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,…
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The vaccination schedule used prevents the typical post-expansion T-cell retraction phase and maintains high frequencies of antigen-specific T cells.
“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]
Both CVnCoV and CV2CoV are based on RNActive technology and consist of non-chemically modified sequence-engineered mRNA without pseudouridine.
“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]
mRNA vaccines have been formulated with synthetic delivery vehicles such as liposomes and cationic polymers to increase potency.
“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]
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.
“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
It has been previously demonstrated that mRNA represents a potent vaccine technology (Kreiter et al, 2010; Fotin‐Mleczek et al, 2011).
“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
Benefits of mRNA vaccines are the induction of balanced and enduring immunity as demonstrated for anti-tumor and prophylactic vaccination, simple supply, and storage at elevated temperature.
“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].”
Adenylate-uridylate-rich elements are involved in mRNA degradation, and degradation rate and translation life cycle can be adjusted by replacing adenylate-uridylate-rich sequences found in the 3′ UTR.
“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]
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Kallen, K., & Theß, A. (2013) · Therapeutic Advances in Vaccines · doi:10.1177/2051013613508729 · Cited by 120 · see citing works
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 120 · see citing works
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 120 · see citing works
A thermostable messenger RNA based vaccine against rabies
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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 124 · see citing works
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 115 · see citing works
“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 · see citing works
“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 · see citing works
“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
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“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 109 · see citing works
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mRNA delivery systems for cancer immunotherapy: Lipid nanoparticles and beyond
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Cationic lipid-assisted nanoparticles for delivery of mRNA cancer vaccine
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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 · see citing works
“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 99 · see citing works
“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 · see citing works
“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 · see citing works
Intradermal Electroporation of Naked Replicon RNA Elicits Strong Immune Responses
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“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 · see citing works
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 · see citing works
“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 · see citing works
“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 · see citing works
“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
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Sugar-Nanocapsules Imprinted with Microbial Molecular Patterns for mRNA Vaccination
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Use of Protamine in Nanopharmaceuticals—A Review
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“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 · see citing works
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 95 · see citing works
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 91 · see citing works
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 88 · see citing works
Uchida, S., & Kataoka, K. (2019) · Journal of Biomedical Materials Research Part A · doi:10.1002/jbm.a.36614 · Cited by 90 · see citing works
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 · see citing works
- 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
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