Development of a vaccine against HIV and AIDS

Lead Research Organisation: MRC Human Immunology Unit

Abstract

a) nature of research - our work aims to develop a protective vaccine against the HIV virus, the causative agent of AIDS; new candidate vaccines/approaches are tested first in animal models and then in human volunteers in UK, Europe and Africa.||b) prospective outcomes - the development of an new vaccine strategy for controlling HIV infection||c) health benefits - potential reduction in the number of HIV infections in developed and developing countries with the aim to eventual control HIV infection and the global AIDS epidemic

Technical Summary

This project aims to develop a vaccine inducing T cell responses that can on its own or in combination with an antibody-inducing vaccine benefit vaccinees by either preventing HIV-1 infection or improving virus control after infection, and therefore delaying development of AIDS and decreasing transmission to other people.||To accelerate our progress, we run mutually complementing studies in mice, non-human primates (NHP) and humans. We were the first to use a heterologous DNA prime and recombinant modified vaccinia virus Ankara (rMVA) boost regimen delivering a common immunogen derived from an central African HIV-1 strain. In humans (collaboration with Professor Andrew McMichael and Dr Lucy Dorrell), rMVA delivered a consistent and strong boost, while DNA primed consistently, but weakly HIV-1-specific T cell responses.||We explore other vaccine vectors acceptable for use in humans. Most recently, we are developing a recombinant mycobacteria BCG, which is used at birth as a TB vaccine in 80% infants born in Africa, as a vaccine platform for prevention of mother-to-child transmission of HIV-1 through breastfeeding.||We also develop novel HIV-1-derived protein immunogens delivered by the above vaccine vectors. Our latest immunogen is based on conserved regions of the HIV-1 proteome and thus targets all the HIV-1 variants in the target population rather than just the one predominant HIV-1 strain as we did in the past and indeed most other current vaccines under development do.||Experimental design - comparative immunogenicity in animal models, randomised controlled trials in humans||a) tissues, cells, animals used - mice, primates, human blood samples||b) techniques/approaches - heterologous prime-boost combinations of various vaccine vectors and modalities including DNA, MVA, SFV, BCG, human and animal adenoviruses and protein-based delivering a common HIV-1 derived immunogen||c) measurements/outcomes - frequency, functionality, longevity and anatomical distribution of vaccine-induced HIV-1-specific T cells

Publications

10 25 50
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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

 
Description EDCTP Clinical Trial Grants
Amount € 3,000,000 (EUR)
Funding ID CT.2006.33111.002 
Organisation Sixth Framework Programme (FP6) 
Department European and Developing Countries Clinical Trials Partnership
Sector Public
Country European Union (EU)
Start 10/2008 
End 09/2012
 
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 European Union (EU)
Start 01/2012 
End 01/2015
 
Description Japanese Foundation for AIDS Prevention
Amount ¥1,000,000 (JPY)
Organisation Japanese Foundation for AIDS Prevention 
Sector Charity/Non Profit
Country Japan
Start  
 
Description MRC DCS
Amount £1,031,751 (GBP)
Funding ID MR/J008605/1 
Organisation Medical Research Council (MRC) 
Sector Academic/University
Country United Kingdom
Start 11/2012 
End 09/2015
 
Description MRC Experimental Medicine II
Amount £1,290,000 (GBP)
Funding ID G0701669 
Organisation Medical Research Council (MRC) 
Sector Academic/University
Country United Kingdom
Start 10/2008 
End 09/2011
 
Description MRC Industrial Studentship
Amount £60,000 (GBP)
Organisation Medical Research Council (MRC) 
Sector Academic/University
Country United Kingdom
Start 10/2008 
End 08/2011
 
Description Programme grant
Amount £1,322,832 (GBP)
Funding ID G1001757/1 
Organisation Medical Research Council (MRC) 
Sector Academic/University
Country United Kingdom
Start 07/2011 
End 06/2016
 
Title Building capacity for infant HIV vaccine trials in two African sites 
Description Two Infant HIV Vaccine Centres established, scientists are being trained, two clinical trials are under way 
Type Of Material Improvements to research infrastructure 
Year Produced 2010 
Provided To Others? Yes  
Impact Training and capacity building, safety and immunogenicity of a novel vaccine in infants 
 
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 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 
 
Title pTH.HIVA and MVA.HIVA vaccines 
Description Vaccine were manufactured for clinical trials in 2000 
Type Of Material Technology assay or reagent 
Provided To Others? Yes  
Impact First clinical assessment of candidate HIV-1 vaccines derived from an African HIV clade and tested in DNA-MVA regimen and a MVA.HIVA alone in infants 
 
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 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 Construction of BCG.HIVA-Pasteur strain 
Organisation University of Barcelona
Country Spain 
Sector Academic/University 
PI Contribution We provided HIVA gene and conducted immunogenicity in mice, Barcelona constructed the vaccine and contributed to the design of AREAS recombinant BCG.HIVA401
Collaborator Contribution Construction of BCG.HIVA derived from the Paster strain
Impact Demonstration of BCG.HIVA immunogenicity and surrogate efficacy. Concept of a dual vaccine platform against TB and HIV-1 conceived Publications 17596303, 20484495, 20468055one manuscript in preparation
Start Year 2007
 
Description Development of HAdV19a.vectored vaccines 
Organisation University of Warwick
Country United Kingdom 
Sector Academic/University 
PI Contribution Our HIVA immunogen was inserted into novel adenovirus (by Warwick) and tested for mouse immunogenicty (MRC)
Collaborator Contribution Novel vaccine vector tested
Impact Novel vaccine has been constructed and tested in mice
Start Year 2008
 
Description Development of HIVB-B*5101 vaccines 
Organisation University of Kumamoto
Country Japan 
Sector Academic/University 
PI Contribution On Kumamotu advice, we have designed and novel immunogen and constructed novel vaccines
Collaborator Contribution Designer on a novel immunogen
Impact Novel vaccines have been constructed tailor designed for HLA-B*5101+ patients Publication 19585509, manuscript in preparation
Start Year 2006
 
Description Development of SLP.HIVconsv vaccine 
Organisation Leiden University Medical Center
Country Netherlands 
Sector Multiple 
PI Contribution We have designed a novel HIV-1 derived immunogen HIVconsv and LUMC synthesized the vaccine designed and Synthetic Long Peptides, both site carry immunogenicty studies NHP challenge experiment using SIVconsv is under way
Collaborator Contribution LUMC provided novel technology for vaccine design
Impact Novel promising vaccine design, which inudced much broader responses than traditional single-open readign-frame genetic vaccines. This has implications for T cell vaccine design in general. Publication 20468055 Grant submitted to B&MGF CAVD multidisciplinary
Start Year 2008
 
Description Development of Semliki Forest Virus replicon vaccines (HIVconsv) 
Organisation Karolinska Institute
Country Sweden 
Sector Academic/University 
PI Contribution We have designed and constructed a novel HIV-1 derived immunogen HIVconsv gene and Karolinska inserted this into virus and DNA-based replicon vaccines (VREP.HIVconsv and DREP.HIVconsv)
Collaborator Contribution Availabilityt of a novel vaccine modality
Impact Strong boosting of HIV_1 specific immune responses in mice and non-human primates Publication 20468055, two publications in preparation On going NHP experiment on going
Start Year 2008
 
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 Development of rBCG vaccines (HIVA and HIVconsv) 
Organisation Aeras
Department Aeras Global TB Vaccine Foundation
Country United States 
Sector Charity/Non Profit 
PI Contribution Aeras are experts in design and construction of recombinant BCG vaccine. They inserted the hiva and HIVconsv genes into their AREAS-401 modified BCG strain with increased safety and immunogenicity, two different constructs made by AERAS are in immunogenicities studies in Oxford
Collaborator Contribution Construction of recombinant BCGs
Impact Documented T cell immunogenicty in mice and primates including primate neonates. Publications 17596303, 20484495, 0375158 and two manuscripts in preparation
Start Year 2008
 
Description Development of replication-competent Ad4 vector 
Organisation PaxVax, Inc.
Country United States 
Sector Private 
PI Contribution We provide immunogen, PaxVAx constructs the vaccine, we do immunogenicity
Collaborator Contribution Construction of replication competent new HIV-1 vaccine candidate
Impact Replication-competent human adenovirus vector serotype 4 will be constructed with MRC immunogen and evaluated as a candidate vaccine. Contract has been signed. Two applications to B&MGF CAVD submitted
Start Year 2009
 
Description Development of sheep atadenovirus vectored vaccine OAdV.HIVA 
Organisation Commonwealth Scientific and Industrial Research Organisation
Department Biotech Equity Partners
Country Australia 
Sector Private 
PI Contribution We designed and constructed the HIVA gene and BEP constructed the OAdV.HIVA vaccine
Collaborator Contribution Availability of a novel vaccine vector
Impact Recombinant sheep atadenovirus vaccine was highly immunogenic in mice and on-human pirmates. Further development will follow. 19853074 and 20375158
Start Year 2007
 
Description Enhancing T cell induction though B. pertussis toxin targeting 
Organisation Academy of Sciences of the Czech Republic
Department Institute of Microbiology
Country Czech Republic 
Sector Public 
PI Contribution We provide immunogen HIVconsv sequence, partners construct experimental vaccine, we do pre-clinical immunogenicity evaluation
Impact So far, experimental vaccine have been prepared by our Czech Partners and initial
Start Year 2010
 
Description GLP pre-clinical toxicology (HIVA) 
Organisation Huntingdon Life Sciences
Country United Kingdom 
Sector Private 
PI Contribution HLS carried pre-clinical toxicology in mice to GLP
Collaborator Contribution GLP pre-clinical toxicology enables us to test novel vaccine concepts in humans
Impact GLP pre-clinical toxicology enables us to test novel vaccine concepts in humans and supports an application to MHRA for Clinical Trial Approval 19770697, 19266489, 18812202, 18440674, 17250931, 17170430, 17013989, 16641265, 16176847, 16641264, 17579081, 17257714
 
Description GMP manufacture of DNA vaccine pTH.HIVA 
Organisation Recipharm
Department Recipharm Cobra Biologics
Country Sweden 
Sector Private 
PI Contribution We designed and constructed an HIV-1-derived immunogene and the expression cassette, and used Cobra's Operator-Repressor Titration system for manufacture of plasmid with any antibiotic-resistance genes
Collaborator Contribution GMP products enable us to test novel vaccine concepts in humans
Impact GMP products enable us to test novel vaccine concepts in humans 19770697, 19266489, 18812202, 18440674, 17250931, 17170430, 17013989, 16641265, 16176847
 
Description GMP manufacture of MVA.HIVA 
Organisation IDT Biologika GmbH
Country Germany 
Sector Private 
PI Contribution We hva designed and constructed the vaccine IDT manufactured it to GMP
Collaborator Contribution GMP products enable us to test novel vaccine concepts in humans
Impact GMP products enable us to test novel vaccine concepts in humans 19770697, 19266489, 18812202, 18440674, 17250931, 17170430, 17013989, 16641265, 16176847, 16641264, 17579081, 17257714 Currently, the MVA.HIVA vaccine is in two clinical trials ininfants in Africa funded by EDCTP
 
Description IAVI-replication-competent virus vectors 
Organisation International AIDS Vaccine Initiative (IAVI)
Country Global 
Sector Charity/Non Profit 
PI Contribution MRC-owned insert HIVconsv is being inserted into IAVI-owned vectors by IAVI for joint preclinical and clinical collaborative studies
Collaborator Contribution Provision of highly-purified peptides for the immunologicla readout of HIVconsv-specific responses in animals and humans
Impact vector are being constructed
Start Year 2010
 
Description Murine EcoHIV challenge model 
Organisation Columbia University
Department Molecular Virology Division Columbia
Country United States 
Sector Academic/University 
PI Contribution We have constructed a modified version of the EcoHIV virus and use it in preclinical testing of vaccines
Collaborator Contribution Provided an early efficacy test for our vaccines in mice
Impact Publication 19585509 and manuscript submitted
Start Year 2008
 
Description Targeting vaccine-induced T cell to the gut 
Organisation Imperial College London
Department Faculty of Medicine
Country United Kingdom 
Sector Academic/University 
PI Contribution Demonstrated targeting of vaccine-induced Th1 T cell responses to the gut
Collaborator Contribution Development of organ-homing expertise
Impact Improving of vaccine efficacy through targetting or redirecting T cells into the gut, the main site of initial HIV-1 replication Manuscript in preparation followed by grant application to B&MGF
Start Year 2010
 
Description Vaccine immunogenicity in non-human primate neonates and adults 
Organisation Defence Science & Technology Laboratory (DSTL)
Country United Kingdom 
Sector Public 
PI Contribution We disigned the study and Dstl housed the animals and carried out the study procedures
Collaborator Contribution Housing of animals and performance of procedures
Impact Immunogenicity of BCG.HIVA401, MVA.HIVA and OAdV.HIVA vaccines was evaluated in non-human neonates and adults Publications 20375158 and 20484495
Start Year 2008
 
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 Immunogen HIVconsv 
Description HIV Consv is a DNA construct that comprises the 14 most conserved regions of the HIV-1 genome. It has been inserted into a range of recombinant vaccine formats and has been shown to be highly immunogenic in mice and non-human primates. Phase I clinical trials with the vaccine will begin in 2010. 
IP Reference US2008089901 
Protection Patent granted
Year Protection Granted 2008
Licensed No
Impact The invention relates to a novel vaccine candidate against HIV infection. The vaccine construct comprises domains from various HIV proteins. The vaccine is shown to induce cellular immune response in mice and non-human primates.
 
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 SLP.HIVconsv 
Description Cross-licence between MRCT and Leiden University Medical Center alow a joint development of the synthetic long peptide-HIVconsv technoogy 
IP Reference  
Protection Protection not required
Year Protection Granted 2011
Licensed Yes
Impact The crosslincence has been only just singed. It is expected to support a VC invenstment.
 
Title PedVacc 001 
Description A candidate HIV vaccine MVA.HIVA administered to 20-week-old infants in The Gambia It is a prophylactic, not therapeutic vaccine 
Type Therapeutic Intervention - Vaccines
Current Stage Of Development Early clinical assessment
Year Development Stage Completed 2012
Development Status On hold
Clinical Trial? Yes
Impact The first MVA vectored HIV vaccine tested in African infants. the trial was mainly safety and capacity building 
URL http://clinicaltrials.gov/show/NCT00982579
 
Title PedVacc 002 
Description A candidate HIV vaccine MVA.HIVA delivered to 20-week old infants in Nairobi, Kenya born to HIV-infected mothers. The trial was mainly vaccine safety and capacity building. It is a prophylactic, not therapeutic vaccine. 
Type Therapeutic Intervention - Vaccines
Current Stage Of Development Early clinical assessment
Year Development Stage Completed 2012
Development Status On hold
Clinical Trial? Yes
Impact The first MVA-vectored candidate HIV vaccine administered to African infants; only the third HIV candidate infant vaccine trial in Africa 
URL http://clinicaltrials.gov/show/NCT00981695
 
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 News of the Jenner Vaccine Foundation 
Form Of Engagement Activity A magazine, newsletter or online publication
Part Of Official Scheme? No
Geographic Reach Regional
Primary Audience Public/other audiences
Results and Impact publication

The articles were noted locally
Year(s) Of Engagement Activity 2010,2011
 
Description Vaccine in Practice 
Form Of Engagement Activity A magazine, newsletter or online publication
Part Of Official Scheme? No
Geographic Reach National
Primary Audience Health professionals
Results and Impact Publication

none noted by us
Year(s) Of Engagement Activity 2010