The DOI matches its Crossref record.
Messenger RNA-based Vaccines With Dual Activity Induce Balanced TLR-7 Dependent Adaptive Immune Responses and Provide Antitumor Activity
Abstract
Direct vaccination with messenger RNA (mRNA) molecules encoding tumor-associated antigens is a novel and promising approach in cancer immunotherapy. The main advantage of using mRNA for vaccination is that the same molecule not only provides an antigen source for adaptive immunity, but can simultaneously bind to pattern recognition receptors, thus stimulating innate immunity. However, achieving both features remains challenging, as the complexation of mRNA required for immune-stimulating activity may inhibit its translatability. In this study, we present a new and more effective vaccine design: a two-component mRNA-based tumor vaccine that supports both: antigen expression and immune stimulation, mediated by Toll like receptor 7 (TLR7). The two-component mRNA vaccines, containing free and protamine-complexed mRNA, induce balanced adaptive immune responses providing humoral as well as T cell mediated immunity. This balanced immune response is based on the induction of antigen-specific CD4(+) T helper cells and cytotoxic CD8(+) T cells. Once activated, these CD4(+) and CD8(+) T cells secrete a wide set of cytokines, which drive a TH1 response. Immunization with the two-component vaccines induces sustained memory responses, mediated by antigen-specific memory T cells. Moreover, treatment of mice with the two-component mRNA vaccine mediates a strong antitumor response against OVA-expressing tumor cells, not only in a prophylactic but also in a therapeutic setting. In conclusion,…
Overview
Integrity signals
Registry
Cites
Statistics
Verification
Claims the paper makes
Claims other papers make about this one
Each is checked against this paper’s own text: does it say what the citing paper says it does?
In the citing paper
“The schedule was designed to prevent the typical post-expansion T-cell retraction phase and maintain high frequencies of antigen-specific T cells.”
From mRNA vaccine with unmodified uridine induces robust type I interferon-dependent anti-tumor immunity in a melanoma model (2022) · cites this paper as [34]
In the citing paper
“Both CVnCoV and CV2CoV are based on RNActive technology4–7 and consist of non-chemically modified sequence-engineered mRNA without pseudouridine6–12.”
From Optimization of non-coding regions for a non-modified mRNA COVID-19 vaccine (2022) · cites this paper as [6]
In the citing paper
“Hence, mRNA vaccines have been formulated with synthetic delivery vehicles such as liposomes (16) and cationic polymers (17) to increase potency.”
From Nonviral delivery of self-amplifying RNA vaccines (2012) · cites this paper as [17]
In the citing paper
“Several studies have demonstrated the utility of mRNA as the basis of vaccines in cancer immunotherapy as well as to promote prophylactic protection from infectious diseases (Hoerr et al, 2000; Fotin‐Mleczek et al, 2011; Petsch et al, 2012; Kubler et al, 2015; Kranz et al, 2016).”
From mRNA mediates passive vaccination against infectious agents, toxins, and tumors (2017) · cites this paper as Fotin‐Mleczek et al, 2011
In the citing paper
“In addition, it has been previously demonstrated that mRNA represents a potent vaccine technology (Kreiter et al, 2010; Fotin‐Mleczek et al, 2011).”
From mRNA mediates passive vaccination against infectious agents, toxins, and tumors (2017) · cites this paper as Fotin‐Mleczek et al, 2011
In the citing paper
“Benefits are the induction of balanced and enduring immunity as demonstrated for anti-tumor and prophylactic vaccination [14–16], simple supply, and storage at elevated temperature, as reviewed elsewhere [17,18].”
In the citing paper
“Studies have shown that adenylate-uridylate-rich elements are involved in mRNA degradation. Degradation rate and translation life cycle can be adjusted by replacing adenylate-uridylate-rich sequences found in the 3′ UTR.137–139”
From Advances in COVID-19 mRNA vaccine development (2022) · cites this paper as [138]
Citations
Cited by
Sorted by citations
mRNA vaccines — a new era in vaccinology
Pardi, N., Hogan, M. J., Porter, F. W., & Weissman, D. (2018) · Nature Reviews Drug Discovery · doi:10.1038/nrd.2017.243 · Cited by 4,667
mRNA-based therapeutics--developing a new class of drugs
Sahin, U., Karikó, K., & Türeci, Ö. (2014) · Nature Reviews Drug Discovery · doi:10.1038/nrd4278 · Cited by 2,474
“This vaccine showed potent activity in preclinical studies 62 and is currently being tested in ongoing clinical trials in patients with prostate cancer (ClinicalTrials. gov identifiers: NCT00831467 and NCT01817738) and non-small-cell lung cancer (ClinicalTrials.gov identifiers: NCT00923312 and…”
Pardi, N., Tuyishime, S., Muramatsu, H., Kariko, K., Mui, B. L., Tam, Y. K., Madden, T. D., Hope, M. J., & Weissman, D. (2015) · Journal of Controlled Release · doi:10.1016/j.jconrel.2015.08.007 · Cited by 1,014
Karikó, K., Muramatsu, H., Ludwig, J., & Weissman, D. (2011) · Nucleic Acids Research · doi:10.1093/nar/gkr695 · Cited by 898
“For uses that require further purification, such as NMR (12), crystallography (13) and therapeutic applications (14), a number of techniques have been developed.”
MethodmRNA-based therapeutics: powerful and versatile tools to combat diseases
Qin, S., Tang, X., Chen, Y., Chen, K., Fan, N., Xiao, W., Zheng, Q., Li, G., Teng, Y., Wu, M., et al. (2022) · Signal Transduction and Targeted Therapy · doi:10.1038/s41392-022-01007-w · Cited by 852
Lipid Nanoparticle Assisted mRNA Delivery for Potent Cancer Immunotherapy
Oberli, M. A., Reichmuth, A. M., Dorkin, J. R., Mitchell, M. J., Fenton, O. S., Jaklenec, A., Anderson, D. G., Langer, R., & Blankschtein, D. (2017) · Nano Letters · doi:10.1021/acs.nanolett.6b03329 · Cited by 719
Nonviral delivery of self-amplifying RNA vaccines
Geall, A. J., Verma, A., Otten, G. R., Shaw, C. A., Hekele, A., Banerjee, K., Cu, Y., Beard, C. W., Brito, L. A., Krucker, T., et al. (2012) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.1209367109 · Cited by 675
“Hence, mRNA vaccines have been formulated with synthetic delivery vehicles such as liposomes (16) and cationic polymers (17) to increase potency.”
BackgroundmRNA vaccine delivery using lipid nanoparticles
Reichmuth, A. M., Oberli, M. A., Jaklenec, A., Langer, R., & Blankschtein, D. (2016) · Therapeutic Delivery · doi:10.4155/tde-2016-0006 · Cited by 624
Developing mRNA-vaccine technologies
Schlake, T., Thess, A., Fotin-Mleczek, M., & Kallen, K.-J. (2012) · RNA Biology · doi:10.4161/rna.22269 · Cited by 622
“Recently, research on protamine-complexed RNA culminated in a simplified vaccine approach, combining naked and protamine-formulated mRNA.(9) The resulting mRNA vaccine consists of two components complementing each other; while antigen supply is mainly driven by the naked mRNA, the protamine complexes contribute a stro…”
InfluentialSelf-citationAdvances in COVID-19 mRNA vaccine development
Fang, E., Liu, X., Li, M., Zhang, Z., Song, L., Zhu, B., Wu, X., Liu, J., Zhao, D., & Li, Y. (2022) · Signal Transduction and Targeted Therapy · doi:10.1038/s41392-022-00950-y · Cited by 601
Opportunities and Challenges in the Delivery of mRNA-Based Vaccines
Wadhwa, A., Aljabbari, A., Lokras, A., Foged, C., & Thakur, A. (2020) · Pharmaceutics · doi:10.3390/pharmaceutics12020102 · Cited by 584
“This may be accomplished by introducing adenylate‐uridylate‐rich elements in the 3’‐UTRs of the mRNA, eventually resulting in faster mRNA degradation and shortening of the duration of protein expression [63].”
BackgroundNanomaterial Delivery Systems for mRNA Vaccines
Buschmann, M. D., Carrasco, M. J., Alishetty, S., Paige, M., Alameh, M. G., & Weissman, D. (2021) · Vaccines · doi:10.3390/vaccines9010065 · Cited by 582
“Later, a mixture of free mRNA with protamine-complexed mRNA was introduced [63] since protamine-complexed mRNA partly inhibited protein expression [64].”
BackgroundWang, H.-X., Li, M., Lee, C. M., Chakraborty, S., Kim, H.-W., Bao, G., & Leong, K. W. (2017) · Chemical Reviews · doi:10.1021/acs.chemrev.6b00799 · Cited by 560
New Vaccine Technologies to Combat Outbreak Situations
Rauch, S., Jasny, E., Schmidt, K. E., & Petsch, B. (2018) · Frontiers in Immunology · doi:10.3389/fimmu.2018.01963 · Cited by 579
mRNA as a Transformative Technology for Vaccine Development to Control Infectious Diseases
Maruggi, G., Zhang, C., Li, J., Ulmer, J. B., & Yu, D. (2019) · Molecular Therapy · doi:10.1016/j.ymthe.2019.01.020 · Cited by 507
Thess, A., Grund, S., Mui, B. L., Hope, M. J., Baumhof, P., Fotin-Mleczek, M., & Schlake, T. (2015) · Molecular Therapy · doi:10.1038/mt.2015.103 · Cited by 513
Self-citationPetsch, B., Schnee, M., Vogel, A. B., Lange, E., Hoffmann, B., Voss, D., Schlake, T., Thess, A., Kallen, K.-J., Stitz, L., et al. (2012) · Nature Biotechnology · doi:10.1038/nbt.2436 · Cited by 464
Self-citationRNA Drugs and RNA Targets for Small Molecules: Principles, Progress, and Challenges
Yu, A., Choi, Y. H., & Tu, M. (2020) · Pharmacological Reviews · doi:10.1124/pr.120.019554 · Cited by 421
Materials for non-viral intracellular delivery of messenger RNA therapeutics
Kauffman, K. J., Webber, M. J., & Anderson, D. G. (2015) · Journal of Controlled Release · doi:10.1016/j.jconrel.2015.12.032 · Cited by 407
mRNA Vaccine Era—Mechanisms, Drug Platform and Clinical Prospection
Xu, S., Yang, K., Li, R., & Zhang, L. (2020) · International Journal of Molecular Sciences · doi:10.3390/ijms21186582 · Cited by 368
COVID-19 Vaccine Frontrunners and Their Nanotechnology Design
Chung, Y. H., Beiss, V., Fiering, S., & Steinmetz, N. F. (2020) · ACS Nano · doi:10.1021/acsnano.0c07197 · Cited by 354
A Cationic Nanoemulsion for the Delivery of Next-generation RNA Vaccines
Brito, L. A., Chan, M., Shaw, C. A., Hekele, A., Carsillo, T., Schaefer, M., Archer, J., Seubert, A., Otten, G. R., Beard, C. W., et al. (2014) · Molecular Therapy · doi:10.1038/mt.2014.133 · Cited by 338
Kübler, H., Scheel, B., Gnad-Vogt, U., Miller, K., Schultze-Seemann, W., vom Dorp, F., Parmiani, G., Hampel, C., Wedel, S., Trojan, L., et al. (2015) · Journal for Immunotherapy of Cancer · doi:10.1186/s40425-015-0068-y · Cited by 287
“First, mRNA was complexed by the addition of protamine-Ringer lactate solution and, after stable complexation, free mRNA was added [14].”
BackgroundMethodSelf-citationUnmodified mRNA in LNPs constitutes a competitive technology for prophylactic vaccines
Lutz, J., Lazzaro, S., Habbeddine, M., Schmidt, K. E., Baumhof, P., Mui, B. L., Tam, Y. K., Madden, T. D., Hope, M. J., Heidenreich, R., et al. (2017) · npj Vaccines · doi:10.1038/s41541-017-0032-6 · Cited by 257
“These vaccines contained free and protaminecomplexed mRNA to support both strong antigen expression and immunostimulation.(9) This approach was specifically optimized for i.”
Self-citationEmerging mRNA technologies: delivery strategies and biomedical applications
Xiao, Y., Tang, Z., Huang, X., Chen, W., Zhou, J., Liu, H., Liu, C., Kong, N., & Tao, W. (2022) · Chemical Society Reviews · doi:10.1039/d1cs00617g · Cited by 255
Lipid nanoparticles in the development of mRNA vaccines for COVID-19
Wilson, B., & Geetha, K. M. (2022) · Journal of Drug Delivery Science and Technology · doi:10.1016/j.jddst.2022.103553 · Cited by 265
“mRNAs have self-adjuvanting characteristics as they have the ability to bind with toll-like receptor 7 (TLR7) and improve cellular immunity [17].”
BackgroundmRNA vaccines in disease prevention and treatment
Zhang, G., Tang, T., Chen, Y., Huang, X., & Liang, T. (2023) · Signal Transduction and Targeted Therapy · doi:10.1038/s41392-023-01579-1 · Cited by 273
“In 2011, Fotin-Mleczek et al. reported the use of a two-component mRNA vaccine (protamine-complexed) encoding TLR7 and tumor antigen Gallus gallus OVA, HsPSMA, or HsSTEAP for treating T-cell lymphoma in an E. G7-OVA-based mouse model, in which E. G7-OVA is a mouse T-cell lymphoma cell line stably expressing Gallus gal…”
BackgroundMechanism of action of mRNA-based vaccines
Iavarone, C., O’hagan, D. T., Yu, D., Delahaye, N. F., & Ulmer, J. B. (2017) · Expert Review of Vaccines · doi:10.1080/14760584.2017.1355245 · Cited by 234
“Cancer BioNTech Melanoma Complete NCT01684241 nr [36] BioNTech, Sanofi Melanoma Phase I NCT02410733 Assessing safety and tolerability [26] Curevac Prostate cancer Complete NCT00831467 Failed to meet primary end point of improving overall survival [37] Curevac NSCLC Phase I NCT01915524 Improved survival [19] TübingenUn…”
BackgroundAn RNA toolbox for cancer immunotherapy
Pastor, F., Berraondo, P., Etxeberria, I., Frederick, J., Sahin, U., Gilboa, E., & Melero, I. (2018) · Nature Reviews Drug Discovery · doi:10.1038/nrd.2018.132 · Cited by 229
Weissman, D. (2015) · Expert Review of Vaccines · doi:10.1586/14760584.2015.973859 · Cited by 228
“Reprogramming of cells DCs: HIV antigens [141-143] Infectious disease vaccines DCs: pancreatic adenocarcinoma [122,123], prostate cancer [124,125], melanoma [126-130], colon cancer [131] renal cell carcinoma [12], melanoma [14] T cells: CAR-Her-2/neo [117], CAR-mesothelin [118,119], CAR-CD19 [120,121] DCs: MUC1[114],…”
BackgroundA novel, disruptive vaccination technology: Self-adjuvanted RNActive ® vaccines
Kallen, K.-J., Heidenreich, R., Schnee, M., Petsch, B., Schlake, T., Thess, A., Baumhof, P., Scheel, B., Koch, S. D., & Fotin-Mleczek, M. (2013) · Human Vaccines & Immunotherapeutics · doi:10.4161/hv.25181 · Cited by 223
“The “naked” mRNA described above achieved high antigen expression, but only weak immunostimlation.(20) Previous evidence had demonstrated that complexation of mRNA with protamine helped to arise Th1 responses against antigens with the possible involvement of TLR7/TLR8.”
BackgroundInfluentialSelf-citationRNA-Based Vaccines in Cancer Immunotherapy
McNamara, M. A., Nair, S. K., & Holl, E. K. (2015) · Journal of Immunology Research · doi:10.1155/2015/794528 · Cited by 229
“[55] M.”
Lindsay, K. E., Bhosle, S. M., Zurla, C., Beyersdorf, J., Rogers, K. A., Vanover, D., Xiao, P., Araínga, M., Shirreff, L. M., Pitard, B., et al. (2019) · Nature Biomedical Engineering · doi:10.1038/s41551-019-0378-3 · Cited by 218
Schnee, M., Vogel, A. B., Voss, D., Petsch, B., Baumhof, P., Kramps, T., & Stitz, L. (2016) · PLOS Neglected Tropical Diseases · doi:10.1371/journal.pntd.0004746 · Cited by 212
“inclusion of enhanced UTRs, and complexation with protamine (Valeant Pharmaceuticals, Eschborn, Germany) as described elsewhere [14,15].”
MethodFormulation and Delivery Technologies for mRNA Vaccines
Zeng, C., Zhang, C., Walker, P. G., & Dong, Y. (2020) · Current topics in microbiology and immunology · doi:10.1007/82_2020_217 · Cited by 228
Preclinical Evaluation of TriMix and Antigen mRNA-Based Antitumor Therapy
Lint, S. V., Goyvaerts, C., Maenhout, S. K., Goethals, L., Disy, A., Benteyn, D., Pen, J. J., Bonehill, A., Heirman, C., Breckpot, K., et al. (2012) · Cancer Research · doi:10.1158/0008-5472.can-11-2957 · Cited by 210
Pepini, T., Pulichino, A.-M., Carsillo, T., Carlson, A. L., Sari-Sarraf, F., Ramsauer, K., Debasitis, J. C., Maruggi, G., Otten, G. R., Geall, A. J., et al. (2017) · The Journal of Immunology · doi:10.4049/jimmunol.1601877 · Cited by 208
“These findings are in agreement with previous reports for an mRNA-based tumor vaccine in which in vivo immune stimulation was TLR7 dependent (37).”
ResultSebastian, M., Schröder, A., Scheel, B., Hong, H. S., Muth, A., von Boehmer, L., Zippelius, A., Mayer, F., Reck, M., Atanackovic, D., et al. (2019) · Cancer Immunology, Immunotherapy · doi:10.1007/s00262-019-02315-x · Cited by 209
Self-citationLipid-based mRNA vaccine delivery systems
Midoux, P., & Pichon, C. (2014) · Expert Review of Vaccines · doi:10.1586/14760584.2015.986104 · Cited by 213
“The translatability of mRNA encoding luciferase complexed with protamine is also strongly inhibited in vivo after intradermal injection while luciferase expression is obtained after injection of naked mRNA [48].”
How mRNA therapeutics are entering the monoclonal antibody field
Van Hoecke, L., & Roose, K. (2019) · Journal of Translational Medicine · doi:10.1186/s12967-019-1804-8 · Cited by 205
Wang, Y., Zhang, L., Xu, Z., Miao, L., & Huang, L. (2018) · Molecular Therapy · doi:10.1016/j.ymthe.2017.11.009 · Cited by 206
Li, M., Zhao, M., Fu, Y., Li, Y., Gong, T., Zhang, Z., & Sun, X. (2016) · Journal of Controlled Release · doi:10.1016/j.jconrel.2016.02.043 · Cited by 201
Biomaterials for vaccine-based cancer immunotherapy
Zhang, R., Billingsley, M. M., & Mitchell, M. J. (2018) · Journal of Controlled Release · doi:10.1016/j.jconrel.2018.10.008 · Cited by 204
Diken, M., Kreiter, S., Selmi, A., Britten, C. M., Huber, C. G., Türeci, Ö., & Şahin, U. (2011) · Gene Therapy · doi:10.1038/gt.2011.17 · Cited by 192
Lipopolyplex potentiates anti-tumor immunity of mRNA-based vaccination
Persano, S., Guevara, M. L., Li, Z., Mai, J., Ferrari, M., Pompa, P. P., & Shen, H. (2017) · Biomaterials · doi:10.1016/j.biomaterials.2017.02.019 · Cited by 187
Edwards, D. K., Jasny, E., Yoon, H., Horscroft, N., Schanen, B., Geter, T., Fotin-Mleczek, M., Petsch, B., & Wittman, V. (2017) · Journal of Translational Medicine · doi:10.1186/s12967-016-1111-6 · Cited by 186
“For all three phases of this study an mRNA vaccine encoding influenza A hemagglutinin of the pandemic strain H1N1pdm09 from the isolate A/Netherlands/602/2009 was used as the model [43, 45].”
MethodSelf-citationRNA: The new revolution in nucleic acid vaccines
Geall, A. J., Mandl, C. W., & Ulmer, J. B. (2013) · Seminars in Immunology · doi:10.1016/j.smim.2013.05.001 · Cited by 193
Clinical and immunological effects of mRNA vaccines in malignant diseases
Heine, A., Juranek, S., & Brossart, P. (2021) · Molecular Cancer · doi:10.1186/s12943-021-01339-1 · Cited by 186
Ulmer, J. B., Mason, P. W., Geall, A. J., & Mandl, C. W. (2012) · Vaccine · doi:10.1016/j.vaccine.2012.04.060 · Cited by 183
Biomaterials for mRNA delivery
Islam, M. A., Reesor, E. K. G., Xu, Y., Zope, H. R., Zetter, B. R., & Shi, J. (2015) · Biomaterials Science · doi:10.1039/c5bm00198f · Cited by 176
Nucleic acid vaccines: prospects for non-viral delivery of mRNA vaccines
Deering, R. P., Kommareddy, S., Ulmer, J. B., Brito, L. A., & Geall, A. J. (2014) · Expert Opinion on Drug Delivery · doi:10.1517/17425247.2014.901308 · Cited by 180
Wang, Y., Kumari, M., Chen, G., Hong, M.-H., Yuan, J. P., Tsai, J.-L., & Wu, H. (2023) · Journal of Biomedical Science · doi:10.1186/s12929-023-00977-5 · Cited by 198
“For example, protamine is an arginine-rich peptide that can be used to stabilize and deliver mRNA, and protamine-mRNA complexes have been applied in cancer and viral vaccines [63, 194].”
BackgroundRecent Advances in Lipid Nanoparticles for Delivery of mRNA
Yang, L., Gong, L., Wang, P., Zhao, X., Zhao, F. H., Zhang, Z., Li, Y., & Huang, W. (2022) · Pharmaceutics · doi:10.3390/pharmaceutics14122682 · Cited by 190
Udhayakumar, V. K., De Beuckelaer, A., McCaffrey, J., McCrudden, C. M., Kirschman, J. L., Vanover, D., Van Hoecke, L., Roose, K., Deswarte, K., De Geest, B. G., et al. (2017) · Advanced Healthcare Materials · doi:10.1002/adhm.201601412 · Cited by 169
mRNA mediates passive vaccination against infectious agents, toxins, and tumors
Thran, M., Mukherjee, J., Pönisch, M., Fiedler, K., Thess, A., Mui, B. L., Hope, M. J., Tam, Y. K., Horscroft, N., Heidenreich, R., et al. (2017) · EMBO Molecular Medicine · doi:10.15252/emmm.201707678 · Cited by 166
“Several studies have demonstrated the utility of mRNA as the basis of vaccines in cancer immunotherapy as well as to promote prophylactic protection from infectious diseases (Hoerr et al, 2000; Fotin-Mleczek et al, 2011; Petsch et al, 2012; Kubler et al, 2015; Kranz et al, 2016).”
BackgroundSelf-citationRauch, S., Roth, N., Schwendt, K., Fotin-Mleczek, M., Mueller, S. O., & Petsch, B. (2021) · npj Vaccines · doi:10.1038/s41541-021-00311-w · Cited by 165
Self-citationmRNA cancer vaccines: Advances, trends and challenges
He, Q., Gao, H., Tan, D., Zhang, H., & Wang, J. (2022) · Acta Pharmaceutica Sinica B · doi:10.1016/j.apsb.2022.03.011 · Cited by 171
“In 2014, Fotin-Mleczek et al. 101 showed the strong synergistic antitumor effect of a combination of a protamine-complexed OVA-encoding mRNA cancer vaccine and preclinical radiation.”
Vaccine Adjuvants: Mode of Action
Gregorio, E. D., Caproni, E., & Ulmer, J. B. (2013) · Frontiers in Immunology · doi:10.3389/fimmu.2013.00214 · Cited by 154
“component RNA vaccine (mRNA to mediate antigen expression in situ and non-coding dsRNA to stimulate the innate immune system via TLR3) is efficacious in animal models of influenza and cancer (47), and has been shown to be safe and immunogenic as a cancer vaccine strategy in humans (48).”
BackgroundLai, I. K., Swaminathan, S., Baylot, V., Mosley, A. R., Dhanasekaran, R., Gabay, M., & Felsher, D. W. (2018) · Journal for ImmunoTherapy of Cancer · doi:10.1186/s40425-018-0431-x · Cited by 151
Lazăr, D. C., Avram, M. F., Romosan, I., Cornianu, M., Tăban, S. M., & Goldiș, A. (2018) · World Journal of Gastroenterology · doi:10.3748/wjg.v24.i32.3583 · Cited by 146
da Silva, J. R., Rodrigues, K. B., Pelegrin, G. F., Sales, N. S., Muramatsu, H., Silva, M. D. O., Porchia, B. F. M. M., Moreno, A. C. R., Aps, L. R. M. M., Venceslau-Carvalho, A. A., et al. (2023) · Science Translational Medicine · doi:10.1126/scitranslmed.abn3464 · Cited by 155
Sebastian, M., Papachristofilou, A., Weiß, C., Früh, M., Cathomas, R. L., Hilbe, W., Wehler, T., Rippin, G., Koch, S. D., Scheel, B., et al. (2014) · BMC Cancer · doi:10.1186/1471-2407-14-748 · Cited by 143
“RNActive® (CureVac GmbH, Germany) self-adjuvanted mRNA vaccines are a novel technology in which the mRNA sequences are optimized to enhance antigen expression by up to 4-5 orders of magnitude [25,26].”
BackgroundSelf-citationNanomedicine-Based Approaches for mRNA Delivery
Uchida, S., Perche, F., Pichon, C., & Cabral, H. (2020) · Molecular Pharmaceutics · doi:10.1021/acs.molpharmaceut.0c00618 · Cited by 139
Self-replicating alphavirus RNA vaccines
Ljungberg, K., & Liljeström, P. (2014) · Expert Review of Vaccines · doi:10.1586/14760584.2015.965690 · Cited by 141
Challenges and advances towards the rational design of mRNA vaccines
Pollard, C., Koker, S. D., Saelens, X., Vanham, G. L., & Grooten, J. (2013) · Trends in Molecular Medicine · doi:10.1016/j.molmed.2013.09.002 · Cited by 138
Induction of HIV-1 gag specific immune responses by cationic micelles mediated delivery of gag mRNA
Zhao, M., Li, M., Zhang, Z., Gong, T., & Sun, X. (2016) · Drug Delivery · doi:10.3109/10717544.2015.1038856 · Cited by 132
“…the field of tumor derivate antigenencoding mRNA vaccines (Bringmann et al., 2010; Kreiter et al., 2011; Perche et al., 2011). mRNA molecules were able to induce strong immune response as the binding ability to pattern recognition receptors, stimulating innate immunity (Fotin-Mleczek et al., 2011).”
BackgroundNanoplatforms for mRNA Therapeutics
Meng, C., Chen, Z., Li, G., Welte, T., & Shen, H. (2021) · Advanced Therapeutics · doi:10.1002/adtp.202000099 · Cited by 130
Optimization of non-coding regions for a non-modified mRNA COVID-19 vaccine
Gebre, M. S., Rauch, S., Roth, N., Yu, J., Chandrashekar, A., Mercado, N. B., He, X., Liu, J., McMahan, K., Martinot, A., et al. (2022) · Nature · doi:10.1038/s41586-021-04231-6 · Cited by 127
Broos, K., Van der Jeught, K., Puttemans, J., Goyvaerts, C., Heirman, C., Dewitte, H., Verbeke, R., Lentacker, I., Thielemans, K., & Breckpot, K. (2016) · Molecular Therapy — Nucleic Acids · doi:10.1038/mtna.2016.38 · Cited by 121
Kallen, K., & Theß, A. (2013) · Therapeutic Advances in Vaccines · doi:10.1177/2051013613508729 · Cited by 122
Self-citationmRNA therapeutics deliver a hopeful message
Zhong, Z., Cafferty, S. M., Combes, F., Huysmans, H., Temmerman, J. D., Gitsels, A., Vanrompay, D. C. G., Catani, J. P., & Sanders, N. N. (2018) · Nano Today · doi:10.1016/j.nantod.2018.10.005 · Cited by 124
Tumor vaccination using messenger RNA: prospects of a future therapy
Kreiter, S., Diken, M., Selmi, A., Türeci, Ö., & Şahin, U. (2011) · Current Opinion in Immunology · doi:10.1016/j.coi.2011.03.007 · Cited by 122
A thermostable messenger RNA based vaccine against rabies
Stitz, L., Vogel, A., Schnee, M., Voss, D., Rauch, S., Mutzke, T., Ketterer, T., Kramps, T., & Petsch, B. (2017) · PLOS Neglected Tropical Diseases · doi:10.1371/journal.pntd.0006108 · Cited by 117
Dendritic Cell Vaccines: A Shift from Conventional Approach to New Generations
Lee, K.-W., Yam, J. W. P., & Mao, X. (2023) · Cells · doi:10.3390/cells12172147 · Cited by 130
mRNA vaccine CV9103 and CV9104 for the treatment of prostate cancer
Rausch, S., Schwentner, C., Stenzl, A., & Bedke, J. (2014) · Human Vaccines & Immunotherapeutics · doi:10.4161/hv.29553 · Cited by 117
“As the protamine/mRNA complexes are very tight, the adjuvant effect comes at the cost of a weak antigen expression and depends strongly on the ratio between protamine and mRNA.(33,34) The components do not interact with each other and are both taken up by endocytic, yet distinct pathways into the cell as no colocaliza…”
BackgroundDesigning a novel mRNA vaccine against SARS-CoV-2: An immunoinformatics approach
Ahammad, I., & Lira, S. S. (2020) · International Journal of Biological Macromolecules · doi:10.1016/j.ijbiomac.2020.06.213 · Cited by 112
“Besides, when administered naked, mRNA itself has been reported to be self-adjuvanting [57].”
Evading innate immunity in nonviral mRNA delivery: don't shoot the messenger.
Devoldere, J., Dewitte, H., De Smedt, S. C., & Remaut, K. (2016) · Drug Discovery Today · doi:10.1016/j.drudis.2015.07.009 · Cited by 112
“Although this naturally occurring protein is demonstrated to protect the mRNA from degradation, mRNA–protamine complexes were shown to induce the innate immune response strongly [73].”
Engineering of the current nucleoside-modified mRNA-LNP vaccines against SARS-CoV-2
Granados-Riveron, J. T., & Aquino‐Jarquín, G. (2021) · Biomedicine & Pharmacotherapy · doi:10.1016/j.biopha.2021.111953 · Cited by 115
“Moreover, mRNA exhibits self-adjuvating properties as a result of its capacity to bind to pattern-recognition receptors (PRRs) like Toll-like receptor 7 (TLR7), promoting cellular immunity [7], and at the same time provides the technological basis to deliver in a single molecule, open reading frames encoding a wide va…”
BackgroundType I Interferons Modulate CD8 + T Cell Immunity to mRNA Vaccines
Beuckelaer, A. D., Grooten, J., & Koker, S. D. (2017) · Trends in Molecular Medicine · doi:10.1016/j.molmed.2017.01.006 · Cited by 110
Tse, S., McKinney, K. M., Walker, W., Nguyen, M., Iacovelli, J., Small, C. G., Hopson, K., Zaks, T. Z., & Huang, E. (2021) · Molecular Therapy · doi:10.1016/j.ymthe.2021.03.002 · Cited by 114
mRNA delivery systems for cancer immunotherapy: Lipid nanoparticles and beyond
Sentí, M. E., del Valle, L. G., & Schiffelers, R. M. (2024) · Advanced Drug Delivery Reviews · doi:10.1016/j.addr.2024.115190 · Cited by 124
Cationic lipid-assisted nanoparticles for delivery of mRNA cancer vaccine
Fan, Y.-N., Li, M., Luo, Y., Chen, Q., Wang, L., Zhang, H., Shen, S., Gu, Z., & Wang, J. (2018) · Biomaterials Science · doi:10.1039/c8bm00908b · Cited by 106
Fotin‐Mleczek, M., Zanzinger, K., Heidenreich, R., Lorenz, C., Thess, A., Duchardt, K. M., & Kallen, K. (2012) · The Journal of Gene Medicine · doi:10.1002/jgm.2605 · Cited by 103
“As shown previously, the two-component vaccines activate the innate immune system via TLR-7 [13].”
BackgroundInfluentialSelf-citationRecent developments of RNA-based vaccines in cancer immunotherapy
Faghfuri, E., Pourfarzi, F., Faghfouri, A. H., Shadbad, M. A., Hajiasgharzadeh, K., & Baradaran, B. (2020) · Expert Opinion on Biological Therapy · doi:10.1080/14712598.2020.1815704 · Cited by 100
“Fotin-Mleczek and colleagues have demonstrated that mice vaccination with the RNActive® causes a robust antitumoral immune response against OVA-expressing tumor cells, in both preventive and therapeutic approaches [56].”
BackgroundKowalczyk, A., Doener, F., Zanzinger, K., Noth, J., Baumhof, P., Fotin-Mleczek, M., & Heidenreich, R. (2016) · Vaccine · doi:10.1016/j.vaccine.2016.05.046 · Cited by 101
“and protamine-complexed mRNA responsible for the selfadjuvanting properties of the vaccine [8].”
BackgroundResultInfluentialSelf-citationZhang, R., Tang, L., Tian, Y., Xiao, J., Hu, Q., Zhou, B., Ding, Z., Xu, H., & Yang, L. (2020) · Journal of Controlled Release · doi:10.1016/j.jconrel.2020.08.023 · Cited by 101
Intradermal Electroporation of Naked Replicon RNA Elicits Strong Immune Responses
Johansson, D. X., Ljungberg, K., Kakoulidou, M., & Liljeström, P. (2012) · PLoS ONE · doi:10.1371/journal.pone.0029732 · Cited by 98
“The use of both naked and liposome-encapsulated mRNA has been validated in animal models for induction of antibodies and cytotoxic T lymphocytes (CTL) targeting cancer and infectious diseases [3,4,5,6,7].”
BackgroundResultImmunotherapy in gastric cancer
Matsueda, S. (2014) · World Journal of Gastroenterology · doi:10.3748/wjg.v20.i7.1657 · Cited by 98
The ReNAissanCe of mRNA-based cancer therapy
Van Lint, S., Renmans, D., Broos, K., Dewitte, H., Lentacker, I., Heirman, C., Breckpot, K., & Thielemans, K. (2015) · Expert Review of Vaccines · doi:10.1586/14760584.2015.957685 · Cited by 95
“The two-component vaccine was shown to activate DCs in a TLR7-dependent fashion [64].”
BackgroundProtamine-Based Strategies for RNA Transfection
Jarzebska, N. T., Mellett, M., Frei, J., Kündig, T. M., & Pascolo, S. (2021) · Pharmaceutics · doi:10.3390/pharmaceutics13060877 · Cited by 95
“Fotin-Mleczek and colleagues explored another aspect of immunostimulatory RNA formulations for cancer immunotherapy [40].”
BackgroundAdvances in RNA vaccines for preventive indications: A case study of a vaccine against rabies
Armbruster, N., Jasny, E., & Petsch, B. (2019) · Vaccines · doi:10.3390/vaccines7040132 · Cited by 95
“We have been applying our expertise with mRNA to target different infectious diseases employing a range of additional technologies to augment and direct the immune response [26,27].”
MethodMessenger RNA-Based Vaccines Against Infectious Diseases
Alameh, M.-G., Weissman, D., & Pardi, N. (2020) · Current Topics in Microbiology and Immunology · doi:10.1007/82_2020_202 · Cited by 96
Sugar-Nanocapsules Imprinted with Microbial Molecular Patterns for mRNA Vaccination
Son, S., Nam, J., Zenkov, I., Ochyl, L. J., Xu, Y., Scheetz, L. M., Shi, J., Farokhzad, O. C., & Moon, J. J. (2020) · Nano Letters · doi:10.1021/acs.nanolett.9b03483 · Cited by 94
Use of Protamine in Nanopharmaceuticals—A Review
Ruseska, I., Fresacher, K., Petschacher, C., & Zimmer, A. (2021) · Nanomaterials · doi:10.3390/nano11061508 · Cited by 93
“Giving a foretaste of this final part of the review, nanoparticles, consisting of protamine and antigen-encoding mRNA, evidentially created an immune response against the antigen after injection [41,42], and improved cell uptake was observed for protamineantigen nanocapsules [43].”
BackgroundEngineering intranasal mRNA vaccines to enhance lymph node trafficking and immune responses
Li, M., Li, Y., Peng, K., Wang, Y., Gong, T., Zhang, Z., He, Q., & Sun, X. (2017) · Acta Biomaterialia · doi:10.1016/j.actbio.2017.10.019 · Cited by 91
Exploration of Pattern Recognition Receptor Agonists as Candidate Adjuvants
Ong, G. H., Lian, B. S. X., Kawasaki, T., & Kawai, T. (2021) · Frontiers in Cellular and Infection Microbiology · doi:10.3389/fcimb.2021.745016 · Cited by 100
Recent Advances in RNA Therapeutics and RNA Delivery Systems Based on Nanoparticles
Shin, H., Park, S. D., Yim, Y., Kim, J., Choi, C., Won, C., & Min, D. (2018) · Advanced Therapeutics · doi:10.1002/adtp.201800065 · Cited by 95
Lazzaro, S., Giovani, C., Mangiavacchi, S., Magini, D., Maione, D., Baudner, B. C., Geall, A. J., Gregorio, E. D., D’Oro, U., & Buonsanti, C. (2015) · Immunology · doi:10.1111/imm.12505 · Cited by 89
Uchida, S., & Kataoka, K. (2019) · Journal of Biomedical Materials Research Part A · doi:10.1002/jbm.a.36614 · Cited by 90
Golombek, S., Pilz, M., Steinle, H., Kochba, E., Levin, Y., Lunter, D., Schlensak, C., Wendel, H. P., & Avci-Adali, M. (2018) · Molecular Therapy Nucleic Acids · doi:10.1016/j.omtn.2018.03.005 · Cited by 88
Metadata
- Authors
- Fotin-Mleczek, M., Duchardt, K. M., Lorenz, C., Pfeiffer, R., Ojkić-Zrna, S., Probst, J., & Kallen, K.-J.
- Affiliations
- CureVac (Germany) (DE)
- Venue
- Journal of Immunotherapy
- Published
- 2011-01
- Volume
- 34
- Issue
- 1
- Pages
- 1-15
- ISSN
- 1524-9557 (ISSN-L)
- OpenAlex
- W2014992495
- Cited by
- 335
- References
- 0
- Citations by year
- 2026: 11 · 2025: 15 · 2024: 26 · 2023: 32 · 2022: 34 · 2021: 26 · 2020: 28 · 2019: 18 · 2018: 24 · 2017: 22 · 2016: 19 · 2015: 18 · 2014: 23 · 2013: 19 · 2012: 11
- FWCI
- 5.35
- Type
- journal article
- Language
- en
- Open access
- closed
- Locations
- Journal of Immunotherapy (publishedVersion)
- PubMed (publishedVersion)
- Topics
- Life Sciences › Immunology and Microbiology › Immunology › Immunotherapy and Immune Responses
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › RNA Interference and Gene Delivery
- Health Sciences › Medicine › Oncology › Cancer Immunotherapy and Biomarkers
- Keywords
- mRNA vaccines, TLR7, tumor-associated antigens, cancer immunotherapy, antitumor immunity, CD4+ T helper cells, CD8+ cytotoxic T lymphocytes, Th1 response, memory T cells, innate immune activation, self-adjuvanting vaccine
- MeSH terms
- Animals, Antigens, Neoplasm, B-Lymphocytes, Humans, Immunity, Cellular, Immunologic Memory, Immunotherapy, Mice, Inbred BALB C, Mice, Inbred C57BL, Neoplasms, Experimental, Protamines, RNA, Messenger, Vaccines, Synthetic, CD4-Positive T-Lymphocytes, Cytokines, CD8-Positive T-Lymphocytes, Cancer Vaccines, Mice, Adaptive Immunity, Immunity, Humoral
About these checks
Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.
Statistics and arithmetic are recomputed, not judged.
Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.
What counts as a claim ›How we measure confidence ›How we check this ›
Are you an author, or do you see a problem with this page? Request a review
