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.

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

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Jönsson P (2016) Remarkably low affinity of CD4/peptide-major histocompatibility complex class II protein interactions. in Proceedings of the National Academy of Sciences of the United States of America

 
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 European Union (EU)
Start 01/2017 
End 12/2021
 
Description Martin Delaney Collaboratories for HIV Cure Research (UM1)
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 04/2016 
End 03/2021
 
Description VDRG
Amount $1,200,000 (USD)
Funding ID OX-14007-044-0037-212 
Organisation Advanced BioScience Laboratories Inc 
Sector Private
Country United States
Start 01/2017 
End 08/2019
 
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 2011 
Provided To Others? Yes  
Impact Selecting for vaccine immunogens conserved regions of microbes common to many variants - HIV, HCV, Flu, Dengue 
 
Description A Phase I/II Randomized, Placebo-Controlled Trial of Therapeutic Vaccination with Conserved HIV-1 Immunogens in Adults Initiated on Suppressive Antiretroviral Therapy during Acute HIV-1 Infection 
Organisation University of Pittsburgh
Country United States 
Sector Academic/University 
PI Contribution Provision of four GMP vaccines for a clinical trial in HIV-positive adults
Collaborator Contribution Run a clinical trials and outcome assays
Impact none as yet
Start Year 2017
 
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 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 (DNA sequence) and carry 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 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 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 
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Collaborator Contribution Pre-GMP vaccine rescue, single vision purification and GMP manufacture
Impact Early times
Start Year 2016
 
Description 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 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 Globally Relevant HIV Vaccine Africa-Europe Trials Partnership 
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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 Globally Relevant HIV Vaccine Africa-Europe Trials Partnership 
Organisation Medical Research Council (MRC)
Department MRC Mitochondrial Biology Unit
Country United Kingdom 
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 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 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 Globally Relevant HIV Vaccine Africa-Europe Trials Partnership 
Organisation Zambia Emory HIV Research Project
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 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 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 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 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 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 designed the experiment, provided vaccines and animals, collected samples, analysis of TCR.
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 Vaccine Manufacturing project 
Organisation Advent S.r.l
Country Italy 
Sector Private 
PI Contribution Provision of starting material and guidance throughout the manufacturing process
Collaborator Contribution Pre-GMP development
Impact non yet
Start Year 2016
 
Description 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
 
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 PCT/US2014/058422 and UK Application No 61/884705 
Protection Patent application published
Year Protection Granted 2014
Licensed No
Impact N/A
 
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