Developmental Clinical Studies - Depletion of serum amyloid P component to enhance the immune response to DNA vaccination

Lead Research Organisation: University College London
Department Name: Medicine

Abstract

We envisage a new approach to vaccination which will be applicable to all human diseases for which effective vaccines do not yet exist, including HIV-AIDS, malaria, tuberculosis and cancer. Success in the clinical trial proposed here with an HIV-1 vaccine will establish a critical proof of concept, opening the way to general application of our new approach. Vaccination is one of the most important achievements of medicine. Injection of modified germs, or materials from them, induces protective immunity against the infections which they cause. Smallpox has been eradicated from the planet, polio is almost gone. Diphtheria, tetanus and pertussis have been essentially eliminated from developed countries and, had it not been for the mendacious campaign against MMR vaccine, measles could also have been greatly reduced. Successful immunisation induces a protective immune response against particular component(s) of the target germ, the so-called immunogen(s). For some diseases the immunogens are not known and for others they are difficult and expensive to produce, transport and administer, for example influenza vaccine must be produced in millions of chicken eggs. A very attractive potential solution is to inject the DNA gene encoding the immunogen rather than the immunogen itself. In this process, known as DNA vaccination, the DNA enters cells, predominantly at the site of injection, and causes them to produce the immunogen locally within the body. DNA vaccination works well and stimulates excellent protective immunity against a variety of different infections, and even some cancers, in mice, horses, dogs, rabbits and pigs. But in humans and other primates, and in cows and sheep, the immune response to DNA vaccination is very feeble. Despite enormous academic and pharmaceutical industry efforts, the reasons for this failure have not been understood or overcome. We previously discovered, in work funded by the MRC, that a protein in human blood, known as serum amyloid P component (SAP), is the only normal blood protein which binds strongly to DNA. We have now found that, in each of the animal species in which DNA vaccination is effective, this protein is either absent or, if it is present, it binds only weakly to DNA. In contrast, non-human primates, cows and sheep share with humans the presence of SAP proteins which strongly bind to DNA. We believe that binding of DNA by SAP may be responsible for blocking induction of immune responses by DNA and that removal of SAP may overcome this inhibition. SAP contributes to important human diseases, amyloidosis and Alzheimer's disease, and, in MRC funded work towards treatment for these conditions, we have previously developed a drug, CPHPC, which safely removes almost all SAP from the blood in humans. Another laboratory has recently reported that the presence of human SAP inhibits DNA vaccination in mice and that this effect is reversed by our drug, CPHPC. These observations confirm our hypothesis. We now propose to undertake the first human clinical study of DNA vaccination after SAP depletion. We will measure the immune responses to HIV-1 in normal adult men, comparing a group in whom SAP has been completely depleted at the time of DNA vaccination and a control group vaccinated without SAP depletion. We predict that SAP depletion at the time of vaccination will enhance the immune response. The DNA vaccine to be tested is a promising new vaccine against HIV-AIDS, developed and manufactured with previous MRC awards. A positive result, consistent with improved protective immunity against HIV-1, will be very encouraging. Furthermore, proof of the concept that SAP depletion can enhance immune responses to DNA vaccination in humans will open up this approach for the many other diseases for which effective vaccination does not yet exist and in which it could have therapeutic as well as prophylactic applications. The potential worldwide health and economic benefits are therefore very great.

Technical Summary

Parenteral injection of naked DNA encoding immunogenic epitopes is a highly desirable approach to vaccination but, for reasons which have not hitherto been understood, it is not efficacious in some species, including humans. Serum amyloid P component (SAP) is the single normal human plasma protein which binds avidly to DNA under physiological conditions. We have lately discovered that, among species tested so far, there is complete concordance between the efficacy of DNA vaccination and the absence of circulating SAP which binds strongly to DNA. Mice respond well to DNA vaccination and their SAP binds DNA very weakly. It has lately been reported that human SAP potently blocks murine immune responses to DNA vaccination and that this inhibition is completely abrogated by CPHPC, the SAP depleting drug developed by Pepys. We now propose to conduct the first human clinical trial of DNA vaccination in subjects undergoing SAP depletion by CPHPC. Medicinal CPHPC and a suitable GMP DNA vaccine against HIV-1 are available, together with extensive expertise in conduct of HIV vaccine trials and monitoring of SAP and CPHPC. Forty healthy adult male volunteers will receive three priming doses of DNA vaccine, followed by a protein antigen boost. Half the subjects will be randomly allocated to receive a CPHPC infusion to provide maximal SAP depletion at the time of each DNA injection; controls will receive saline alone. Comprehensive assessment of the T cell immune response to each priming dose and to boosting, including viral suppression assays, will establish whether the immune response is significantly enhanced by SAP depletion and achieves a clinically useful level. A positive result will open the way in humans to use of prophylactic and therapeutic DNA vaccination against major infections including HIV, malaria and tuberculosis, and also cancer, with enormous potential health and economic benefits.

Planned Impact

Convincing evidence that SAP depletion enhances immune responses to DNA vaccination to an extent consistent with practical clinical benefit, will reignite the interest of the pharmaceutical and vaccine industry, and trigger further academic and commercial research. Despite its great theoretical and practical advantages as a strategy for prophylactic and therapeutic immunisation in a very wide range of diseases, DNA vaccination has been abandoned by almost all major pharmaceutical companies and vaccine manufacturers, because of its poor efficacy in humans. Elucidation of the reasons for this failure and provision of a solution will enable development of effective vaccines and make them much more widely available. Major beneficiaries will be the individuals and populations who can be protected from infections which are currently widespread and poorly treatable, as well as the vaccine and pharmaceutical sectors of industry. The capacity to arrest the spread of HIV-AIDS would obviously have a major impact on health and wealth, especially in Africa and other developing countries, but also in the developed world. Reduction of the enormous burden of malaria, tuberculosis and other infections for which no prophylactic immunisation is yet available, would also provide massive international benefits. Conduct in the UK of the world's first proof of concept demonstration in humans, and the presence here of the leading expertise related to this innovation, will be highly beneficial to UK industry, government and society generally.
 
Description UCL/UCLH BRC
Amount £900,000 (GBP)
Organisation National Institute for Health Research 
Department UCLH/UCL Biomedical Research Centre
Sector Academic/University
Country United Kingdom
Start 07/2012 
End 07/2016
 
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 Mapping of subdominant HLA-class I and II-restricted T cell epitopes 
Description we define novel protective T-cell epitopes subdominant in natural HIV infection. 
Type Of Material Technology assay or reagent 
Year Produced 2017 
Provided To Others? Yes  
Impact Mainly academic - We contribute to the collection of CD8+ and CD4+ T-cell determinants in HIV-1, which will drive iterative vaccine improvements especially in the light of the increasingly recognized important roles of T cells in the generation of protective anti-HIV-1 responses. 
 
Title Romidespin + vaccine - signal of post-antiretroviral treatment control of rebound HIV 
Description BCN 02 was an open-label, single-arm, phase I clinical trial, which enrolled 15 early-treated HIV-1-infected individuals and tested the combination of histone-deacetylase inhibitor romidepsin, a latency-reversing agent, and the MVA.HIVconsv vaccine. 
Type Of Material Model of mechanisms or symptoms - human 
Year Produced 2020 
Provided To Others? Yes  
Impact Results from this pilot study show that the kick&kill intervention was safe and suggest a role for this strategy in achieving an immune-driven durable viremic control. 
 
Title Vaccine focus on conserved regions of microbes 
Description The biggest roadblock for many vaccines is the pathogens' variability. This is best tackled by focusing both antibodies and T cells on the functionally most conserved regions of proteins common to many variants including escape mutants. For vectored vaccines, these 'universal' subunit immunogens are most efficiently delivered using heterologous prime-boost regimens, which can be further optimized by adjuvantation and route of delivery. 
Type Of Material Model of mechanisms or symptoms - human 
Year Produced 2007 
Provided To Others? Yes  
Impact Selecting for vaccine immunogens conserved regions of microbes common to many variants - HIV, HCV, Flu, Dengue 
 
Title Vaccine recipients' samples in BioBank 
Description Cryopreserved PBMC samples from recipient of HIV conserved region vaccines expanding and revealing naturally subdominant responses 
Type Of Material Biological samples 
Year Produced 2015 
Provided To Others? Yes  
Impact Mainly academic - Improving early prediction of vaccine success/failure. 
 
Title Vorinostat in the first randomised, double blind trial of kick-and-kill HIV cure 
Description The first randomised, double blind trial of kick-and-kill HIV cure. Antiretroviral therapy (ART) cannot cure HIV infection because of a persistent reservoir of latently infected cells. Approaches that force HIV transcription from these cells, making them susceptible to killing-termed kick and kill regimens-have been explored as a strategy towards an HIV cure. RIVER is the first randomised trial to determine the effect of ART-only versus ART plus kick and kill on markers of the HIV reservoir. 
Type Of Material Model of mechanisms or symptoms - human 
Year Produced 2020 
Provided To Others? Yes  
Impact This kick-and-kill approach conferred no significant benefit compared with ART alone on measures of the HIV reservoir. Although this does not disprove the efficacy kick and kill strategy, for future trials enhancement of both kick and kill agents will be required. 
 
Title Clinical trial data management 
Description Each clinical trial developed Data Management databases based on OpenClinical, REDCap or used EMMES 
Type Of Material Database/Collection of data 
Year Produced 2010 
Provided To Others? Yes  
Impact Mainly academic as a guidance for other/future trials 
 
Description 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 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 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 T-cell clonality in responses to mosaic vaccination 
Organisation University of Oxford
Department Department of Zoology
Country United Kingdom 
Sector Academic/University 
PI Contribution We conceived and designed the experiment, provided vaccines and animals, collected samples, analysis of TCR. We are technically guided for TCR PCR amplification by Arian Smith's laboratory
Collaborator Contribution Know-how for analysis of T cell clonality, TCR sequencing and analysis
Impact In progress
Start Year 2018
 
Description The BCN 02 Trial 
Organisation IrsiCaixa Institute for AIDS Research
Country Spain 
Sector Academic/University 
PI Contribution Provision of four GMP vaccines for a clinical trial in HIV-positive adults with monitored antiretroviral pause
Collaborator Contribution Run a clinical trials and outcome assays
Impact Submitted two publications
Start Year 2017
 
Title Mosaic conserved region HIV immunogenic polypeptides 
Description Disclosed herein are mosaic conserved region HIV polypeptides that can elicit an immune response to HIV (such as cytotoxic T cell (CTL), helper T cell, and/or hum oral responses). Also disclosed herein are immunogenic polypeptides including one or more of the mosaic conserved region polypeptides. In some examples, two or more of the mosaic conserved region polypeptides are included in a fusion (or chimeric) immunogenic polypeptide. In some 30 embodiments, the disclosed immunogenic polypeptides are included in an immunogenic composition, such as a polyvalent immunogenic composition. Also disclosed herein are methods for treating or inhibiting HIV in a subject including administering one or more (such as two or more) of the disclosed immunogenic polypeptides orcompositions to a subject infected with HIV or at risk of HIV infection. Also disclosed are methods of inducing an immune response to HIV in a subject by administering to the subject at least one (such as two or more) of the immunogenic polypeptides or a nucleic acid encoding at least one of the immunogenic polypeptides disclosed herein. 
IP Reference WO2015048785 
Protection Patent application published
Year Protection Granted 2014
Licensed No
Impact N/A
 
Title BCN 01 
Description The first immunogenicity evaluation of ChAdV63.HIVconsv prime-MVA.HIVconsv boost vaccine regimen delivering conserved regions of the HIV-1 proteome in HIV-1-infected individuals early on HAART 
Type Therapeutic Intervention - Vaccines
Current Stage Of Development Early clinical assessment
Year Development Stage Completed 2015
Development Status On hold
Clinical Trial? Yes
Impact Background Strong and broad antiviral T-cell responses targeting vulnerable sites of HIV-1 will likely be a critical component for any effective cure strategy. Methods BCN 01 trial was a phase I, open-label, non-randomised, multicenter study in HIV-1-positive individuals diagnosed and treated during early HIV-1 infection to evaluate two vaccination regimen arms, which differed in the time (8 versus 24 week) between the ChAdV63.HIVconsv prime and MVA.HIVconsv boost vaccinations. The primary outcome was safety. Secondary endpoints included frequencies of vaccine-induced IFN-?+ CD8+ T cells, in vitro virus-inhibitory capacity, plasma HIV-1 RNA and total CD4+ T cells associated HIV-1 DNA. (NCT01712425) Findings No differences in safety, peak magnitude or durability of vaccine-induced responses were observed between the long and short interval vaccination arms. Grade 1/2 local and systemic post-vaccination events occurred in 22/24 individuals and resolved within 3 days. Weak responses to conserved HIV-1 regions were detected in 50% of the individuals before cART initiation, representing median of less than 10% of their total HIV-1-specific T cells. All participants significantly elevated these subdominant T-cell responses, which after MVA.HIVconsv peaked at median (range) of 938 (73-6,805) IFN-? SFU/106 PBMC, representing on average 58% of their total anti-HIV-1 T cells. The decay in the size of the HIV-1 reservoir was consistent with the first year of early cART initiation in both arms. Interpretation Heterologous prime-boost vaccination with ChAdV63-MVA/HIVconsv was well-tolerated and refocuses pre-cART T-cell responses towards more protective epitopes, in which immune escape is frequently associated with reduced HIV-1 replicative fitness and which are common to most global HIV-1 variants. 
URL https://www.clinicaltrialsregister.eu/ctr-search/search?query=eudract_number:2011-000846-39
 
Title BCN 02 
Description The first generation HIVconsv vaccines in early treated individuals with romidepsin and monitored antiretroviral treatment pause ISCIII PI15/01188 grant, the HIVACAT Catalan research program for an HIV vaccine and the Fundació Gloria Soler. The vaccine GMP manufacture was jointly funded by the UK Medical Research Council and the UK Department for International Development (DFID) under the MRC/DFID Concordat agreements (MRC G0701669). Some sub-analyses were partly funded by the European Union's Horizon 2020 research and innovation program under grant agreement 681137-EAVI2020 and by NIH grant P01-AI131568. 
Type Therapeutic Intervention - Vaccines
Current Stage Of Development Initial development
Year Development Stage Completed 2017
Development Status On hold
Clinical Trial? Yes
Impact Background Kick&kill strategies, which combine drugs reactivating the viral reservoir with therapeutic vaccines inducing effective cytotoxic T-cell responses, hold potential to achieve a functional cure for HIV-1 infection. Methods BCN02 was an open-label, single-arm, phase I clinical trial, which enrolled 15 early-treated HIV-1-infected individuals and tested the combination of histone-deacetylase inhibitor romidepsin, a latency-reversing agent, and the MVA.HIVconsv vaccine. Findings Romidepsin treatment resulted in increased histone acetylation, cell-associated HIV-1 RNA and T-cell activation, which were associated with a marginally significant reduction of the viral reservoir. Vaccinations boosted robust and broad HIVconsv-specific T cells, which were strongly refocused towards conserved regions of the HIV-1 proteome. During a monitored ART-interruption phase using plasma viral load over 2,000 copies/ml as a criterium for ART resumption, 23% of individuals showed sustained suppression of viremia for planned 32 weeks without evidence for reseeding the viral reservoir. Interpretation Results from this pilot study show that the kick&kill intervention was safe and suggest a role for this strategy in achieving an immune-driven durable viremic control. 
URL http://www.croiconference.org/sessions/viral-control-induced-hivconsv-vaccines-romidepsin-early-trea...
 
Title DC 04 
Description Dendritic cell (DC)-based therapeutic vaccines have shown the most promise for controlling HIV replication without antiretroviral therapy (ART). Although two seminal clinical trials demonstrated significant decreases in plasma viremia without ART that were associated with vaccine-induced HIV-specific immune responses, other DC-based vaccine studies have shown equivocal or no virologic efficacy. The disconnect between a DC-based vaccine's theoretical capability, supported by strong in vitro evidence of priming of effector T-cells, and the variable results of clinical trials, highlight important gaps in understanding the determinants of DC vaccine efficacy in vivo. We therefore propose a comparative analysis to confirm prior efficacy of DC vaccines and to test new, innovative DC vaccines with the dual goals of improving virological efficacy and identifying key determinants of DC vaccine efficacy. Specifically, we will conduct an initial phase I/II, randomized, double-blind, pilot study to compare safety and anti-HIV efficacy of four different DC-based vaccines and two corresponding placebos. The trial will evaluate two DC maturation techniques (the prostaglandin E2-matured DCs, which were partially effective in the two seminal clinical trials, and the alpha-type-1 DCs, which have shown improved antigen-presenting and T-cell priming function ex vivo), two HIV immunogens (whole, inactivated, autologous HIV that was partially effective in the two trials, and a pool of HIV peptides covering the most highly-conserved regions in Gag and Pol combined with epitopes known to be associated with control of viremia in untreated HIV-infected individuals), and two dosing strategies (3 vs 6 doses). The primary efficacy outcome will be change in the inducible HIV reservoir from pre-vaccination to 2 weeks after the final vaccine dose. We will also further evaluate the in vivo anti-HIV efficacy of the DC vaccines by performing an extensive analysis of vaccine-induced changes in virologic and immunologic parameters with the secondary goal of identifying immune correlates of vaccine-induced virologic responses. The parameters measured will include residual plasma viremia, the number and transcriptional activity of HIV-infected cells, CD8+ T-cell inhibition of autologous virus replication, the magnitude, breadth, and polyfunctionality of immune responses, and immunoregulatory responses including regulatory T-cells and myeloid-derived suppressor cells. We propose a second clinical trial to assess reproducibility of initial findings from the first trial and to assess the impact of further refinements of DC vaccine designs on efficacy. We have developed pre-specified Go/No-Go criteria for moving forward to a second trial. The decision whether a specific DC vaccine will be evaluated in the second trial will be based on the primary and secondary virologic and immunologic endpoints of the first trial. This innovative, sequential, and iterative approach will evaluate multiple DC vaccines, elucidate determinants of vaccine efficacy, identify immune correlates of vaccine-induced reductions in HIV reservoirs, and provide new insights into the potential for DC vaccines to achieve durable HIV remission without ART. 
Type Therapeutic Intervention - Vaccines
Current Stage Of Development Refinement. Clinical
Year Development Stage Completed 2020
Development Status Under active development/distribution
Clinical Trial? Yes
Impact On going 
 
Title Depletion of serum amyloid P component to enhance the immune response to DNA vaccination 
Description Successful immunisation induces a protective immune response against particular component(s) of the target pathogen, the so-called immunogen(s). For some diseases the immunogens are not known and for others they are difficult and expensive to produce, transport and administer, for example influenza vaccine must be produced in millions of chicken eggs. A very attractive potential solution is to inject the DNA gene encoding the immunogen rather than the immunogen itself. In this process, known as DNA vaccination, the DNA enters cells, predominantly at the site of injection, and causes them to produce the immunogen locally within the body. DNA vaccination works well and stimulates excellent protective immunity against a variety of different infections, and even some cancers, in mice, horses, dogs, rabbits and pigs. But in humans and other primates, and in cows and sheep, the immune response to DNA vaccination is very feeble. Despite enormous academic and pharmaceutical industry efforts, the reasons for this failure have not been understood or overcome. We previously discovered, in work funded by the MRC, that a protein in human plasma, known as serum amyloid P component (SAP), is the only normal plasma protein which binds avidly to DNA. We have now found that, in each of the animal species in which DNA vaccination is effective, this protein is either absent or, if it is present, it binds only weakly to DNA. In contrast, non-human primates, cows and sheep share with humans the presence of SAP proteins which strongly bind to DNA. We believe that binding of DNA by SAP may be responsible for blocking induction of immune responses by DNA and that removal of SAP may overcome this inhibition. SAP contributes to important human diseases, amyloidosis and Alzheimer's disease, and, in MRC funded work towards treatment for these conditions, we have previously developed a drug, CPHPC, which safely removes almost all SAP from the blood in humans. Another laboratory has recently reported that the presence of human SAP inhibits DNA vaccination in mice and that this effect is reversed by our drug, CPHPC. These observations confirm our hypothesis. We are now undertaking the first human clinical study of DNA vaccination after SAP depletion, funded by an MRC DCS award. We will measure the immune responses to HIV-1 in normal adult men, comparing a group in whom SAP has been completely depleted at the time of DNA vaccination and a control group vaccinated without SAP depletion. We predict that SAP depletion at the time of vaccination will enhance the immune response. The DNA vaccine to be tested is a promising new vaccine against HIV-AIDS, developed and manufactured with previous MRC awards. A positive result, consistent with improved protective immunity against HIV-1, will be very encouraging. Furthermore, proof of the concept that SAP depletion can enhance immune responses to DNA vaccination in humans will open up this approach for the many other diseases for which effective vaccination does not yet exist and in which it could have therapeutic as well as prophylactic benefits. Success in the clinical trial undertaken here with an HIV-1 vaccine will establish a critical proof of concept, opening the way to general application of our new approach. The clinical trial has begun. The first two subjects have been successfully screened and randomised and have been admitted to the CRF. CPHPC infusion has taken place and they have now received the first DNA vaccination. The programme is funded by MRC DCS award MR/J008605/1. 
Type Therapeutic Intervention - Vaccines
Current Stage Of Development Early clinical assessment
Year Development Stage Completed 2014
Development Status Under active development/distribution
Clinical Trial? Yes
Impact The intervention is still in early stage clinical assessment. 
URL http://public.ukcrn.org.uk/Search/StudyDetail.aspx?StudyID=14680
 
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 003 
Description Background The failure of DNA vaccination in humans, in contrast to its efficacy in some species, is unexplained. Observational and interventional experimental evidence suggests that DNA immunogenicity may be prevented by binding of human serum amyloid P component (SAP). SAP is the single normal DNA binding protein in human plasma. The drug (R)-1-[6-[(R)-2-carboxypyrrolidin-1-yl]-6-oxo-hexanoyl]pyrrolidine-2-carboxylic acid (CPHPC, miridesap), developed for treatment of systemic amyloidosis and Alzheimer's disease, depletes circulating SAP by 95-99%. The proof-of-concept HIV-CORE 003 clinical trial tested whether SAP depletion by CPHPC would enhance the immune response in human volunteers to DNA vaccination delivering the HIVconsv immunogen derived from conserved sub-protein regions of HIV-1. Methods Human volunteers received 3 intramuscular immunizations with an experimental DNA vaccine (DDD) expressing HIV-1-derived immunogen HIVconsv, with or without prior depletion of SAP by CPHPC. All subjects were subsequently boosted by simian (chimpanzee) adenovirus (C)- and poxvirus MVA (M)-vectored vaccines delivering the same immunogen. After administration of each vaccine modality, the peak total magnitudes, kinetics, functionality and memory subsets of the T-cell responses to HIVconsv were thoroughly characterized. Results No differences were observed between the CPHPC treated and control groups in any of the multiple quantitative and qualitative parameters of the T-cell responses to HIVconsv, except that after SAP depletion, there was a statistically significantly greater breadth of T-cell specificities, that is the number of recognized epitopes, following the DDDC vaccination. Conclusions The protocol used here for SAP depletion by CPHPC prior to DNA vaccination produced only a very modest suggestion of enhanced immunogenicity. Further studies will be required to determine whether SAP depletion might have a practical value in DNA vaccination for other plasmid backbones and/or immunogens. 
Type Therapeutic Intervention - Vaccines
Current Stage Of Development Early clinical assessment
Year Development Stage Completed 2015
Development Status On hold
Clinical Trial? Yes
Impact Proof of concept trial 
URL https://www.clinicaltrialsregister.eu/ctr-search/search?query=eudract_number:2012-004052-11
 
Title HIV-CORE 004 
Description The first evaluation of the conserved region vaccines delivered by DNA (electroporated), MVA and HAdV-35 in healthy HIV-uninfected adults in Nairobi, Kenya Prophylactic, not therapeutic vaccine Trial is in not completed Mainly supported by EDCTP award 
Type Therapeutic Intervention - Vaccines
Current Stage Of Development Refinement. Clinical
Year Development Stage Completed 2015
Development Status On hold
Clinical Trial? Yes
UKCRN/ISCTN Identifier Ref no. PPB/ECCT/13/07/01/2013/(100) (Kenya regulator)
Impact We are developing a pan-clade HIV-1 T-cell vaccine HIVconsv, which could complement Env vaccines for prophylaxis and be key to HIV cure. Our strategy focuses vaccine-elicited effector T-cells on functionally and structurally conserved regions (not full-length proteins and not epitopes) of the HIV-1 proteome, which are common to most global variants and which, if mutated, cause a replicative fitness loss. Our first clinical trial in low risk HIV-1-negative adults in Oxford demonstrated the principle that mostly naturally subdominant epitopes, when taken out of the context of full-length proteins/virus and delivered by potent regimens involving combinations of simian adenovirus and poxvirus MVA, can induce robust CD8+ T cells of broad specificities and functions capable of inhibiting in vitro HIV-1 replication. Here and for the first time, we tested this strategy in low risk HIV-1-negative adults in Africa. We showed that the vaccines were well tolerated and induced high frequencies of broadly HIVconsv-specific plurifunctional T cells, which inhibited in vitro viruses from four major clades A, B, C and D. Because sub-Saharan Africa is globally the region most affected by HIV-1/AIDS, trial HIV-CORE 004 represents an important stage in the path towards efficacy evaluation of this highly rational and promising vaccine strategy. 
URL https://clinicaltrials.gov/show/NCT02099994
 
Title HIV-CORE 006 
Description A Phase 1 Trial of ChAdOx1- and MVA-vectored Conserved Mosaic HIV-1 Vaccines in Healthy, Adult HIV-1-negative Volunteers in Eastern and Southern Africa. MVA-based vaccines The two MVA-vectored vaccines are called MVA.tHIVconsv3 and MVA.tHIVconsv4. Both were manufactured, labeled and technically released by IDT Biologika GmbH in Dessau-Rosslau, Germany. MVA is an efficient single-round expression vaccine vector that is itself incapable of replication and spread in mammals. Both MVA.tHIVconsv3 and MVA.tHIVconsv4 contain a transgene (insert) coding for 6 conserved HIV regions that are fused together to form a chimeric protein immunogen. These 6 regions are arranged in different unique orders, MVA.tHIVconsv3 as 3-6-2-5-1-4 and MVA.tHIVconsv4 as 4-1-5-2-6-3. Chimpanzee Adenovirus-based vaccine The Chimpanzee Adenovirus-vectored vaccine is called ChAdOx1.tHIVconsv1. It was manufactured, labeled and technically released by Advent S.r.l. in Rome, Italy. The ChAdOx1 vaccine vector is an engineered, non-replicating vector derived from simian adenovirus. ChAdOx1.tHIVconsv1 contains a transgene (insert) coding for 6 conserved HIV regions that are fused together to form chimeric protein immunogen in the region order of 1-2-3-4-5-6. 
Type Therapeutic Intervention - Vaccines
Current Stage Of Development Early clinical assessment
Year Development Stage Completed 2020
Development Status Under active development/distribution
Clinical Trial? Yes
Impact Seeking approvals 
 
Title M&M Study 
Description A Phase I Pilot Study to Evaluate the Safety and Immunogenicity of the HIV-1 Vaccines MVA.tHIVconsv3 (M3) and MVA.tHIVconsv4 (M4) Given Alone or In Combination in HIV-1Infected Adults Suppressed on Antiretroviral Therapy - The M&M Study 
Type Therapeutic Intervention - Vaccines
Current Stage Of Development Initial development
Year Development Stage Completed 2020
Development Status Under active development/distribution
Clinical Trial? Yes
UKCRN/ISCTN Identifier IGHID 11810
Impact On going 
 
Title PEACHI 04 
Description We shall test novel potent T cell vaccines delivered in combination to safely induce anti-HCV and anti-HIV T cell immunity simultaneously in a single host. 
Type Therapeutic Intervention - Vaccines
Current Stage Of Development Early clinical assessment
Year Development Stage Completed 2016
Development Status On hold
Clinical Trial? Yes
Impact Background: Nearly 3 million people worldwide are coinfected with HIV and HCV. Affordable strategies for prevention are needed. We developed a novel vaccination regimen involving replication-defective and serologically distinct chimpanzee adenovirus (ChAd3, ChAd63) vector priming followed by modified vaccinia Ankara (MVA) boosts, for simultaneous delivery of HCV non-structural (NSmut) and HIV-1 conserved (HIVconsv) region immunogens. Methods: We conducted a phase I trial in which 33 healthy volunteers were sequentially enrolled and vaccinated via the intramuscular route as follows: 9 received ChAd3-NSmut [2.5 × 1010 vp] and MVA-NSmut [2 × 108 pfu] at weeks 0 and 8, respectively; 8 received ChAdV63.HIVconsv [5 × 1010 vp] and MVA.HIVconsv [2 × 108 pfu] at the same interval; 16 were co-primed with ChAd3-NSmut [2.5 × 1010 vp] and ChAdV63.HIVconsv [5 × 1010 vp] followed at week 8 by MVA-NSmut and MVA.HIVconsv [both 1 × 108 pfu]. Immunogenicity was assessed using peptide pools in ex vivo ELISpot and intracellular cytokine assays. Vaccine-induced whole blood transcriptome changes were assessed by microarray analysis. Results: All vaccines were well tolerated and no vaccine-related serious adverse events occurred. Co-administration of the prime-boost vaccine regimens induced high magnitude and broad T cell responses that were similar to those observed following immunization with either regimen alone.Median (interquartile range, IQR) peak responses to NSmut were 3,480 (2,728-4,464) and 3,405 (2,307-7,804) spot-forming cells (SFC)/106 PBMC for single and combined HCV vaccinations, respectively (p = 0.8). Median (IQR) peak responses to HIVconsv were 1,305 (1,095-4,967) and 1,005 (169-2,482) SFC/106 PBMC for single and combined HIV-1 vaccinations, respectively (p = 0.5). Responses were maintained above baseline to 34 weeks post-vaccination. Intracellular cytokine analysis indicated that the responding populations comprised polyfunctional CD4+ and CD8+ T cells. Canonical pathway analysis showed that in the single and combined vaccination groups, pathways associated with antiviral and innate immune responses were enriched for upregulated interferon-stimulated genes 24 h after priming and boosting vaccinations. Conclusions: Serologically distinct adenoviral vectors encoding HCV and HIV-1 immunogens can be safely co-administered without reducing the immunogenicity of either vaccine. This provides a novel strategy for targeting these viruses simultaneously and for other pathogens that affect the same populations. 
 
Title RIVER 
Description Assessment of decreasing latent HIV pool by reactivation and vaccination the first randomised, double blind study of kick and kill using vorinostat 
Type Therapeutic Intervention - Vaccines
Current Stage Of Development Early clinical assessment
Year Development Stage Completed 2018
Development Status On hold
Clinical Trial? Yes
Impact Background: Antiretroviral therapy (ART) cannot cure HIV infection because of a persistent reservoir of latently infected cells. Approaches that force HIV transcription from these cells, making them susceptible to killing - termed 'kick and kill' - have been explored as a strategy towards an HIV cure. RIVER is the first randomized trial to determine the impact of ART alone versus ART plus 'kick-and-kill' on markers of the HIV reservoir. Methods: RIVER (Trial registration: NCT02336074) was an open-label, multicenter, 1:1 randomized controlled trial of ART-only (control) versus ART plus the histone deacetylase inhibitor vorinostat (the 'kick') and replication-deficient viral vector vaccines encoding conserved HIV sequences ChAdV63.HIVconsv-prime, MVA.HIVconsv-boost T-cell vaccination (the 'kill') (ART+V+V; intervention) in HIV-positive adults treated in recent HIV-infection. The primary endpoint was total HIV DNA in peripheral blood CD4+ T-cells at weeks 16 and 18 post-randomization. Secondary endpoints included safety, alternative measures of the HIV reservoir including quantitative viral outgrowth, HIV-specific T-cell frequencies, and CD8+ T-cell mediated viral inhibition. Findings: Between December 2015 and November 2017, 60 HIV-positive male participants were randomized (computer-based and stratified by time since diagnosis; 30 participants in each trial arm) and completed the study interventions, with no loss-to-follow-up. There were no intervention-related serious adverse events. Mean total HIV DNA at weeks 16 and 18 was 3.02 log10 copies HIV DNA/106 CD4+ T-cells in the control and 3.06 log10 copies HIV DNA/106 CD4+ T-cells in the intervention arm, with no statistically significant difference (mean difference of 0.04 (95%CI -0.03, 0.11) log10 total HIV DNA copies/106 CD4+ T-cells (p=0.26)). Interpretation: This 'kick-and-kill' approach conferred no significant benefit compared to ART alone on measures of the HIV reservoir. Although this does not disprove the 'kick and kill' strategy, for future trials significant enhancement of both 'kick' and 'kill' agents will be required.