2015-1066 
Organisation Sixth Framework Programme (FP6) 
Department European and Developing Countries Clinical Trials Partnership
Sector Public
Country Netherlands
Start 01/2017 
End 12/2023
 
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 NIAID VDRG
Amount $554,705 (USD)
Funding ID OX-14007-044-0037-212 
Organisation Advanced BioScience Laboratories Inc 
Sector Private
Country United States
Start 09/2016 
End 08/2019
 
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 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 Identification of HLA-E binding peptides 
Description Non-classical class Ib MHC-E molecule is becoming an increasingly interesting component of the immune response. It is involved in both the adaptive and innate immune responses to several chronic infections including HIV-1 and, under very specific circumstances, likely mediated a unique vaccine protection of rhesus macaques against pathogenic SIV challenge. Despite being recently in the spotlight for HIV-1 vaccine development, to date there is only one reported human leukocyte antigen (HLA)-E-binding peptide derived from HIV-1. In an effort to help start understanding the possible functions of HLA-E in HIV-1 infection, we determined novel HLA-E binding peptides derived from HIV-1 Gag, Pol and Vif proteins. These peptides were identified in three independent assays, all quantifying cell-surface stabilization of HLA-E*01:01 or HLA-E*01:03 molecules upon peptide binding, which was detected by HLA-E-specific monoclonal antibody and flow cytometry. Thus, following initial screen of over 400 HIV-1-derived 15-mer peptides, 4 novel 9-mer peptides PM9, RL9, RV9 and TP9 derived from 15-mer binders specifically stabilized surface expression of HLA-E*01:03 on the cell surface in two separate assays and 5 other binding candidates EI9, MD9, NR9, QF9 and YG9 gave a binding signal in only one of the two assays, but not both. Overall, we have expanded the current knowledge of HIV-1-derived target peptides stabilizing HLA-E cell-surface expression from 1 to 5, thus broadening inroads for future studies. This is a small, but significant contribution towards studying the fine mechanisms behind HLA-E actions and their possible use in development of a new kind of vaccines. 
Type Of Material Technology assay or reagent 
Year Produced 2018 
Provided To Others? Yes  
Impact Mainly academic - New tools for studying the role of HLA-e functions 
 
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 Novel universal HIV-1 vaccines HIVconsv 
Description Vaccines targeting the conserved regions of HIV-1, therefore potentially controlling all clade in the target population and all escape mutants in infected individuals The HIVconsv immunogen is delivered by DNA, MVA, chimp adenovirus, Semiliki Forest virus replicons and synthetic long peptides 
Type Of Material Technology assay or reagent 
Year Produced 2007 
Provided To Others? Yes  
Impact Tested in 7 clinical trials 
 
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 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 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 Collaboratory of AIDS Researchers for Eradication (CARE) 
Organisation University of North Carolina at Chapel Hill
Country United States 
Sector Academic/University 
PI Contribution Provide the second generation tHIVconsvX vaccines
Collaborator Contribution A small therapeutic trial in HIV patients will be run
Impact Early days
Start Year 2016
 
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 Development of A.I.R. vectored vaccines 
Organisation BioNTech AG
Country Germany 
Sector Private 
PI Contribution We contributed the immunogen design and carried out pre-clinical immunogenicity
Collaborator Contribution manufacture of research-grease vaccines
Impact Promising mouse immunogenicity of the mRNA platform
Start Year 2016
 
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 RCMV vaccine against filoviruses 
Organisation Los Alamos National Laboratory
Department Theoretical Biology and Biophysics
Country United States 
Sector Public 
PI Contribution We provide vaccines immunogens FILOcepX and shall test the vaccines in pre-clinical models
Collaborator Contribution Construct RCMV.FILOcepX vaccines
Impact early stages
Start Year 2017
 
Description Development of a RCMV vaccine against filoviruses 
Organisation University of Plymouth
Department Institute of Translational and Stratified Medicine
Country United Kingdom 
Sector Academic/University 
PI Contribution We provide vaccines immunogens FILOcepX and shall test the vaccines in pre-clinical models
Collaborator Contribution Construct RCMV.FILOcepX vaccines
Impact early stages
Start Year 2017
 
Description Development of mRNA-Liponanoparticle vaccines 
Organisation University of Pennsylvania
Department Perelman School of Medicine
Country United States 
Sector Academic/University 
PI Contribution Vaccine design and preclinical immunogenicity
Collaborator Contribution Vaccine preparation and formulation
Impact Early times
Start Year 2016
 
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 simian adenovirus vaccine 
Organisation Advent S.r.l
Country Italy 
Sector Private 
PI Contribution Design vaccine, provided starting material and transferred and pre-GMP assay
Collaborator Contribution Pre-GMP vaccine rescue, single vision purification and GMP manufacture
Impact Early times
Start Year 2016
 
Description GMP manufacture of simian adenovirus vaccine 
Organisation National Institute of Allergy and Infectious Diseases (NIAID)
Country United States 
Sector Public 
PI Contribution Design vaccine, provided starting material and transferred and pre-GMP assay
Collaborator Contribution Pre-GMP vaccine rescue, single vision purification and GMP manufacture
Impact Early times
Start Year 2016
 
Description GREAT - Globally Relevant HIV Vaccine Africa-Europe Trials Partnership 
Organisation Imperial College London
Country United Kingdom 
Sector Academic/University 
PI Contribution Co-ordination of capacity building and vaccine clinical trial HIv-CORE 006
Collaborator Contribution Build capacity and help with trial
Impact Early stages
Start Year 2017
 
Description GREAT - Globally Relevant HIV Vaccine Africa-Europe Trials Partnership 
Organisation International AIDS Vaccine Initiative (IAVI)
Country Global 
Sector Charity/Non Profit 
PI Contribution Co-ordination of capacity building and vaccine clinical trial HIv-CORE 006
Collaborator Contribution Build capacity and help with trial
Impact Early stages
Start Year 2017
 
Description GREAT - Globally Relevant HIV Vaccine Africa-Europe Trials Partnership 
Organisation MRC/UVRI Uganda Research Unit on AIDS
Country Uganda 
Sector Public 
PI Contribution Co-ordination of capacity building and vaccine clinical trial HIv-CORE 006
Collaborator Contribution Build capacity and help with trial
Impact Early stages
Start Year 2017
 
Description GREAT - Globally Relevant HIV Vaccine Africa-Europe Trials Partnership 
Organisation Medical Research Council (MRC)
Department MRC Mitochondrial Biology Unit
Country United Kingdom 
Sector Academic/University 
PI Contribution Co-ordination of capacity building and vaccine clinical trial HIv-CORE 006
Collaborator Contribution Build capacity and help with trial
Impact Early stages
Start Year 2017
 
Description GREAT - Globally Relevant HIV Vaccine Africa-Europe Trials Partnership 
Organisation United States Agency for International Development
Department USAID Nove Pravosuddya Justice Sector Reform Program
Country Ukraine 
Sector Public 
PI Contribution Co-ordination of capacity building and vaccine clinical trial HIv-CORE 006
Collaborator Contribution Build capacity and help with trial
Impact Early stages
Start Year 2017
 
Description GREAT - Globally Relevant HIV Vaccine Africa-Europe Trials Partnership 
Organisation University of Nairobi
Department KAVI Institute of Clinical Research
Country Kenya 
Sector Hospitals 
PI Contribution Co-ordination of capacity building and vaccine clinical trial HIv-CORE 006
Collaborator Contribution Build capacity and help with trial
Impact Early stages
Start Year 2017
 
Description GREAT - Globally Relevant HIV Vaccine Africa-Europe Trials Partnership 
Organisation Zambia Emory HIV Research Project
Country Zambia 
Sector Charity/Non Profit 
PI Contribution Co-ordination of capacity building and vaccine clinical trial HIv-CORE 006
Collaborator Contribution Build capacity and help with trial
Impact Early stages
Start Year 2017
 
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 Impovements to clinical biomanufacturing of recombinant simian adenoviruses 
Organisation Oxford BioMedica UK Ltd
Country United Kingdom 
Sector Private 
PI Contribution Provision of reagents and know-how for generation of recombinant adenovirus vaccines, construction of vaccines, pre-=clinical expression and immunogenicity
Collaborator Contribution Provision of recombinant cell line and TRiP suppression system, reagent/vaccine generation
Impact Early times
Start Year 2017
 
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 Pan-filovirus T-cell Vaccine Designed as Bi-valent Conserved Region Epigraphs 
Organisation Los Alamos National Laboratory
Country United States 
Sector Public 
PI Contribution Construction and provision of pan-filovirus T-cell vaccines, pre-GMP development
Collaborator Contribution Non-human primate vaccine-immunisation and challenge studies using EBOV and MARV
Impact Will start April 1, 2017, but mouse immunogenicity has been demonstrated
Start Year 2017
 
Description Pan-filovirus T-cell Vaccine Designed as Bi-valent Conserved Region Epigraphs 
Organisation Public Health Agency of Canada
Country Canada 
Sector Public 
PI Contribution Construction and provision of pan-filovirus T-cell vaccines, pre-GMP development
Collaborator Contribution Non-human primate vaccine-immunisation and challenge studies using EBOV and MARV
Impact Will start April 1, 2017, but mouse immunogenicity has been demonstrated
Start Year 2017
 
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 Protection of neonate macaques against SIV challenge 
Organisation Duke University Medical Centre
Country United States 
Sector Academic/University 
PI Contribution Provide macaque vaccines, which are analogous to the 2nd generation human tHIVocnsvX vaccines
Collaborator Contribution Immunize and challenge neonate macaques with SIV
Impact Early stages
Start Year 2016
 
Description Provision of GMP cell line for manufacturing adenoviruses 
Organisation Nouscom AG
Country Switzerland 
Sector Private 
PI Contribution Nothing
Collaborator Contribution Access to GMP cell line
Impact Early times
Start Year 2016
 
Description RNA vaccine delivery platform for HIVconsvX 
Organisation International AIDS Vaccine Initiative (IAVI)
Country Global 
Sector Charity/Non Profit 
PI Contribution Design of novel 2nd generation conserved region T-cell vaccine immunogens and mouse immunogenicity
Collaborator Contribution Manufacture of RNA vaccines
Impact Protection of mice against lethal challenge with EBOV and MARV
Start Year 2018
 
Description RNA vaccine delivery platform for HIVconsvX 
Organisation Moderna
Country United States 
Sector Private 
PI Contribution Design of novel 2nd generation conserved region T-cell vaccine immunogens and mouse immunogenicity
Collaborator Contribution Manufacture of RNA vaccines
Impact Protection of mice against lethal challenge with EBOV and MARV
Start Year 2018
 
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 TRiPAdeno system in comparison to the tet-repressor (tetR) system in generation of Adenovirus-vectored vaccines 
Organisation Oxford BioMedica UK Ltd
Country United Kingdom 
Sector Private 
PI Contribution Design and provision of vaccine transgenes and preparation of recombinant viruses
Collaborator Contribution Preparation of transfer plasmids and provision of TRIPAdeno cell lines
Impact none yet
Start Year 2016
 
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
 
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 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 
URL https://clinicaltrials.gov/show/NCT03758625
 
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 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
UKCRN/ISCTN Identifier OXTREC Ref: 56-19
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 
URL https://clinicaltrials.gov/show/NCT03844386
 
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 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 Research in Harmony 
Form Of Engagement Activity A broadcast e.g. TV/radio/film/podcast (other than news/press)
Part Of Official Scheme? No
Geographic Reach Regional
Primary Audience Public/other audiences
Results and Impact Open day science at UOXF
Year(s) Of Engagement Activity 2019