{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,30]],"date-time":"2026-10-30T00:50:04Z","timestamp":1793321404202,"version":"4.5.0"},"reference-count":44,"publisher":"Oxford University Press (OUP)","issue":"10","license":[{"start":{"date-parts":[[2017,5,1]],"date-time":"2017-05-01T00:00:00Z","timestamp":1493596800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/academic.oup.com\/pages\/standard-publication-reuse-rights"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2017,5,15]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                  <jats:p>RNA-based vaccines have recently emerged as a promising alternative to the use of DNA-based and viral vector vaccines, in part because of the potential to simplify how vaccines are made and facilitate a rapid response to newly emerging infections. SAM vaccines are based on engineered self-amplifying mRNA (SAM) replicons encoding an Ag, and formulated with a synthetic delivery system, and they induce broad-based immune responses in preclinical animal models. In our study, in vivo imaging shows that after the immunization, SAM Ag expression has an initial gradual increase. Gene expression profiling in injection-site tissues from mice immunized with SAM-based vaccine revealed an early and robust induction of type I IFN and IFN-stimulated responses at the site of injection, concurrent with the preliminary reduced SAM Ag expression. This SAM vaccine-induced type I IFN response has the potential to provide an adjuvant effect on vaccine potency, or, conversely, it might establish a temporary state that limits the initial SAM-encoded Ag expression. To determine the role of the early type I IFN response, SAM vaccines were evaluated in IFN receptor knockout mice. Our data indicate that minimizing the early type I IFN responses may be a useful strategy to increase primary SAM expression and the resulting vaccine potency. RNA sequence modification, delivery optimization, or concurrent use of appropriate compounds might be some of the strategies to finalize this aim.<\/jats:p>","DOI":"10.4049\/jimmunol.1601877","type":"journal-article","created":{"date-parts":[[2017,4,17]],"date-time":"2017-04-17T20:20:19Z","timestamp":1492460419000},"page":"4012-4024","source":"Crossref","is-referenced-by-count":207,"title":["Induction of an IFN-Mediated Antiviral Response by a Self-Amplifying RNA Vaccine: Implications for Vaccine Design"],"prefix":"10.1093","volume":"198","author":[{"given":"Timothy","family":"Pepini","sequence":"first","affiliation":[{"name":"GSK Vaccines , Rockville, MD 20850"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Anne-Marie","family":"Pulichino","sequence":"additional","affiliation":[{"name":"Novartis Vaccines and Diagnostics , Cambridge, MA 02139"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Thomas","family":"Carsillo","sequence":"additional","affiliation":[{"name":"Novartis Institute for BioMedical Research , Cambridge, MA 02139"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Alicia L","family":"Carlson","sequence":"additional","affiliation":[{"name":"Novartis Institute for BioMedical Research , Cambridge, MA 02139"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5439-4469","authenticated-orcid":false,"given":"Farid","family":"Sari-Sarraf","sequence":"additional","affiliation":[{"name":"Novartis Institute for BioMedical Research , Cambridge, MA 02139"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9132-9407","authenticated-orcid":false,"given":"Katrin","family":"Ramsauer","sequence":"additional","affiliation":[{"name":"Novartis Vaccines and Diagnostics , Cambridge, MA 02139"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jason C","family":"Debasitis","sequence":"additional","affiliation":[{"name":"Novartis Vaccines and Diagnostics , Cambridge, MA 02139"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Giulietta","family":"Maruggi","sequence":"additional","affiliation":[{"name":"GSK Vaccines , Rockville, MD 20850"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Gillis R","family":"Otten","sequence":"additional","affiliation":[{"name":"Novartis Vaccines and Diagnostics , Cambridge, MA 02139"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Andrew J","family":"Geall","sequence":"additional","affiliation":[{"name":"Novartis Vaccines and Diagnostics , Cambridge, MA 02139"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Dong","family":"Yu","sequence":"additional","affiliation":[{"name":"GSK Vaccines , Rockville, MD 20850"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jeffrey B","family":"Ulmer","sequence":"additional","affiliation":[{"name":"GSK Vaccines , Rockville, MD 20850"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Carlo","family":"Iavarone","sequence":"additional","affiliation":[{"name":"GSK Vaccines , Rockville, MD 20850"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"286","published-online":{"date-parts":[[2017,5,15]]},"reference":[{"key":"2025030615144259500_r1","doi-asserted-by":"crossref","first-page":"152","DOI":"10.1016\/j.smim.2013.05.001","article-title":"RNA: the new revolution in nucleic acid vaccines","volume":"25","author":"Geall","year":"2013","journal-title":"Semin. Immunol."},{"key":"2025030615144259500_r2","doi-asserted-by":"crossref","first-page":"18","DOI":"10.1016\/j.coi.2016.05.008","article-title":"Recent innovations in mRNA vaccines","volume":"41","author":"Ulmer","year":"2016","journal-title":"Curr. Opin. Immunol."},{"key":"2025030615144259500_r3","doi-asserted-by":"crossref","first-page":"279","DOI":"10.1002\/rmv.360","article-title":"Alphavirus vectors and vaccination","volume":"12","author":"Rayner","year":"2002","journal-title":"Rev. Med. Virol."},{"key":"2025030615144259500_r4","doi-asserted-by":"crossref","first-page":"1395","DOI":"10.1086\/319857","article-title":"Self-replicative RNA vaccines elicit protection against influenza A virus, respiratory syncytial virus, and a tickborne encephalitis virus","volume":"183","author":"Fleeton","year":"2001","journal-title":"J. Infect. Dis."},{"key":"2025030615144259500_r5","doi-asserted-by":"crossref","first-page":"343","DOI":"10.1038\/ni.3123","article-title":"Control of adaptive immunity by the innate immune system","volume":"16","author":"Iwasaki","year":"2015","journal-title":"Nat. Immunol."},{"key":"2025030615144259500_r6","doi-asserted-by":"crossref","first-page":"364","DOI":"10.1038\/nature04267","article-title":"Control of B-cell responses by Toll-like receptors","volume":"438","author":"Pasare","year":"2005","journal-title":"Nature"},{"key":"2025030615144259500_r7","doi-asserted-by":"crossref","first-page":"505","DOI":"10.1038\/nrmicro1681","article-title":"The perfect mix: recent progress in adjuvant research","volume":"5","author":"Guy","year":"2007","journal-title":"Nat. Rev. Microbiol."},{"key":"2025030615144259500_r8","doi-asserted-by":"crossref","first-page":"824","DOI":"10.1016\/j.addr.2008.02.002","article-title":"Forward genetic analysis of TLR-signaling pathways: an evaluation","volume":"60","author":"Hoebe","year":"2008","journal-title":"Adv. Drug Deliv. Rev."},{"key":"2025030615144259500_r9","doi-asserted-by":"crossref","first-page":"4213","DOI":"10.4049\/jimmunol.1003585","article-title":"A point mutation in the amino terminus of TLR7 abolishes signaling without affecting ligand binding","volume":"186","author":"Iavarone","year":"2011","journal-title":"J. Immunol."},{"key":"2025030615144259500_r10","doi-asserted-by":"crossref","first-page":"14604","DOI":"10.1073\/pnas.1209367109","article-title":"Nonviral delivery of self-amplifying RNA vaccines","volume":"109","author":"Geall","year":"2012","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"2025030615144259500_r11","doi-asserted-by":"crossref","first-page":"9962","DOI":"10.1128\/JVI.01067-06","article-title":"Catalytic core of alphavirus nonstructural protein nsP4 possesses terminal adenylyltransferase activity","volume":"80","author":"Tomar","year":"2006","journal-title":"J. Virol."},{"key":"2025030615144259500_r12","doi-asserted-by":"crossref","first-page":"1027","DOI":"10.1099\/0022-1317-82-5-1027","article-title":"The \u2018cleavage\u2019 activities of foot-and-mouth disease virus 2A site-directed mutants and naturally occurring \u20182A-like\u2019 sequences","volume":"82","author":"Donnelly","year":"2001","journal-title":"J. Gen. Virol."},{"key":"2025030615144259500_r13","doi-asserted-by":"crossref","first-page":"276","DOI":"10.1016\/j.jconrel.2005.06.014","article-title":"Cationic lipid saturation influences intracellular delivery of encapsulated nucleic acids","volume":"107","author":"Heyes","year":"2005","journal-title":"J. Control. Release"},{"key":"2025030615144259500_r14","doi-asserted-by":"crossref","first-page":"10394","DOI":"10.1128\/JVI.77.19.10394-10403.2003","article-title":"An alphavirus replicon particle chimera derived from venezuelan equine encephalitis and sindbis viruses is a potent gene-based vaccine delivery vector","volume":"77","author":"Perri","year":"2003","journal-title":"J. Virol."},{"key":"2025030615144259500_r15","doi-asserted-by":"crossref","first-page":"9619","DOI":"10.1073\/pnas.1106536108","article-title":"Structural basis for immunization with postfusion respiratory syncytial virus fusion F glycoprotein (RSV F) to elicit high neutralizing antibody titers","volume":"108","author":"Swanson","year":"2011","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"2025030615144259500_r16","doi-asserted-by":"crossref","first-page":"335","DOI":"10.1128\/JVI.01080-07","article-title":"Distinct RIG-I and MDA5 signaling by RNA viruses in innate immunity","volume":"82","author":"Loo","year":"2008","journal-title":"J. Virol."},{"key":"2025030615144259500_r17","doi-asserted-by":"crossref","first-page":"Article3","DOI":"10.2202\/1544-6115.1027","article-title":"Linear models and empirical Bayes methods for assessing differential expression in microarray experiments","volume":"3","author":"Smyth","year":"2004","journal-title":"Stat. Appl. Genet. Mol. Biol."},{"key":"2025030615144259500_r18","doi-asserted-by":"crossref","first-page":"44","DOI":"10.1038\/nprot.2008.211","article-title":"Systematic and integrative analysis of large gene lists using DAVID bioinformatics resources","volume":"4","author":"Huang da","year":"2009","journal-title":"Nat. Protoc."},{"key":"2025030615144259500_r19","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1093\/nar\/gkn923","article-title":"Bioinformatics enrichment tools: paths toward the comprehensive functional analysis of large gene lists","volume":"37","author":"Huang da","year":"2009","journal-title":"Nucleic Acids Res."},{"key":"2025030615144259500_r20","doi-asserted-by":"crossref","first-page":"402","DOI":"10.1006\/meth.2001.1262","article-title":"Analysis of relative gene expression data using real-time quantitative PCR and the 2(-Delta Delta C(T)) Method","volume":"25","author":"Livak","year":"2001","journal-title":"Methods"},{"key":"2025030615144259500_r21","doi-asserted-by":"crossref","first-page":"199","DOI":"10.1101\/pdb.ip067876","article-title":"Design and construction of 2A peptide-linked multicistronic vectors","volume":"2012","author":"Szymczak-Workman","year":"2012","journal-title":"Cold Spring Harb. Protoc."},{"key":"2025030615144259500_r22","doi-asserted-by":"crossref","first-page":"5652","DOI":"10.4049\/jimmunol.178.9.5652","article-title":"Plasmid DNA vaccine-elicited cellular immune responses limit in vivo vaccine antigen expression through Fas-mediated apoptosis","volume":"178","author":"Greenland","year":"2007","journal-title":"J. Immunol."},{"key":"2025030615144259500_r23","doi-asserted-by":"crossref","first-page":"S460","DOI":"10.1067\/mai.2003.108","article-title":"2. Cytokines and chemokines","volume":"111","author":"Borish","year":"2003","journal-title":"J. Allergy Clin. Immunol."},{"key":"2025030615144259500_r24","doi-asserted-by":"crossref","first-page":"551","DOI":"10.1038\/nri3479","article-title":"Newly described pattern recognition receptors team up against intracellular pathogens","volume":"13","author":"Broz","year":"2013","journal-title":"Nat. Rev. Immunol."},{"key":"2025030615144259500_r25","doi-asserted-by":"crossref","first-page":"434","DOI":"10.1038\/cmi.2012.38","article-title":"TLR8: the forgotten relative revindicated","volume":"9","author":"Cervantes","year":"2012","journal-title":"Cell. Mol. Immunol."},{"key":"2025030615144259500_r26","doi-asserted-by":"crossref","first-page":"169","DOI":"10.1016\/j.imlet.2011.10.001","article-title":"Impact of delivery systems on siRNA immune activation and RNA interference","volume":"141","author":"Forsbach","year":"2012","journal-title":"Immunol. Lett."},{"key":"2025030615144259500_r27","doi-asserted-by":"crossref","first-page":"3729","DOI":"10.4049\/jimmunol.180.6.3729","article-title":"Identification of RNA sequence motifs stimulating sequence-specific TLR8-dependent immune responses","volume":"180","author":"Forsbach","year":"2008","journal-title":"J. Immunol."},{"key":"2025030615144259500_r28","doi-asserted-by":"crossref","first-page":"165","DOI":"10.1016\/j.immuni.2005.06.008","article-title":"Suppression of RNA recognition by Toll-like receptors: the impact of nucleoside modification and the evolutionary origin of RNA","volume":"23","author":"Karik\u00f3","year":"2005","journal-title":"Immunity"},{"key":"2025030615144259500_r29","doi-asserted-by":"crossref","first-page":"559","DOI":"10.1016\/j.imbio.2009.09.003","article-title":"Alternating 2\u2032-O-ribose methylation is a universal approach for generating non-stimulatory siRNA by acting as TLR7 antagonist","volume":"215","author":"Hamm","year":"2010","journal-title":"Immunobiology"},{"key":"2025030615144259500_r30","doi-asserted-by":"crossref","first-page":"732","DOI":"10.1038\/35099560","article-title":"Recognition of double-stranded RNA and activation of NF-kappaB by Toll-like receptor 3","volume":"413","author":"Alexopoulou","year":"2001","journal-title":"Nature"},{"key":"2025030615144259500_r31","doi-asserted-by":"crossref","first-page":"1322","DOI":"10.1016\/j.imbio.2013.06.007","article-title":"Master sensors of pathogenic RNA - RIG-I like receptors","volume":"218","author":"Schlee","year":"2013","journal-title":"Immunobiology"},{"key":"2025030615144259500_r32","doi-asserted-by":"crossref","first-page":"804","DOI":"10.1089\/jir.2006.26.804","article-title":"Blocking monoclonal antibodies specific for mouse IFN-alpha\/beta receptor subunit 1 (IFNAR-1) from mice immunized by in vivo hydrodynamic transfection","volume":"26","author":"Sheehan","year":"2006","journal-title":"J. Interferon Cytokine Res."},{"key":"2025030615144259500_r33","doi-asserted-by":"crossref","first-page":"432","DOI":"10.1016\/j.chom.2012.09.007","article-title":"IFN-inducible GTPases in host cell defense","volume":"12","author":"Kim","year":"2012","journal-title":"Cell Host Microbe"},{"key":"2025030615144259500_r34","doi-asserted-by":"crossref","first-page":"181","DOI":"10.1016\/j.tim.2013.01.005","article-title":"Interferon-induced ISG15 pathway: an ongoing virus-host battle","volume":"21","author":"Zhao","year":"2013","journal-title":"Trends Microbiol."},{"key":"2025030615144259500_r35","doi-asserted-by":"crossref","first-page":"419","DOI":"10.1016\/j.micinf.2011.11.015","article-title":"Viperin, a key player in the antiviral response","volume":"14","author":"Mattijssen","year":"2012","journal-title":"Microbes Infect."},{"key":"2025030615144259500_r36","doi-asserted-by":"crossref","first-page":"425","DOI":"10.1016\/j.biochi.2010.02.009","article-title":"STAT1 and pathogens, not a friendly relationship","volume":"92","author":"Najjar","year":"2010","journal-title":"Biochimie"},{"key":"2025030615144259500_r37","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1097\/CJI.0b013e3181f7dbe8","article-title":"Messenger RNA-based vaccines with dual activity induce balanced TLR-7 dependent adaptive immune responses and provide antitumor activity","volume":"34","author":"Fotin-Mleczek","year":"2011","journal-title":"J. Immunother."},{"key":"2025030615144259500_r38","doi-asserted-by":"crossref","first-page":"17","DOI":"10.1016\/j.coi.2006.11.003","article-title":"Principles of intracellular viral recognition","volume":"19","author":"Saito","year":"2007","journal-title":"Curr. Opin. Immunol."},{"key":"2025030615144259500_r39","doi-asserted-by":"crossref","first-page":"370","DOI":"10.1016\/j.immuni.2007.08.012","article-title":"Innate recognition of viruses","volume":"27","author":"Pichlmair","year":"2007","journal-title":"Immunity"},{"key":"2025030615144259500_r40","doi-asserted-by":"crossref","first-page":"251","DOI":"10.1038\/mt.2012.202","article-title":"Type I IFN counteracts the induction of antigen-specific immune responses by lipid-based delivery of mRNA vaccines","volume":"21","author":"Pollard","year":"2013","journal-title":"Mol. Ther."},{"key":"2025030615144259500_r41","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1016\/j.virol.2009.12.031","article-title":"Modulation of type I IFN induction by a virulence determinant within the alphavirus nsP1 protein","volume":"399","author":"Cruz","year":"2010","journal-title":"Virology"},{"key":"2025030615144259500_r42","doi-asserted-by":"crossref","first-page":"254","DOI":"10.1016\/j.virol.2013.07.021","article-title":"Engineered alphavirus replicon vaccines based on known attenuated viral mutants show limited effects on immunogenicity","volume":"447","author":"Maruggi","year":"2013","journal-title":"Virology"},{"key":"2025030615144259500_r43","doi-asserted-by":"crossref","first-page":"376","DOI":"10.1016\/j.virol.2006.10.049","article-title":"Alphavirus replicon approach to promoterless analysis of IRES elements","volume":"360","author":"Kamrud","year":"2007","journal-title":"Virology"},{"key":"2025030615144259500_r44","doi-asserted-by":"crossref","first-page":"2053","DOI":"10.1084\/jem.20101664","article-title":"Type I interferon: friend or foe?","volume":"207","author":"Trinchieri","year":"2010","journal-title":"J. Exp. Med."}],"container-title":["The Journal of Immunology"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/academic.oup.com\/jimmunol\/article-pdf\/198\/10\/4012\/61452077\/1601877.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"syndication"},{"URL":"https:\/\/academic.oup.com\/jimmunol\/article-pdf\/198\/10\/4012\/61452077\/1601877.pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,3,6]],"date-time":"2025-03-06T12:34:28Z","timestamp":1741264468000},"score":1,"resource":{"primary":{"URL":"https:\/\/academic.oup.com\/jimmunol\/article\/198\/10\/4012\/7955925"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2017,5]]},"references-count":44,"journal-issue":{"issue":"10","published-print":{"date-parts":[[2017,5,15]]}},"URL":"https:\/\/doi.org\/10.4049\/jimmunol.1601877","relation":{},"ISSN":["0022-1767","1550-6606"],"issn-type":[{"value":"0022-1767","type":"print"},{"value":"1550-6606","type":"electronic"}],"subject":[],"published-other":{"date-parts":[[2017,5]]},"published":{"date-parts":[[2017,5]]}}}