{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,4,27]],"date-time":"2026-04-27T10:28:35Z","timestamp":1777285715310,"version":"3.51.4"},"reference-count":59,"publisher":"MDPI AG","issue":"4","license":[{"start":{"date-parts":[[2017,3,23]],"date-time":"2017-03-23T00:00:00Z","timestamp":1490227200000},"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>Vaccination is one of the most efficient tools for disease prevention, and a continuously growing field of research. However, despite progress, we still need more efficient and cost-effective vaccines that would improve access to those in need. In this review, we will describe the status of virus-vectored vaccine technology with a focus on adenoviral-based vaccines. Adenovirus (Ad) vaccines have proven to be efficient in military vaccinations against Ad4 and Ad7 and as highly efficient vectored vaccines against rabies. The question of how other adenovirus-based vaccines can become as efficient as the rabies vaccine is the underlying theme in this review. Here, we will first give an overview of the basic properties of vectored vaccines, followed by an introduction to the characteristics of adenoviral vectors and previously tested modifications of the vector backbone and expression cassettes, with a focus on how they can contribute to increased vaccine cost-effectiveness. Finally, we will highlight a few successful examples of research that have attempted to improve the use of adenoviral-based vaccines by improving the transgene immunogenicity.<\/jats:p>","DOI":"10.3390\/ijms18040686","type":"journal-article","created":{"date-parts":[[2017,4,21]],"date-time":"2017-04-21T04:51:46Z","timestamp":1492750306000},"page":"686","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":44,"title":["Future Prospects for the Development of Cost-Effective Adenovirus Vaccines"],"prefix":"10.3390","volume":"18","author":[{"given":"Cyrielle","family":"Fougeroux","sequence":"first","affiliation":[{"name":"Department of Immunology and Microbiology, Copenhagen University, K\u00f8benhavn K 1014, Denmark"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Peter","family":"Holst","sequence":"additional","affiliation":[{"name":"Department of Immunology and Microbiology, Copenhagen University, K\u00f8benhavn K 1014, Denmark"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1968","published-online":{"date-parts":[[2017,3,23]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"140","DOI":"10.2471\/BLT.07.040089","article-title":"Vaccination greatly reduces disease, disability, death and inequity worldwide","volume":"86","author":"Andre","year":"2008","journal-title":"Bull. World Health Organ."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"1926","DOI":"10.2105\/AJPH.94.11.1926","article-title":"A global perspective on vaccine safety and public health: The Global Advisory Committee on Vaccine Safety","volume":"94","author":"Folb","year":"2004","journal-title":"Am. J. Public Health"},{"key":"ref_3","first-page":"1","article-title":"Surveillance for safety after immunization: Vaccine Adverse Event Reporting System (VAERS)\u2014United States, 1991\u20132001","volume":"52","author":"Zhou","year":"2003","journal-title":"MMWR Surveill. Summ."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"13512","DOI":"10.1128\/JVI.78.24.13512-13521.2004","article-title":"Circulation of type 1 vaccine-derived poliovirus in the Philippines in 2001","volume":"78","author":"Shimizu","year":"2004","journal-title":"J. Virol."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"3","DOI":"10.7205\/MILMED.170.4S.3","article-title":"History of U.S. military contributions to the study of vaccines against infectious diseases","volume":"170","author":"Artenstein","year":"2005","journal-title":"Mil. Med."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"4558","DOI":"10.1016\/j.vaccine.2016.07.033","article-title":"Safety evaluation of adenovirus type 4 and type 7 vaccine live, oral in military recruits","volume":"34","author":"Choudhry","year":"2016","journal-title":"Vaccine"},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"235","DOI":"10.1017\/S0950268800052535","article-title":"The development and use of a vaccinia-rabies recombinant oral vaccine for the control of wildlife rabies; a link between Jenner and Pasteur","volume":"116","author":"Pastoret","year":"1996","journal-title":"Epidemiol. Infect."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"947","DOI":"10.20506\/rst.15.3.965","article-title":"Field use of a vaccinia-rabies recombinant vaccine for the control of sylvatic rabies in Europe and North America","volume":"15","author":"Brochier","year":"1996","journal-title":"Rev. Sci. Tech."},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"1257","DOI":"10.1016\/S0264-410X(96)00012-6","article-title":"Human adenovirus type 5 vectors expressing rabies glycoprotein","volume":"14","author":"Yarosh","year":"1996","journal-title":"Vaccine"},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"363","DOI":"10.7589\/0090-3558-45.2.363","article-title":"Aerial distribution of ONRAB baits as a tactic to control rabies in raccoons and striped skunks in Ontario, Canada","volume":"45","author":"Rosatte","year":"2009","journal-title":"J. Wildl. Dis."},{"key":"ref_11","unstructured":"(2016, March 31). Ontario Resuming Rabies Vaccination Bait Drops. Available online: https:\/\/news.ontario.ca\/mnr\/en\/2016\/03\/ontario-resuming-rabies-vaccination-bait-drops.html."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"6619","DOI":"10.1016\/j.vaccine.2009.08.005","article-title":"Safety studies on an adenovirus recombinant vaccine for rabies (AdRG1.3-ONRAB) in target and non-target species","volume":"27","author":"Knowles","year":"2009","journal-title":"Vaccine"},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"459","DOI":"10.7589\/0090-3558-47.2.459","article-title":"High-density baiting with ONRAB(R) rabies vaccine baits to control Arctic-variant rabies in striped skunks in Ontario, Canada","volume":"47","author":"Rosatte","year":"2011","journal-title":"J. Wildl. Dis."},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"2718","DOI":"10.1128\/jvi.62.8.2718-2727.1988","article-title":"High-level eucaryotic in vivo expression of biologically active measles virus hemagglutinin by using an adenovirus type 5 helper-free vector system","volume":"62","author":"Alkhatib","year":"1988","journal-title":"J. Virol."},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"1333","DOI":"10.1038\/mt.2009.130","article-title":"New insights on adenovirus as vaccine vectors","volume":"17","author":"Lasaro","year":"2009","journal-title":"Mol. Ther."},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"S184","DOI":"10.1002\/jgm.503","article-title":"Development and optimization of an adenovirus production process","volume":"6","author":"Kamen","year":"2004","journal-title":"J. Gene Med."},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"1707","DOI":"10.1038\/sj.gt.3301301","article-title":"Production of first generation adenovirus vectors: A review","volume":"7","author":"Danthinne","year":"2000","journal-title":"Gene Ther."},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"145","DOI":"10.1006\/biol.1995.0025","article-title":"Recombinant adenoviruses as vaccines","volume":"23","author":"Perricaudet","year":"1995","journal-title":"Biologicals"},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"1143","DOI":"10.1016\/0264-410X(95)00032-V","article-title":"Adenovirus vectors as recombinant viral vaccines","volume":"13","author":"Imler","year":"1995","journal-title":"Vaccine"},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"46","DOI":"10.1634\/theoncologist.7-1-46","article-title":"Adenoviral gene therapy","volume":"7","author":"Vorburger","year":"2002","journal-title":"Oncologist"},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"13407","DOI":"10.1128\/JVI.77.24.13407-13411.2003","article-title":"Detailed analysis of the CD8+ T-cell response following adenovirus vaccination","volume":"77","author":"Yang","year":"2003","journal-title":"J. Virol."},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"203","DOI":"10.2174\/1566523053544236","article-title":"Adenoviral gene delivery for HIV-1 vaccination","volume":"5","author":"Vanniasinkam","year":"2005","journal-title":"Curr. Gene Ther."},{"key":"ref_23","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_24","doi-asserted-by":"crossref","first-page":"S73","DOI":"10.1038\/sj.gt.3302618","article-title":"Use of adenoviral vectors as veterinary vaccines","volume":"12","author":"Ferreira","year":"2005","journal-title":"Gene Ther."},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"267","DOI":"10.1128\/jvi.57.1.267-274.1986","article-title":"Development of a helper-independent human adenovirus vector and its use in the transfer of the herpes simplex virus thymidine kinase gene","volume":"57","author":"Graham","year":"1986","journal-title":"J. Virol."},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"2573","DOI":"10.1099\/0022-1317-81-11-2573","article-title":"Update on adenovirus and its vectors","volume":"81","author":"Russell","year":"2000","journal-title":"J. Gen. Virol."},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"255","DOI":"10.1586\/14760584.6.2.255","article-title":"Use of viral vectors for the development of vaccines","volume":"6","author":"Liniger","year":"2007","journal-title":"Expert Rev. Vaccines"},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"51","DOI":"10.1016\/S1040-8428(03)00172-0","article-title":"Immune responses against adenoviral vectors and their transgene products: A review of strategies for evasion","volume":"50","author":"Schagen","year":"2004","journal-title":"Crit. Rev. Oncol. Hematol."},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"38666","DOI":"10.1038\/srep38666","article-title":"Early life vaccination: Generation of adult-quality memory CD8+ T cells in infant mice using non-replicating adenoviral vectors","volume":"6","author":"Nazerai","year":"2016","journal-title":"Sci. Rep."},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"2451","DOI":"10.1089\/10430349950016807","article-title":"High-capacity adenoviral vectors for gene transfer and somatic gene therapy","volume":"10","author":"Kochanek","year":"1999","journal-title":"Hum. Gene Ther."},{"key":"ref_31","doi-asserted-by":"crossref","unstructured":"Weaver, E.A., Nehete, P.N., Buchl, S.S., Senac, J.S., Palmer, D., Ng, P., Sastry, K.J., and Barry, M.A. (2009). Comparison of replication-competent, first generation, and helper-dependent adenoviral vaccines. PLoS ONE, 4.","DOI":"10.1371\/journal.pone.0005059"},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"10200","DOI":"10.1128\/JVI.79.16.10200-10209.2005","article-title":"Replicating rather than nonreplicating adenovirus-human immunodeficiency virus recombinant vaccines are better at eliciting potent cellular immunity and priming high-titer antibodies","volume":"79","author":"Peng","year":"2005","journal-title":"J. Virol."},{"key":"ref_33","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_34","doi-asserted-by":"crossref","first-page":"3414","DOI":"10.1128\/JVI.02453-06","article-title":"A replication-competent adenovirus-human immunodeficiency virus (Ad-HIV) tat and Ad-HIV env priming\/Tat and envelope protein boosting regimen elicits enhanced protective efficacy against simian\/human immunodeficiency virus SHIV89.6P challenge in rhesus macaques","volume":"81","author":"Demberg","year":"2007","journal-title":"J. Virol."},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"3677","DOI":"10.1128\/jvi.71.5.3677-3683.1997","article-title":"The use of an E1-deleted, replication-defective adenovirus recombinant expressing the rabies virus glycoprotein for early vaccination of mice against rabies virus","volume":"71","author":"Wang","year":"1997","journal-title":"J. Virol."},{"key":"ref_36","doi-asserted-by":"crossref","unstructured":"Khurana, S., Coyle, E.M., Manischewitz, J., King, L.R., Ishioka, G., Alexander, J., Smith, J., Gurwith, M., and Golding, H. (2015). Oral priming with replicating adenovirus serotype 4 followed by subunit H5N1 vaccine boost promotes antibody affinity maturation and expands H5N1 cross-clade neutralization. PLoS ONE, 10.","DOI":"10.1371\/journal.pone.0115476"},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"988","DOI":"10.1172\/JCI200422374","article-title":"Kinetics of protective antibodies are determined by the viral surface antigen","volume":"114","author":"Pinschewer","year":"2004","journal-title":"J. Clin. Invest."},{"key":"ref_38","first-page":"482","article-title":"Local and systemic response after simultaneous intranasal inoculation of temperature-sensitive mutants of parainfluenza 3, IBR and bovine adenovirus 3","volume":"28","author":"Zygraich","year":"1975","journal-title":"Dev. Biol. Stand."},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"669","DOI":"10.1128\/JVI.02184-14","article-title":"Amplified and persistent immune responses generated by single-cycle replicating adenovirus vaccines","volume":"89","author":"Crosby","year":"2015","journal-title":"J. Virol."},{"key":"ref_40","doi-asserted-by":"crossref","unstructured":"Crosby, C.M., Matchett, W.E., Anguiano-Zarate, S.S., Parks, C.A., Weaver, E.A., Pease, L.R., Webby, R.J., and Barry, M.A. (2017). Replicating Single-Cycle Adenovirus Vectors Generate Amplified Influenza Vaccine Responses. J. Virol., 91.","DOI":"10.1128\/JVI.00720-16"},{"key":"ref_41","first-page":"3395","article-title":"The development of conditionally replicative adenoviruses for cancer therapy","volume":"6","author":"Curiel","year":"2000","journal-title":"Clin. Cancer Res."},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"844","DOI":"10.1038\/nbt.2666","article-title":"MicroRNA-based strategy to mitigate the risk of gain-of-function influenza studies","volume":"31","author":"Langlois","year":"2013","journal-title":"Nat. Biotechnol."},{"key":"ref_43","doi-asserted-by":"crossref","first-page":"696","DOI":"10.4254\/wjh.v7.i4.696","article-title":"Host cellular microRNA involvement in the control of hepatitis B virus gene expression and replication","volume":"7","author":"Mizuguchi","year":"2015","journal-title":"World J. Hepatol."},{"key":"ref_44","doi-asserted-by":"crossref","first-page":"11009","DOI":"10.1128\/JVI.01608-08","article-title":"Generation of a conditionally replicating adenovirus based on targeted destruction of E1A mRNA by a cell type-specific MicroRNA","volume":"82","author":"Ylosmaki","year":"2008","journal-title":"J. Virol."},{"key":"ref_45","doi-asserted-by":"crossref","first-page":"198","DOI":"10.1016\/j.virol.2016.07.026","article-title":"Complete replication-competent adenovirus 11p vectors with E1 or E3 insertions show improved heat stability","volume":"497","author":"Mei","year":"2016","journal-title":"Virology"},{"key":"ref_46","doi-asserted-by":"crossref","first-page":"720","DOI":"10.1038\/sj.cgt.7700944","article-title":"Oncolysis and suppression of tumor growth by a GFP-expressing oncolytic adenovirus controlled by an hTERT and CMV hybrid promoter","volume":"13","author":"Davis","year":"2006","journal-title":"Cancer Gene Ther."},{"key":"ref_47","doi-asserted-by":"crossref","unstructured":"Richardson, J.S., Yao, M.K., Tran, K.N., Croyle, M.A., Strong, J.E., Feldmann, H., and Kobinger, G.P. (2009). Enhanced protection against Ebola virus mediated by an improved adenovirus-based vaccine. PLoS ONE, 4.","DOI":"10.1371\/journal.pone.0005308"},{"key":"ref_48","doi-asserted-by":"crossref","first-page":"3822","DOI":"10.1128\/JVI.02568-07","article-title":"Single-dose protection against Plasmodium berghei by a simian adenovirus vector using a human cytomegalovirus promoter containing intron A","volume":"82","author":"Sridhar","year":"2008","journal-title":"J. Virol."},{"key":"ref_49","doi-asserted-by":"crossref","first-page":"49","DOI":"10.1016\/j.vaccine.2015.11.028","article-title":"Enhancing cellular immunogenicity of MVA-vectored vaccines by utilizing the F11L endogenous promoter","volume":"34","author":"Alharbi","year":"2016","journal-title":"Vaccine"},{"key":"ref_50","doi-asserted-by":"crossref","unstructured":"Spencer, A.J., Cottingham, M.G., Jenks, J.A., Longley, R.J., Capone, S., Colloca, S., Folgori, A., Cortese, R., Nicosia, A., and Bregu, M. (2014). Enhanced vaccine-induced CD8+ T cell responses to malaria antigen ME-TRAP by fusion to MHC class ii invariant chain. PLoS ONE, 9.","DOI":"10.1371\/journal.pone.0100538"},{"key":"ref_51","doi-asserted-by":"crossref","first-page":"3339","DOI":"10.4049\/jimmunol.180.5.3339","article-title":"MHC class II-associated invariant chain linkage of antigen dramatically improves cell-mediated immunity induced by adenovirus vaccines","volume":"180","author":"Holst","year":"2008","journal-title":"J. Immunol."},{"key":"ref_52","doi-asserted-by":"crossref","first-page":"2147","DOI":"10.1016\/j.vaccine.2015.06.087","article-title":"An adenoviral cancer vaccine co-encoding a tumor associated antigen together with secreted 4-1BBL leads to delayed tumor progression","volume":"34","author":"Ragonnaud","year":"2016","journal-title":"Vaccine"},{"key":"ref_53","doi-asserted-by":"crossref","unstructured":"Forbes, E.K., de Cassan, S.C., Llewellyn, D., Biswas, S., Goodman, A.L., Cottingham, M.G., Long, C.A., Pleass, R.J., Hill, A.V., and Hill, F. (2012). T cell responses induced by adenoviral vectored vaccines can be adjuvanted by fusion of antigen to the oligomerization domain of C4b-binding protein. PLoS ONE, 7.","DOI":"10.1371\/journal.pone.0044943"},{"key":"ref_54","doi-asserted-by":"crossref","first-page":"18848","DOI":"10.1038\/srep18848","article-title":"Enhancing immunogenicity and transmission-blocking activity of malaria vaccines by fusing Pfs25 to IMX313 multimerization technology","volume":"6","author":"Li","year":"2016","journal-title":"Sci. Rep."},{"key":"ref_55","doi-asserted-by":"crossref","first-page":"3","DOI":"10.1021\/mp100214b","article-title":"Capsid-incorporation of antigens into adenovirus capsid proteins for a vaccine approach","volume":"8","author":"Matthews","year":"2011","journal-title":"Mol. Pharm."},{"key":"ref_56","doi-asserted-by":"crossref","first-page":"5523","DOI":"10.1128\/JVI.02667-05","article-title":"Epitopes expressed in different adenovirus capsid proteins induce different levels of epitope-specific immunity","volume":"80","author":"Krause","year":"2006","journal-title":"J. Virol."},{"key":"ref_57","doi-asserted-by":"crossref","first-page":"617","DOI":"10.1016\/j.ymthe.2004.01.012","article-title":"Use of adenovirus protein IX (pIX) to display large polypeptides on the virion\u2014Generation of fluorescent virus through the incorporation of pIX-GFP","volume":"9","author":"Meulenbroek","year":"2004","journal-title":"Mol. Ther."},{"key":"ref_58","doi-asserted-by":"crossref","first-page":"268","DOI":"10.1128\/IAI.02626-14","article-title":"A replicating adenovirus capsid display recombinant elicits antibodies against Plasmodium falciparum sporozoites in Aotus nancymaae monkeys","volume":"83","author":"Karen","year":"2015","journal-title":"Infect. Immun."},{"key":"ref_59","doi-asserted-by":"crossref","first-page":"1140","DOI":"10.1016\/j.vaccine.2017.01.016","article-title":"Novel adenovirus encoded virus-like particles displaying the placental malaria associated VAR2CSA antigen","volume":"35","author":"Andersson","year":"2017","journal-title":"Vaccine"}],"container-title":["International Journal of Molecular Sciences"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/1422-0067\/18\/4\/686\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,11]],"date-time":"2025-10-11T18:31:06Z","timestamp":1760207466000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/1422-0067\/18\/4\/686"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2017,3,23]]},"references-count":59,"journal-issue":{"issue":"4","published-online":{"date-parts":[[2017,4]]}},"alternative-id":["ijms18040686"],"URL":"https:\/\/doi.org\/10.3390\/ijms18040686","relation":{},"ISSN":["1422-0067"],"issn-type":[{"value":"1422-0067","type":"electronic"}],"subject":[],"published":{"date-parts":[[2017,3,23]]}}}