{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,25]],"date-time":"2026-09-25T04:21:17Z","timestamp":1790310077781,"version":"4.1.0"},"reference-count":91,"publisher":"MDPI AG","issue":"5","license":[{"start":{"date-parts":[[2021,2,28]],"date-time":"2021-02-28T00:00:00Z","timestamp":1614470400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>Adenovirus-based gene transfer vectors are the most frequently used vector type in gene therapy clinical trials to date, and they play an important role as genetic vaccine candidates during the ongoing SARS-CoV-2 pandemic. Immediately upon delivery, adenovirus-based vectors exhibit multiple complex vector-host interactions and induce innate and adaptive immune responses. This can severely limit their safety and efficacy, particularly after delivery through the blood stream. In this review article we summarize two strategies to modulate Ad vector-induced immune responses: extensive genomic and chemical capsid modifications. Both strategies have shown beneficial effects in a number of preclinical studies while potential synergistic effects warrant further investigations.<\/jats:p>","DOI":"10.3390\/ijms22052417","type":"journal-article","created":{"date-parts":[[2021,2,28]],"date-time":"2021-02-28T20:43:32Z","timestamp":1614545012000},"page":"2417","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":36,"title":["Capsid and Genome Modification Strategies to Reduce the Immunogenicity of Adenoviral Vectors"],"prefix":"10.3390","volume":"22","author":[{"given":"Florian","family":"Kreppel","sequence":"first","affiliation":[{"name":"Center for Biomedical Education and Research (ZBAF), Witten\/Herdecke University (UW\/H), Stockumer Str. 10, 58448 Witten, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7010-4807","authenticated-orcid":false,"given":"Claudia","family":"Hagedorn","sequence":"additional","affiliation":[{"name":"Center for Biomedical Education and Research (ZBAF), Witten\/Herdecke University (UW\/H), Stockumer Str. 10, 58448 Witten, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2021,2,28]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"1071","DOI":"10.1126\/science.1187292","article-title":"Crystal structure of human adenovirus at 3.5 A resolution","volume":"329","author":"Reddy","year":"2010","journal-title":"Science"},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"1038","DOI":"10.1126\/science.1187433","article-title":"Atomic structure of human adenovirus by cryo-EM reveals interactions among protein networks","volume":"329","author":"Liu","year":"2010","journal-title":"Science"},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"3","DOI":"10.1038\/nbt0104-3","article-title":"China approves first gene therapy","volume":"22","author":"Pearson","year":"2004","journal-title":"Nat. Biotechnol."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"4407","DOI":"10.1073\/pnas.91.10.4407","article-title":"Cellular immunity to viral antigens limits E1-deleted adenoviruses for gene therapy","volume":"91","author":"Yang","year":"1994","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"433","DOI":"10.1016\/1074-7613(94)90074-4","article-title":"MHC class I-restricted cytotoxic T lymphocytes to viral antigens destroy hepatocytes in mice infected with E1-deleted recombinant adenoviruses","volume":"1","author":"Yang","year":"1994","journal-title":"Immunity"},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"926","DOI":"10.1128\/JVI.72.2.926-933.1998","article-title":"Production and characterization of improved adenovirus vectors with the E1, E2b, and E3 genes deleted","volume":"72","author":"Amalfitano","year":"1998","journal-title":"J. Virol."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"6196","DOI":"10.1073\/pnas.91.13.6196","article-title":"Ablation of E2A in recombinant adenoviruses improves transgene persistence and decreases inflammatory response in mouse liver","volume":"91","author":"Engelhardt","year":"1994","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"8934","DOI":"10.1128\/jvi.70.12.8934-8943.1996","article-title":"Biology of adenovirus vectors with E1 and E4 deletions for liver-directed gene therapy","volume":"70","author":"Gao","year":"1996","journal-title":"J. Virol."},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"393","DOI":"10.1038\/sj.gt.3300404","article-title":"Persistent transgene expression in mouse liver following in vivo gene transfer with a delta E1\/delta E4 adenovirus vector","volume":"4","author":"Wang","year":"1997","journal-title":"Gene Ther."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"2408","DOI":"10.1128\/jvi.71.3.2408-2416.1997","article-title":"Effect of the E4 region on the persistence of transgene expression from adenovirus vectors","volume":"71","author":"Armentano","year":"1997","journal-title":"J. Virol."},{"key":"ref_11","doi-asserted-by":"crossref","unstructured":"Rosewell, A., Vetrini, F., and Ng, P. (2011). Helper-Dependent Adenoviral Vectors. J. Genet. Syndr. Gene Ther.","DOI":"10.4172\/2157-7412.S5-001"},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"148","DOI":"10.1016\/j.ymgme.2003.08.016","article-title":"Fatal systemic inflammatory response syndrome in a ornithine transcarbamylase deficient patient following adenoviral gene transfer","volume":"80","author":"Raper","year":"2003","journal-title":"Mol. Genet. Metab."},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"2605","DOI":"10.1099\/0022-1317-81-11-2605","article-title":"Blood clearance rates of adenovirus type 5 in mice","volume":"81","author":"Alemany","year":"2000","journal-title":"J. Gen. Virol."},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"965","DOI":"10.1089\/10430349950018364","article-title":"Adenoviral gene therapy leads to rapid induction of multiple chemokines and acute neutrophil-dependent hepatic injury in vivo","volume":"10","author":"Muruve","year":"1999","journal-title":"Hum. Gene Ther."},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"708","DOI":"10.1006\/mthe.2001.0330","article-title":"Activation of innate immunity in nonhuman primates following intraportal administration of adenoviral vectors","volume":"3","author":"Schnell","year":"2001","journal-title":"Mol. Ther. J. Am. Soc. Gene Ther."},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"697","DOI":"10.1006\/mthe.2001.0329","article-title":"Acute cytokine response to systemic adenoviral vectors in mice is mediated by dendritic cells and macrophages","volume":"3","author":"Zhang","year":"2001","journal-title":"Mol. Ther. J. Am. Soc. Gene Ther."},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"8798","DOI":"10.1128\/jvi.71.11.8798-8807.1997","article-title":"The role of Kupffer cell activation and viral gene expression in early liver toxicity after infusion of recombinant adenovirus vectors","volume":"71","author":"Lieber","year":"1997","journal-title":"J. Virol."},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"3941","DOI":"10.1128\/JVI.74.9.3941-3947.2000","article-title":"Adenovirus vector-induced expression of the C-X-C chemokine IP-10 is mediated through capsid-dependent activation of NF-kappaB","volume":"74","author":"Borgland","year":"2000","journal-title":"J. Virol."},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"367","DOI":"10.1089\/10430340252792503","article-title":"Adenovirus vector-induced inflammation: Capsid-dependent induction of the C-C chemokine RANTES requires NF-kappa B","volume":"13","author":"Bowen","year":"2002","journal-title":"Hum. Gene Ther."},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"1618","DOI":"10.1038\/sj.gt.3301512","article-title":"Intra-arterial administration of a replication-selective adenovirus (dl1520) in patients with colorectal carcinoma metastatic to the liver: A phase I trial","volume":"8","author":"Reid","year":"2001","journal-title":"Gene Ther."},{"key":"ref_21","first-page":"6070","article-title":"Hepatic arterial infusion of a replication-selective oncolytic adenovirus (dl1520): Phase II viral, immunologic, and clinical endpoints","volume":"62","author":"Reid","year":"2002","journal-title":"Cancer Res."},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"287","DOI":"10.1006\/mthe.2002.0658","article-title":"Systemic interleukin-6 responses following administration of adenovirus gene transfer vectors to humans by different routes","volume":"6","author":"McKinney","year":"2002","journal-title":"Mol. Ther. J. Am. Soc. Gene Ther."},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"35","DOI":"10.1089\/10430340460732445","article-title":"Acute toxicity after high-dose systemic injection of helper-dependent adenoviral vectors into nonhuman primates","volume":"15","author":"Palmer","year":"2004","journal-title":"Hum. Gene Ther."},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"588","DOI":"10.1016\/j.ymthe.2006.03.024","article-title":"Multiple innate inflammatory responses induced after systemic adenovirus vector delivery depend on a functional complement system","volume":"14","author":"Kiang","year":"2006","journal-title":"Mol. Ther. J. Am. Soc. Gene Ther."},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"1012","DOI":"10.1038\/sj.gt.3301961","article-title":"Titer determination of Ad5 in blood: A cautionary note","volume":"10","author":"Cichon","year":"2003","journal-title":"Gene Ther."},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"1140","DOI":"10.1016\/j.ymthe.2004.08.015","article-title":"Recombinant adenovirus vectors activate the alternative complement pathway, leading to the binding of human complement protein C3 independent of anti-ad antibodies","volume":"10","author":"Jiang","year":"2004","journal-title":"Mol. Ther. J. Am. Soc. Gene Ther."},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"452","DOI":"10.1038\/nm.3107","article-title":"Coagulation factor X shields adenovirus type 5 from attack by natural antibodies and complement","volume":"19","author":"Xu","year":"2013","journal-title":"Nat. Med."},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"4654","DOI":"10.1128\/JVI.02696-06","article-title":"Comparative Seroprevalence and Immunogenicity of Six Rare Serotype Recombinant Adenovirus Vaccine Vectors from Subgroups B and D","volume":"81","author":"Abbink","year":"2007","journal-title":"J. Virol."},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"455","DOI":"10.1093\/oxfordjournals.aje.a113563","article-title":"Worldwide epidemiology of human adenovirus infections","volume":"117","author":"Schmitz","year":"1983","journal-title":"Am. J. Epidemiol."},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"11421","DOI":"10.1074\/jbc.M113.537498","article-title":"Adenovirus composition, proteolysis, and disassembly studied by in-depth qualitative and quantitative proteomics","volume":"289","author":"Benevento","year":"2014","journal-title":"J. Biol. Chem."},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"9553","DOI":"10.1128\/JVI.77.17.9553-9566.2003","article-title":"Structural and phylogenetic analysis of adenovirus hexons by use of high-resolution x-ray crystallographic, molecular modeling, and sequence-based methods","volume":"77","author":"Rux","year":"2003","journal-title":"J. Virol."},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"1429","DOI":"10.1099\/0022-1317-73-6-1429","article-title":"Antipeptide antisera define neutralizing epitopes on the adenovirus hexon","volume":"73","author":"Toogood","year":"1992","journal-title":"J. Gen. Virol."},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"625","DOI":"10.1128\/JVI.06254-11","article-title":"Adenovirus serotype 5 neutralizing antibodies target both hexon and fiber following vaccination and natural infection","volume":"86","author":"Bradley","year":"2012","journal-title":"J. Virol."},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"7964","DOI":"10.1128\/JVI.07076-11","article-title":"Serotype-Specific Neutralizing Antibody Epitopes of Human Adenovirus Type 3 (HAdV-3) and HAdV-7 Reside in Multiple Hexon Hypervariable Regions","volume":"86","author":"Qiu","year":"2012","journal-title":"J. Virol."},{"key":"ref_35","first-page":"7179","article-title":"Neutralizing antibodies to adenovirus serotype 5 vaccine vectors are directed primarily against the adenovirus hexon protein","volume":"174","author":"Sumida","year":"2005","journal-title":"J. Immunol. Baltim. Md."},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"10366","DOI":"10.1128\/JVI.77.19.10366-10375.2003","article-title":"Identification of adenovirus (ad) penton base neutralizing epitopes by use of sera from patients who had received conditionally replicative ad (addl1520) for treatment of liver tumors","volume":"77","author":"Hong","year":"2003","journal-title":"J. Virol."},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"E3503","DOI":"10.1073\/pnas.1208972109","article-title":"Merck Ad5\/HIV induces broad innate immune activation that predicts CD8+ T-cell responses but is attenuated by preexisting Ad5 immunity","volume":"109","author":"Zak","year":"2012","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"5711","DOI":"10.1128\/JVI.76.11.5711-5719.2002","article-title":"Preexisting immunity to adenovirus in rhesus monkeys fails to prevent vector-induced toxicity","volume":"76","author":"Varnavski","year":"2002","journal-title":"J. Virol."},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"427","DOI":"10.1038\/sj.gt.3302347","article-title":"Evaluation of toxicity from high-dose systemic administration of recombinant adenovirus vector in vector-naive and pre-immunized mice","volume":"12","author":"Varnavski","year":"2005","journal-title":"Gene Ther."},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"2717","DOI":"10.1084\/jem.20081786","article-title":"Activation of a dendritic cell-T cell axis by Ad5 immune complexes creates an improved environment for replication of HIV in T cells","volume":"205","author":"Perreau","year":"2008","journal-title":"J. Exp. Med."},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"14622","DOI":"10.1128\/JVI.79.23.14622-14631.2005","article-title":"Neutrophils interact with adenovirus vectors via Fc receptors and complement receptor 1","volume":"79","author":"Cotter","year":"2005","journal-title":"J. Virol."},{"key":"ref_42","first-page":"7058","article-title":"Antiviral antibodies target adenovirus to phagolysosomes and amplify the innate immune response","volume":"182","author":"Zaiss","year":"2009","journal-title":"J. Immunol. Baltim. Md."},{"key":"ref_43","doi-asserted-by":"crossref","first-page":"312","DOI":"10.1016\/j.virol.2006.01.024","article-title":"Human CD8+ cytotoxic T cell responses to adenovirus capsid proteins","volume":"350","author":"Tang","year":"2006","journal-title":"Virology"},{"key":"ref_44","doi-asserted-by":"crossref","first-page":"2666","DOI":"10.1128\/JVI.78.6.2666-2673.2004","article-title":"Neutralizing Antibodies and CD8+ T Lymphocytes both Contribute to Immunity to Adenovirus Serotype 5 Vaccine Vectors","volume":"78","author":"Sumida","year":"2004","journal-title":"J. Virol."},{"key":"ref_45","doi-asserted-by":"crossref","first-page":"1167","DOI":"10.1089\/104303402320138952","article-title":"The adenovirus capsid protein hexon contains a highly conserved human CD4+ T-cell epitope","volume":"13","author":"Olive","year":"2002","journal-title":"Hum. Gene Ther."},{"key":"ref_46","doi-asserted-by":"crossref","first-page":"5911","DOI":"10.1128\/jvi.67.10.5911-5921.1993","article-title":"Packaging capacity and stability of human adenovirus type 5 vectors","volume":"67","author":"Bett","year":"1993","journal-title":"J. Virol."},{"key":"ref_47","doi-asserted-by":"crossref","first-page":"3293","DOI":"10.1128\/jvi.71.4.3293-3298.1997","article-title":"A helper-dependent system for adenovirus vector production helps define a lower limit for efficient DNA packaging","volume":"71","author":"Parks","year":"1997","journal-title":"J. Virol."},{"key":"ref_48","doi-asserted-by":"crossref","first-page":"8027","DOI":"10.1128\/JVI.73.10.8027-8034.1999","article-title":"Effects of Stuffer DNA on Transgene Expression from Helper-Dependent Adenovirus Vectors","volume":"73","author":"Parks","year":"1999","journal-title":"J. Virol."},{"key":"ref_49","doi-asserted-by":"crossref","first-page":"782","DOI":"10.1038\/35021228","article-title":"Toll-like receptors in the induction of the innate immune response","volume":"406","author":"Aderem","year":"2000","journal-title":"Nature"},{"key":"ref_50","doi-asserted-by":"crossref","first-page":"971","DOI":"10.1038\/ni1004-971","article-title":"The interface between innate and adaptive immunity","volume":"5","author":"Hoebe","year":"2004","journal-title":"Nat. Immunol."},{"key":"ref_51","doi-asserted-by":"crossref","first-page":"131","DOI":"10.1038\/ni1303","article-title":"Innate immune recognition of viral infection","volume":"7","author":"Kawai","year":"2006","journal-title":"Nat. Immunol."},{"key":"ref_52","doi-asserted-by":"crossref","first-page":"1958","DOI":"10.1002\/1521-4141(200207)32:7<1958::AID-IMMU1958>3.0.CO;2-U","article-title":"Bacterial CpG-DNA and lipopolysaccharides activate Toll-like receptors at distinct cellular compartments","volume":"32","author":"Rutz","year":"2002","journal-title":"Eur. J. Immunol."},{"key":"ref_53","doi-asserted-by":"crossref","first-page":"190","DOI":"10.1038\/ni1028","article-title":"TLR9 signals after translocating from the ER to CpG DNA in the lysosome","volume":"5","author":"Latz","year":"2004","journal-title":"Nat. Immunol."},{"key":"ref_54","doi-asserted-by":"crossref","first-page":"378","DOI":"10.1038\/sj.mt.6300031","article-title":"Toll-like receptor 9 triggers an innate immune response to helper-dependent adenoviral vectors","volume":"15","author":"Cerullo","year":"2007","journal-title":"Mol. Ther. J. Am. Soc. Gene Ther."},{"key":"ref_55","doi-asserted-by":"crossref","first-page":"13282","DOI":"10.1073\/pnas.241506298","article-title":"Lifetime correction of genetic deficiency in mice with a single injection of helper-dependent adenoviral vector","volume":"98","author":"Kim","year":"2001","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_56","doi-asserted-by":"crossref","first-page":"3930","DOI":"10.1073\/pnas.0500930102","article-title":"Lifelong elimination of hyperbilirubinemia in the Gunn rat with a single injection of helper-dependent adenoviral vector","volume":"102","author":"Toietta","year":"2005","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_57","doi-asserted-by":"crossref","first-page":"12816","DOI":"10.1073\/pnas.96.22.12816","article-title":"Administration of helper-dependent adenoviral vectors and sequential delivery of different vector serotype for long-term liver-directed gene transfer in baboons","volume":"96","author":"Morral","year":"1999","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_58","doi-asserted-by":"crossref","first-page":"761","DOI":"10.1089\/hum.2013.071","article-title":"Transgene expression up to 7 years in nonhuman primates following hepatic transduction with helper-dependent adenoviral vectors","volume":"24","author":"Ng","year":"2013","journal-title":"Hum. Gene Ther."},{"key":"ref_59","doi-asserted-by":"crossref","first-page":"5966","DOI":"10.1128\/JVI.78.11.5966-5972.2004","article-title":"Helper-Dependent Adenovirus Vectors Elicit Intact Innate but Attenuated Adaptive Host Immune Responses In Vivo","volume":"78","author":"Muruve","year":"2004","journal-title":"J. Virol."},{"key":"ref_60","first-page":"249","article-title":"The uses and properties of PEG-linked proteins","volume":"9","author":"Delgado","year":"1992","journal-title":"Crit. Rev. Ther. Drug Carr. Syst."},{"key":"ref_61","doi-asserted-by":"crossref","first-page":"965","DOI":"10.2165\/00003088-200645100-00002","article-title":"Nanomedicine: Clinical applications of polyethylene glycol conjugated proteins and drugs","volume":"45","author":"Parveen","year":"2006","journal-title":"Clin. Pharmacokinet."},{"key":"ref_62","doi-asserted-by":"crossref","first-page":"341","DOI":"10.1038\/sj.gt.3301389","article-title":"Polymer-coated adenovirus permits efficient retargeting and evades neutralising antibodies","volume":"8","author":"Fisher","year":"2001","journal-title":"Gene Ther."},{"key":"ref_63","doi-asserted-by":"crossref","first-page":"1349","DOI":"10.1089\/10430349950018021","article-title":"PEGylation of adenovirus with retention of infectivity and protection from neutralizing antibody in vitro and in vivo","volume":"10","author":"Lachapelle","year":"1999","journal-title":"Hum. Gene Ther."},{"key":"ref_64","doi-asserted-by":"crossref","first-page":"4792","DOI":"10.1128\/JVI.75.10.4792-4801.2001","article-title":"Stealth adenoviruses blunt cell-mediated and humoral immune responses against the virus and allow for significant gene expression upon readministration in the lung","volume":"75","author":"Croyle","year":"2001","journal-title":"J. Virol."},{"key":"ref_65","doi-asserted-by":"crossref","first-page":"1887","DOI":"10.1089\/104303402760372972","article-title":"PEGylation of E1-deleted adenovirus vectors allows significant gene expression on readministration to liver","volume":"13","author":"Croyle","year":"2002","journal-title":"Hum. Gene Ther."},{"key":"ref_66","doi-asserted-by":"crossref","first-page":"66","DOI":"10.1016\/j.ymthe.2004.09.015","article-title":"Evaluation of polyethylene glycol modification of first-generation and helper-dependent adenoviral vectors to reduce innate immune responses","volume":"11","author":"Mok","year":"2005","journal-title":"Mol. Ther. J. Am. Soc. Gene Ther."},{"key":"ref_67","doi-asserted-by":"crossref","first-page":"152","DOI":"10.1016\/j.jconrel.2008.12.009","article-title":"Coating of adenovirus type 5 with polymers containing quaternary amines prevents binding to blood components","volume":"135","author":"Subr","year":"2009","journal-title":"J. Control Release Off. J. Control Release Soc."},{"key":"ref_68","doi-asserted-by":"crossref","first-page":"1256","DOI":"10.1038\/sj.gt.3302295","article-title":"Extended plasma circulation time and decreased toxicity of polymer-coated adenovirus","volume":"11","author":"Green","year":"2004","journal-title":"Gene Ther."},{"key":"ref_69","doi-asserted-by":"crossref","first-page":"107","DOI":"10.1016\/j.ymthe.2005.03.006","article-title":"Combined genetic and chemical capsid modifications enable flexible and efficient de- and retargeting of adenovirus vectors","volume":"12","author":"Kreppel","year":"2005","journal-title":"Mol. Ther. J. Am. Soc. Gene Ther."},{"key":"ref_70","doi-asserted-by":"crossref","first-page":"1813","DOI":"10.1038\/mt.2008.174","article-title":"Targeting of adenovirus vectors to the LRP receptor family with the high-affinity ligand RAP via combined genetic and chemical modification of the pIX capsomere","volume":"16","author":"Corjon","year":"2008","journal-title":"Mol. Ther. J. Am. Soc. Gene Ther."},{"key":"ref_71","doi-asserted-by":"crossref","first-page":"83","DOI":"10.1038\/mt.2010.229","article-title":"Modifications of adenovirus hexon allow for either hepatocyte detargeting or targeting with potential evasion from Kupffer cells","volume":"19","author":"Prill","year":"2011","journal-title":"Mol. Ther. J. Am. Soc. Gene Ther."},{"key":"ref_72","doi-asserted-by":"crossref","first-page":"379","DOI":"10.1016\/j.jconrel.2016.06.022","article-title":"Substitution of blood coagulation factor X-binding to Ad5 by position-specific PEGylation: Preventing vector clearance and preserving infectivity","volume":"235","author":"Krutzke","year":"2016","journal-title":"J. Control Release Off. J. Control Release Soc."},{"key":"ref_73","doi-asserted-by":"crossref","first-page":"2293","DOI":"10.1128\/JVI.05760-11","article-title":"Identification of adenovirus serotype 5 hexon regions that interact with scavenger receptors","volume":"86","author":"Khare","year":"2012","journal-title":"J. Virol."},{"key":"ref_74","doi-asserted-by":"crossref","unstructured":"Prill, J.-M., Subr, V., Pasquarelli, N., Engler, T., Hoffmeister, A., and Kochanek, S. (2014). Traceless bioresponsive shielding of adenovirus hexon with HPMA copolymers maintains transduction capacity in vitro and in vivo. PLoS ONE, 9.","DOI":"10.1371\/journal.pone.0082716"},{"key":"ref_75","doi-asserted-by":"crossref","first-page":"450","DOI":"10.1038\/s41467-017-02707-6","article-title":"Adenoviral vector with shield and adapter increases tumor specificity and escapes liver and immune control","volume":"9","author":"Schmid","year":"2018","journal-title":"Nat. Commun."},{"key":"ref_76","doi-asserted-by":"crossref","first-page":"453","DOI":"10.1016\/j.virol.2006.01.032","article-title":"Comparison of adenovirus fiber, protein IX, and hexon capsomeres as scaffolds for vector purification and cell targeting","volume":"349","author":"Campos","year":"2006","journal-title":"Virology"},{"key":"ref_77","doi-asserted-by":"crossref","first-page":"1155","DOI":"10.1089\/hum.2009.171","article-title":"Capsomer-specific fluorescent labeling of adenoviral vector particles allows for detailed analysis of intracellular particle trafficking and the performance of bioresponsive bonds for vector capsid modifications","volume":"21","author":"Espenlaub","year":"2010","journal-title":"Hum. Gene Ther."},{"key":"ref_78","doi-asserted-by":"crossref","first-page":"2064","DOI":"10.1080\/21645515.2016.1165908","article-title":"Adenoviral vector-based strategies against infectious disease and cancer","volume":"12","author":"Zhang","year":"2016","journal-title":"Hum. Vaccines Immunother."},{"key":"ref_79","doi-asserted-by":"crossref","first-page":"467","DOI":"10.1016\/S0140-6736(20)31604-4","article-title":"Safety and immunogenicity of the ChAdOx1 nCoV-19 vaccine against SARS-CoV-2: A preliminary report of a phase 1\/2, single-blind, randomised controlled trial","volume":"396","author":"Folegatti","year":"2020","journal-title":"Lancet"},{"key":"ref_80","doi-asserted-by":"crossref","first-page":"479","DOI":"10.1016\/S0140-6736(20)31605-6","article-title":"Immunogenicity and safety of a recombinant adenovirus type-5-vectored COVID-19 vaccine in healthy adults aged 18 years or older: A randomised, double-blind, placebo-controlled, phase 2 trial","volume":"396","author":"Zhu","year":"2020","journal-title":"Lancet"},{"key":"ref_81","doi-asserted-by":"crossref","first-page":"887","DOI":"10.1016\/S0140-6736(20)31866-3","article-title":"Safety and immunogenicity of an rAd26 and rAd5 vector-based heterologous prime-boost COVID-19 vaccine in two formulations: Two open, non-randomised phase 1\/2 studies from Russia","volume":"396","author":"Logunov","year":"2020","journal-title":"Lancet Lond. Engl."},{"key":"ref_82","doi-asserted-by":"crossref","first-page":"671","DOI":"10.1016\/S0140-6736(21)00234-8","article-title":"Safety and efficacy of an rAd26 and rAd5 vector-based heterologous prime-boost COVID-19 vaccine: An interim analysis of a randomised controlled phase 3 trial in Russia","volume":"397","author":"Logunov","year":"2021","journal-title":"Lancet Lond. Engl."},{"key":"ref_83","doi-asserted-by":"crossref","first-page":"1979","DOI":"10.1016\/S0140-6736(20)32466-1","article-title":"Safety and immunogenicity of ChAdOx1 nCoV-19 vaccine administered in a prime-boost regimen in young and old adults (COV002): A single-blind, randomised, controlled, phase 2\/3 trial","volume":"396","author":"Ramasamy","year":"2021","journal-title":"Lancet Lond. Engl."},{"key":"ref_84","doi-asserted-by":"crossref","first-page":"545","DOI":"10.1038\/nm0596-545","article-title":"Immune responses to transgene-encoded proteins limit the stability of gene expression after injection of replication-defective adenovirus vectors","volume":"2","author":"Tripathy","year":"1996","journal-title":"Nat. Med."},{"key":"ref_85","doi-asserted-by":"crossref","first-page":"7209","DOI":"10.1128\/jvi.70.10.7209-7212.1996","article-title":"Role of viral antigens in destructive cellular immune responses to adenovirus vector-transduced cells in mouse lungs","volume":"70","author":"Yang","year":"1996","journal-title":"J. Virol."},{"key":"ref_86","doi-asserted-by":"crossref","first-page":"1617","DOI":"10.1038\/sj.gt.3302332","article-title":"Vaccination with helper-dependent adenovirus enhances the generation of transgene-specific CTL","volume":"11","author":"Harui","year":"2004","journal-title":"Gene Ther."},{"key":"ref_87","doi-asserted-by":"crossref","first-page":"1609","DOI":"10.1038\/mt.2008.141","article-title":"The immunogenicity of adenovirus vectors limits the multispecificity of CD8 T-cell responses to vector-encoded transgenic antigens","volume":"16","author":"Schirmbeck","year":"2008","journal-title":"Mol. Ther. J. Am. Soc. Gene Ther."},{"key":"ref_88","doi-asserted-by":"crossref","unstructured":"Weaver, E.A., Nehete, P.N., Buchl, S.S., Senac, J.S., Palmer, D., and Ng, P. (2009). Comparison of Replication-Competent, First Generation, and Helper-Dependent Adenoviral Vaccines. PLoS ONE, 4.","DOI":"10.1371\/journal.pone.0005059"},{"key":"ref_89","doi-asserted-by":"crossref","first-page":"648","DOI":"10.1002\/jgm.1629","article-title":"High-capacity adenoviral vectors circumvent the limitations of \u0394E1 and \u0394E1\/\u0394E3 adenovirus vectors to induce multispecific transgene product-directed CD8 T-cell responses","volume":"13","author":"Kron","year":"2011","journal-title":"J. Gene Med."},{"key":"ref_90","doi-asserted-by":"crossref","first-page":"154","DOI":"10.1038\/sj.mt.6300306","article-title":"Fully detargeted polyethylene glycol-coated adenovirus vectors are potent genetic vaccines and escape from pre-existing anti-adenovirus antibodies","volume":"16","author":"Wortmann","year":"2008","journal-title":"Mol. Ther. J. Am. Soc. Gene Ther."},{"key":"ref_91","doi-asserted-by":"crossref","first-page":"1369","DOI":"10.1089\/hum.2008.091","article-title":"Effects of Shielding Adenoviral Vectors with Polyethylene Glycol on Vector-Specific and Vaccine-Mediated Immune Responses","volume":"19","author":"Weaver","year":"2008","journal-title":"Hum. Gene Ther."}],"container-title":["International Journal of Molecular Sciences"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/1422-0067\/22\/5\/2417\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,11]],"date-time":"2025-10-11T05:30:20Z","timestamp":1760160620000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/1422-0067\/22\/5\/2417"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2021,2,28]]},"references-count":91,"journal-issue":{"issue":"5","published-online":{"date-parts":[[2021,3]]}},"alternative-id":["ijms22052417"],"URL":"https:\/\/doi.org\/10.3390\/ijms22052417","relation":{},"ISSN":["1422-0067"],"issn-type":[{"value":"1422-0067","type":"electronic"}],"subject":[],"published":{"date-parts":[[2021,2,28]]}}}