Self-adjuvanted mRNA vaccines induce local innate immune responses that lead to a potent and boostable adaptive immunity

Kowalczyk, Aleksandra; Doener, Fatma; Zanzinger, Kai; Noth, Janine; Baumhof, Patrick; Fotin‐Mleczek, Mariola; Heidenreich, Regina

doi:10.1016/j.vaccine.2016.05.046

Cited by 86 publications

(70 citation statements)

References 28 publications

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“…In this case, the antigen is expressed from a naked, unmodified, sequence-optimized mRNA, while the adjuvant activity is provided by co-delivered RNA complexed with protamine (a polycationic peptide), which acts via TLR7 signalling 52,54 . This vaccine format has elicited favourable immune responses in multiple preclinical animal studies for vaccination against cancer and infectious diseases 18,36,55,56 . A recent study provided mechanistic information on the adjuvanticity of RNActive vaccines in mice in vivo and human cells in vitro 54 .…”

Section: Recent Advances In Mrna Vaccine Technologymentioning

confidence: 99%

mRNA vaccines — a new era in vaccinology

Pardi

Hogan

Porter

et al. 2018

Nat Rev Drug Discov

2,903

3,157

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mRNA vaccines represent a promising alternative to conventional vaccine approaches because of their high potency, capacity for rapid development and potential for low-cost manufacture and safe administration. However, their application has until recently been restricted by the instability and inefficient in vivo delivery of mRNA. Recent technological advances have now largely overcome these issues, and multiple mRNA vaccine platforms against infectious diseases and several types of cancer have demonstrated encouraging results in both animal models and humans. This Review provides a detailed overview of mRNA vaccines and considers future directions and challenges in advancing this promising vaccine platform to widespread therapeutic use.

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Section: Recent Advances In Mrna Vaccine Technologymentioning

confidence: 99%

mRNA vaccines — a new era in vaccinology

Pardi

Hogan

Porter

et al. 2018

Nat Rev Drug Discov

2,903

3,157

View full text Add to dashboard Cite

show abstract

“…CureVac developed the RNActive vaccine platform based on protamine-formulated RNA complexes, which serve as a TLR 7/8 agonist to induce Th1 T cell response, whereas the nucleotide-modified mRNA functions as an antigen producer. [166][167][168] Antigen expression strongly depends on the ratio between protamine and mRNA. 169 This vaccine platform has raised favorable immune activations against cancer and infectious diseases in both pre-clinical animal models and in patients.…”

Section: Non-amplifying Mrna Vaccinesmentioning

confidence: 99%

“…Similarly, Cure-Vac's protamine-containing RNActive vaccine platform also utilized TLR 7 and 8 to stimulate type I IFNs and improve anti-cancer immunity. 168 One possible explanation of this paradoxical effect proposed by De Koker et al 187 is the kinetics of type I IFN signaling relative to TCR activation. If TCR activation coincides or shortly precedes type I IFN signaling, mRNA-mediated activation of type I IFN would facilitate an immune response; otherwise, it would be a concern limiting T cells' activity.…”

Section: Sam Vaccinesmentioning

confidence: 99%

Delivering the Messenger: Advances in Technologies for Therapeutic mRNA Delivery

et al. 2019

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mRNA has broad potential as a therapeutic. Current clinical efforts are focused on vaccination, protein replacement therapies, and treatment of genetic diseases. The clinical translation of mRNA therapeutics has been made possible through advances in the design of mRNA manufacturing and intracellular delivery methods. However, broad application of mRNA is still limited by the need for improved delivery systems. In this review, we discuss the challenges for clinical translation of mRNA-based therapeutics, with an emphasis on recent advances in biomaterials and delivery strategies, and we present an overview of the applications of mRNA-based delivery for protein therapy, gene editing, and vaccination. mRNA holds the potential to revolutionize vaccination, protein replacement therapies, and the treatment of genetic diseases. Since the first pre-clinical studies in the 1990s, 1 significant progress in the clinical translation of mRNA therapeutics has been made through advances in the design of mRNA manufacturing and intracellular delivery methods. 2 The translatability and stability of mRNA as well as its immunostimulatory activity are the key factors to be optimized for specific therapeutic application. 3 Increased translation and stability can be affected by many regions of the RNA. mRNA 5 0 and 3 0 UTRs are responsible for recruiting RNA-binding proteins and microRNAs, and they can profoundly affect translational activity. 2,4 The modification of rare codons in protein-coding sequences with synonymous frequently occurring codons, so-called codon optimization, can result in order-of-magnitude changes in expression levels. 5,6 Modification of the 5 0 mRNA cap can also enhance mRNA translation by inhibiting RNA decapping and improving resistance to enzymatic degradation. 7 Chemical modification of RNA bases can be used to modify mRNA immunostimulatory activity. 8,9 The importance of immunostimulation can depend on the application, 10 and, in some cases, it may actually improve performance, as in the case of vaccines. 11Finally, methods and vehicles for intracellular delivery remain the major barrier to the broad application of mRNA therapeutics. 12 With some exceptions, the intracellular delivery of mRNA is generally more challenging than that of small oligonucleotides, and it requires encapsulation into a delivery nanoparticle, in part due to the significantly larger size of mRNA molecules (300-5,000 kDa, 1-15 kb) as compared to other types of RNAs (small interfering RNAs [siRNAs], 14 kDa; antisense oligonucleotides [ASOs], 4-10 kDa). 10,13 In this review, we discuss the challenges for clinical translation of mRNAbased therapeutics, with an emphasis on recent advances in biomaterials and delivery strategies, and we present an overview of the applications of mRNA-based delivery for protein therapy, gene editing, and vaccination. Materials for mRNA Delivery Structural Aspects of Material DesignAmong the many barriers to function, mRNA must cross the cell membrane in order to reach the cytoplasm (Figure 1). The cell me...

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“…mRNA vaccines are another promising alternative to conventional vaccine approaches because they comprise a non‐infectious, rapid, cost‐effective and non‐integrating platform with high potency . Moreover, mRNA can induce protein expression without crossing the nuclear barrier.…”

Section: Cancer Immunotherapy By Regulating Dendritic Cells With Non‐mentioning

confidence: 99%

Non‐viral gene delivery for cancer immunotherapy

Wang

Saeed

Zhou

et al. 2019

The Journal of Gene Medicine

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Recent decades have witnessed the revolutionary development of cancer immunotherapies, which boost cancer‐specific immune responses for long‐term tumor regression. However, immunotherapy still has limitations, including off‐target side effects, long processing times and limited patient responses. These disadvantages of current immunotherapy are being addressed by improving our understanding of the immune system, as well as by establishing combinational approaches. Advanced biomaterials and gene delivery systems overcome some of these delivery issues, harnessing adverse effects and amplifying immunomodulatory effects, and are superior to standard formulations with respect to eliciting antitumor immunity. Nucleic acid‐based nanostructures have diverse functions, ranging from gene expression and gene regulation to pro‐inflammatory effects, as well as the ability to specifically bind different molecules. A brief overview is provided of the recent advances in the non‐viral gene delivery methods that are being used to activate cancer‐specific immune responses. Furthermore, the tumor microenvironment‐responsive synergistic strategies that modulate the immune response by targeting various signaling pathways are discussed. Nanoparticle‐based non‐viral gene delivery strategies have great potential to be implemented in the clinic for cancer immunotherapy.

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Self-adjuvanted mRNA vaccines induce local innate immune responses that lead to a potent and boostable adaptive immunity

Cited by 86 publications

References 28 publications

mRNA vaccines — a new era in vaccinology

mRNA vaccines — a new era in vaccinology

Delivering the Messenger: Advances in Technologies for Therapeutic mRNA Delivery

Non‐viral gene delivery for cancer immunotherapy

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