Adenovirus Vector Technology: Next Generation Systems for Medical Therapy (AD-VEC) AD-VEC involves two industrial and three academic partners with the aim to identify new adenoviral vectors as vehicles in novel medical applications for cardiovascular disease and infectious disease. This will be achieved through broad knowledge exchange between partners with complimentary and cutting edge technological and indepth skills relating to adenovirus phylogeny, biology and pathology in order to explore and exploit adenovirus existing in nature as new vectors in areas of unmet clinical need such as cardiovascular disease and infectious disease. Our major objectives of AD-VEC are: The provision of adenovirus genomes from novel rare human and non-human adenoviruses and engineering of these genomes to develop high quality recombinant adenovirus vectors expressing reporter genes; To provide detailed evaluation of novel adenovirus vectors with respect to infectivity, receptor usage, tropism, and the interaction with the blood and immune system; To evaluate these novel vectors at the pre-clinical level in areas of unmet clinical need, both using in vitro and in vivo studies. These three key objectives will enable excellence in adenovirus research amongst the AD-VEC consortium members through creating a synergistic and unique opportunity in this research field. The synergies are those that cross academic and industrial boundaries and create access to a pipeline of activity that will include basic virology, new assay development, novel preclinical models, pre-clinical manufacture and vector testing. This provides empowerment to the research teams through synergistic industry/academia collaborations developed towards a common goal, i.e. exploiting adenoviruses for medical therapy. Project Partners Andrew Baker, University of Edinburgh, UK (UEDIN) Jerome Custers, Janssen Pharmaceuticals (formerly Crucell), The Netherlands (CRUCELL) Menzo Havenga, Batavia Biosciences, The Netherlands (BATAVIA) Niklas Arnberg, Umeå University, Sweden (UMU) Balázs Harrach, Centre for Agricultural Research, Hungarian Academy of Sciences, Hungary (CAR HAS) AD-VEC Research Objectives of the research programme The overarching aim of the AD-VEC consortium is to exploit the vast array of adenoviruses (AdVs) that exist in nature and harness their potential as vectors in medical applications to go beyond state-of-the-art through derivation an anaysis of new vector technology. This will be achieved through improving our fundamental knowledge of adenovirus phylogeny, biology and pathology in order to explore them as vectors in areas of unmet clinical need such as cardiovascular disease, oncology and infectious disease. The major objectives of AD-VEC are therefore: Provision of adenovirus genomes from novel rare human and non-human adenoviruses and engineering of these genomes to develop high quality recombinant adenovirus vectors expressing reporter genes. Detailed evaluation of novel adenovirus vectors with respect to infectivity, receptor usage, tropism, and the interaction with the blood and immune system. Evaluation of novel vectors at the pre-clinical level in areas of unmet clinical need. These three key objectives will enable excellence in adenovirus research amongst the AD-VEC consortium members through creating a synergistic and unique opportunity in this research field. The synergies are those that cross academic and industrial boundaries and create access to a pipeline of activity that will include basic virology, new assay development, novel preclinical models, pre-clinical manufacture and vector testing. This provides empowerment to the research teams through synergistic industry/academia collaborations developed towards a common goal, i.e. exploiting adenoviruses for medical therapy. Objective 1. Selection of adenovirus genomes from rare human and non-human adenoviruses for engineering new vectors (WP2+3). Introduction: This objective has two key elements. First, is the selection of rare human and non-human adenovirus for immediate vector engineering. The second aspect is the selection of alternate vectors in particular from non-human primate species but adenoviruses originating from other species will be considered as well including rare human adenoviruses. This will be achieved through amplification in cell cultures corresponding to the tropism of the selected virus type, isolation of viral genomes and identification by PCR amplification and DNA sequencing of the hexon, DNA polymerase and IVa2 genes. Novel and promising adenoviruses will be subjected to full viral genome sequencing. Objective 2. Creation and manufacture of novel adenoviral vector systems for production of high quality recombinant adenovirus batches expressing reporter genes (WP2+3). Introduction: This objective is to generate high quality research tools required for basic virology studies. Also, these tools are essential for setting up novel test systems pivotal for larger scale viral vector production such as tests for purity, concentration, stability, VP/IU ratio, aggregation and absence of replication competent vector and identification of optimal producer cell lines. Objective 3. In-depth evaluation of the basic biology of new adenovirus vectors (WP4). Introduction: This objective is to begin to dissect and understand the basic infectivity profile of each new vector created in WP2+3 that defines infectivity in relation to cell tethering, cellular internalisation and trafficking to the nucleus in a range of cell lines expressing individual receptors as well as primary cells applicable to downstream translational objectives. Additionally in vitro serum neutralising assays with human population serums will be performed. Science and technology objectives: S&T objectives will be achieved via a number of methodologies including gene transfer assays in cell culture using both human and non-human cell lines (as appropriate), competition assays with small molecules/antibodies/siRNA studies to assess receptor usage, to assign capsid protein determinants that are responsible for infectivity and to understand cellular internalisation and trafficking mechanisms. This collective series of experiments will improve knowledge of each new vector and help define the experimental design for Objective 4. Objective 4. Evaluation of potential of such vectors at the pre-clinical level in areas of unmet clinical need (WP4). Introduction: This objective will determine the potential utility of each new vector in a series of preclinical experiments that span gene therapy and vaccination. Research methodology and approach The AD-VEC consortium brings strength in multiple facets of adenovirus biology that will allow this consortium to synergistically develop novel adenovirus vectors. The critical components of the research methodology include: - Design and engineering of adenovirus vectors from pre-selected and to be discovered adenovirus genomes. - The array of methodologies available for qualitative and quantitative analysis of adenovirus biology and infectivity profiles in model systems and primary human cells. - The range of relevant and innovative animal models available for pre-clinical evaluation. Collectively, this range of techniques maps our proposal perfectly and will allow rapid integration of work programmes between partners with the secondments proposed. Synergies/complementarities between the partners All partners possess unique tools, expertise, capacities and scientific and technological goals from the AD-VEC. This creates a unique opportunity in adenovirus research and exploitation. The project is based on the concept that adenoviruses are exceptionally important for a variety of clinical indications, not only as human (and animal) pathogens but also in the setting of use in vaccination and gene therapy. The consortium is uniquely placed to add substantial new potential to exploit the above concepts that have been developed through use of a number of previously studied adenoviruses (for example particularly HAdV-5, -35 etc. that have been progressed to clinical use in vaccination and gene therapy). This testifies to the potential of adenoviruses, but it is also very clear that there is an enormous opportunity that has not been exploited, likely due to a key bottleneck – essentially; there are many human adenoviruses, as well as a broad range of non-human adenoviruses, that remain to be studied and exploited. One of the reasons for this is the difficulty and time required to create “vectors” from previously unstudied adenoviruses (i.e. adenovirus vectorization) that limits the transition from adenovirus genome-to-adenovirus vector that can be used for detailed analysis of biology, pathology and, hence, potential exploitation. This is the overarching concept in AD-VEC. Harrach brings strength in depth in non-human adenoviruses (specifically simian, rodent, avian adenoviruses, and AdVs from exotic animals, and their comparative bioinformatic and phylogenetic analysis). Arnberg brings strength in human adenoviruses and their basic biology. These two key partners complement each other perfectly in terms of the access and detailed knowledge relating to non-human and human adenoviruses that have previously been untested as vectors. The consortium will therefore select a range of adenoviruses from the repertoire available to Harrach and Arnberg. Both partners will work closely with Menzo Havenga (Batavia Biosciences), a SME with key expertise and capacity in adenovirus vectorisation and pre-clinical and clinical manufacture. Hence, this key programme in AD-VEC will develop new adenovirus vectors from both non-human and human adenovirus serotypes and manufacture these to a high level of quality control. Thus, the key output from WP2 and WP3 will be new high quality adenoviruses vectors for characterisation and exploitation. This is WP4 and this exploits the synergy between additional partners Crucell (Custers) and Glasgow (Baker) together with Batavia and Umea. The vectors that are created will be used in WP3 and will be utilised for studies on basic adenovirus biology (e.g. receptor usage, gene transfer profiles, infectivity, pre-existing immunity studies etc.). Crucell and Glasgow both have breadth in expertise in this setting) but have complementing objectives from such research – for Crucell, this is for adenovirus vectors that show an effective profile for application to vaccination in the infectious and non-infectious disease setting, for Glasgow it is adenovirus vectors that show profile for application to gene therapy. Taken together, the partners all possess unique skills that create a unique opportunity in adenovirus research with implications for knowledge exchange, research enhancements and commercial uses of adenoviruses in gene therapy and vaccination. Science Dissemination/Outreach activities All members of the AD-VEC consortium are committed to outreach activity and indeed it is part of a full WP within the consortium (WP5). The dissemination of research and the educational value that it brings to the wider public is very important. Viruses are becoming more and more relevant as clinical successes in gene therapy and vaccination become more prominent in areas of substantial unmet need, but also their risks need to be discussed with the general public. Objectives O.5.1. To ensure the research of AD-VEC is published in high impact publications in scientific journals. O.5.2. To ensure attendance and timely contribution to workshops and conferences from all partners, ERs employed through AD-VEC and others engaged within the wider laboratory setting from each partner. O.5.3. To maximise interactions with the co-ordinated training activities with ADVance ITN creating new opportunities for collaboration and networking for all staff categories O.5.4. To develop and foster contribution of AD-VEC to public engagement activities through both commercial and academic partners ensuring the wider public is reliably informed and educated in gene therapy and vaccine development. O.5.5. To promote Marie Curie ambassadors through AD-VEC for education in high schools with the communities of partners nationally/internationally. O.5.6. To maximise Science Festival engagement. O.5.7. To ensure summer student placements are available annually for students to spend time in the partners’ laboratories to learn key skills and develop a keen appetite for science. O.5.8. To perform podcasts with opinion leaders in different sectors. O.5.9. To create and foster multimedia and eNews systems for wide dissemination of AD-VEC and related activity. AD-VEC Management Network organization and management structure The coordinator (CO) will lead the Management Board (MB), which is the core management element. The MB is composed by the one representative from each party. A Consortium Agreement (CA) will be put into place covering all parties and agreeing details on issues such as project management, decision making, IPR access, exploitation, publication and each partner’s obligations and responsibilities. The MB will implement decision making with respect to all aspects of research, training and knowledge exchange, including funding allocation, workpackages, mobility, intellectual property rights etc as well and resolution of any conflict. Economic matters and decisions on major changes in the project plan and other decisions will normally be made by consensus but if a vote is necessary then decisions will be by a straight majority of members. The coordinator will have decisive vote if necessary. The consortium agreement will be signed where among other things details regarding the decision procedure will be settled. Intellectual property. The CA will fix terms and conditions of collaboration and establish IPR rules within the consortium.. It will: (i) encourage the protection of knowledge and its dissemination; (ii) identify all elements in the project likely to need protection; (iii) prepare any exploitation plan. The CA will be dealt with: I) Access to Background Intellectual Property. Background Intellectual Property remains the property of the partner that brings it to the Project. The Foreground Intellectual produced shall be the property of the partner carrying out the work. When several partners have worked jointly generating a new knowledge and where their respective share of work cannot be ascertained, they should have joint ownership. Meetings Meetings of the MB will take place both through electronic means and physically. A kick-off meeting will be organised, followed by six monthly meetings either in person or via video / teleconference. A mid-term review will be scheduled for month 20 of the project. As the project only has 5 Partners, it is expected that every Party will take place in the decision making and there is no need for subgroups. The coordinator will require each Party to report on progress against agreed targets on a 6 monthly basis. Any significant deviation will be highlighted and discussed by the MB in a specially convened meeting. Appropriate action will be agreed at such meetings to take appropriate corrective action. Financial management The coordinator shall be responsible for the distribution of pre-financing and further payments to the partners, as they are received from the EC, in accordance with the budget breakdown in the EC Contract. The European Team within the University of Glasgow’ Finance Office will handle all monetary transactions with the Commission and Partners. The coordinator/project manager will be responsible for obtaining, appropriate interim and final financial and scientific reports from each partner as well as any applicable audit certificates. Management structure of AD-VEC. A simple but effective structure is proposed to ensure efficiency in management activity. Recent publications on adenoviruses of the AD-VEC members 2017 Duffy MR, Alonso-Padilla J, John L, Chandra N, Khan S, Ballmann MZ, Lipiec A, Heemskerk E, Custers J, Arnberg N, Havenga M, Baker AH, Lemckert A. (2017) Generation and characterization of a novel candidate gene therapy and vaccination vector based on human species D adenovirus type 56. J Gen Virol. DOI: 10.1099/jgv.0.000978 Adams MJ, Lefkowitz EJ, King AMQ, Harrach B, Harrison RL, Knowles NJ, Kropinski AM, Krupovic M, Kuhn JH, Mushegian AR, Nibert M, Sabanadzovic S, Sanfaçon H, Siddell SG, Simmonds P, Varsani A, Zerbini FM, Gorbalenya AE, Davison AJ (2017) Changes to taxonomy and the International Code of Virus Classification and Nomenclature ratified by the International Committee on Taxonomy of Viruses. Arch Virol (in press) Salisch NC, Vujadinovic M, van der Helm E, Spek D, Vorthoren L, Serroyen J, Kuipers H, Schuitemaker H, Zahn R, Custers J, Vellinga J (2017) Antigen capsid-display on human adenovirus 35 via pIX fusion is a potent vaccine platform. PLoS One 12 (3) e0174728. doi: 10.1371/journal.pone.0174728 Simmonds P, Adams MJ, Benkő M, Breitbart M, Brister JR, Carstens EB, Davison AJ, Delwart E, Gorbalenya AE, Harrach B, Hull R, King AMQ, Koonin EV, Krupovic M, Kuhn JH, Lefkowitz EJ, Nibert ML, Orton R, Roossinck MJ, Sabanadzovic S, Sullivan MB, Suttle CA, Tesh RB, van der Vlugt RA, Varsani A, Zerbini FM (2017) Virus taxonomy in the age of metagenomics. Nature Reviews Microbiology 15 (3) 161-168 Storm RJ, Persson BD, Skalman LN, Frängsmyr L, Lindström M, Rankin G, Lundmark R, Domellöf FP, Arnberg N (2017). Human adenovirus type 37 uses αVβ1 and α3β1 integrins for infection of human corneal cells. J Virol 91 (5) pii: e02019-16 2016 Adams MJ, Lefkowitz EJ, King AMQ, Gorbalenya AE, Harrach B, Harrison RL, Knowles NJ, Kropinski AM, Krupovic M, Kuhn JH, Mushegian AR, Nibert M, Sabanadzovic S, Sanfaçon H; Siddell SG, Simmonds P, Varsani A, Zerbini FM, Gorbalenya AE, Davison AJ (2016) Ratification vote on taxonomic proposals to the International Committee on Taxonomy of Viruses. Arch Virol 161 (10) 2921-2949 Alonso-Padilla J, Papp T, Kaján GL, Benkő M, Havenga M, Lemckert A, Harrach B, Baker AH (2016) Development of novel adenoviral vectors to overcome challenges observed with HAdV-5 based constructs. Mol Ther 24 (1) 6-16 Ballmann MZ, Harrach B (2016) Detection and partial genetic characterization of novel avi- and siadenoviruses in racing and fancy pigeons (Columba livia domestica). Acta Vet. Hung. 64 (4) 514–528 Duffy MR, Doszpoly A, Turner G, Nicklin SA, Baker AH (2016) The relevance of coagulation factor X protection of adenoviruses in human sera. Gene Ther 23 (7) 592-596 Gilson T, Blanchette P, Ballmann MZ, Papp T, Pénzes JJ, Benkő M, Harrach B, Branton PE (2016) Using the E4orf6-based E3 ubiquitin ligase as a tool to analyze the evolution of adenoviruses. J Virol 90 (16) 7350-7367 Marek A, Kaján GL, Kosiol C, Benkő M, Schachner S, Hess M (2016) Genetic diversity of species Fowl aviadenovirus D and Fowl aviadenovirus E. J Gen Virol 97 (9) 2323-2332 Nguyen TH, Ballmann MZ, Do HT, Truong HN, Benkő M, Harrach B, van Raaij MJ (2016) Crystal structure of raptor adenovirus 1 fibre head and role of the beta-hairpin in siadenovirus fibre head domains. Virol J 13, 106 Podgorski II, Pantó L, Papp T, Harrach B, Benkő M (2016): Genome analysis of four Old World monkey adenoviruses supports the proposed species classification of primate adenoviruses and reveals signs of possible homologous recombination. J Gen Virol 97 (7) 1601-1614 Raddi N, Vigant F, Wagner-Ballon O, Giraudier S, Custers J, Hemmi S, Benihoud K (2016) Pseudotyping serotype 5 adenovirus with the fiber from other serotypes uncovers a key role of the fiber protein in adenovirus 5-induced thrombocytopenia. 27 (2) 193-201 Robertson S, Parker AL, Clarke C, Duffy MR, Alba R, Nicklin SA, Baker AH (2016) . 97 (8) 1911-1916 Storm RJ, Persson BD, Nygård Skalman L, Frängsmyr L, Lindström M, Rankin G, Lundmark R, Pedrosa Domellöf F, Arnberg N (2016) Human adenovirus type 37 uses αVβ1 and α3β1 integrins for infection of human corneal cells. 91 (5) pii: e02019-162016 2015 Baker AH, Thrasher AJ (2015) Editorial overview: New technologies. Curr Opin Pharmacol 2015 24:vii-viii. doi: 10.1016/j.coph.2015.09.005 Caraballo R, Saleeb M, Bauer J, Liaci AM, Chandra N, Storm RJ, Frängsmyr L, Qian W, Stehle T, Arnberg N, Elofsson M (2015) 13 (35) 9194-9205. 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PLoS Pathog 11 (2) e1004673 Nguyen TH, Vidovszky MZ, Ballmann MZ, Sanz-Gaitero M, Singh AK, Harrach B, Benkő M, van Raaij MJ (2015) Crystal structure of the fibre head domain of bovine adenovirus 4, a ruminant atadenovirus. Virol J 12. 81 Pantó L, Podgorski II, Jánoska M, Márkó O, Harrach B (2015) Taxonomy proposal for Old World monkey adenoviruses − characterisation of several non-human, non-ape primate adenovirus lineages. Arch Virol 160 (12) 3165-3177 Singh AK, Berbís MÁ, Ballmann MZ, Kilcoyne M, Menéndez M, Joshi L, Jiménez-Barbero J, Benkő M, Harrach B, van Raaij MJ (2015) Structure and sialyllactose binding of the carboxy-terminal head domain of the fibre from a siadenovirus, turkey adenovirus 3. PLoS One 10 (9): e0139339 Vidovszky MZ, Kohl C, Boldogh S, Görföl T, Wibbelt G, Kurth A, Harrach B (2015) PCR screening of the German and Hungarian bat fauna reveals the existence of numerous hitherto unknown adenoviruses. Acta Vet Hung 63 (4) 508-525 Widjojoatmodjo MN, Bogaert L, Meek B, Zahn R, Vellinga J, Custers J, Serroyen J, Radošević K, Schuitemaker H (2015) Recombinant low-seroprevalent adenoviral vectors Ad26 and Ad35 expressing the respiratory syncytial virus (RSV) fusion protein induce protective immunity against RSV infection in cotton rats. . 33 (41) 5406-5414 2014 Ball I, Behncke H, Schmidt V, Geflügel FT, , Stöhr AC, Marschang RE (2014) Partial characterization of new adenoviruses found in lizards. J Zoo Wildl Med 45 (2) 287-297 Benkő M, , Kremer EJ (2014) Do nonhuman primate or bat adenoviruses pose a risk for human health? Future Microbiology 9 (3) 269-272 Coughlan L, Uusi-Kerttula H, Ma J, Degg B, Parker A, Baker AH (2014) Retargeting adenovirus serotype 48 fiber knob domain by peptide incorporation. 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Acta Cryst F 69 (10) 1135-1139 Parker AL, White KM, Lavery CA, Custers J, Waddington SN, Baker AH (2013) Pseudotyping the adenovirus serotype 5 capsid with both the fibre and penton of serotype 35 enhances vascular smooth muscle cell transduction. Gene Ther 20 (12) 1158-1164 White KM, Alba R, Parker AL, Wright AF, Bradshaw AC, Delles C, McDonald RA, Baker AH (2013) Assessment of a novel, capsid-modified adenovirus with an improved vascular gene transfer profile. J Cardiothorac Surg 8 (1) 183. Last update: April 6, 2017 Project funded by European Commission This article was published on 2024-03-19