mRNA vaccines have become a versatile technology for the prevention of infectious diseases and the treatment of cancers. 2017). These chip-based microfluidic devices mix two laminar flows, the RNA-containing aqueous phase and the carriers-containing solvent phase, through a confined microchannel equipped with chaotic mixers at a controlled speed, leading to rapid diffusion, change of polarity and self-assembly of mRNA-LNP at the interface (Belliveau et al. A Capitol police special agent was quoted as saying that he pegged Angeli by his “unique attire and … Trends Immunol 24:289–93, Warren L, Manos PD, Ahfeldt T et al (2010) Highly efficient reprogramming to pluripotency and directed differentiation of human cells with synthetic modified mRNA. In addition, IN injection was seldom used mostly because of the relatively complicated procedure (Johansen and Kundig 2014; Senti and Kündig 2015). 2019). 2012; Guardo et al. The three self-amplifying mRNAs expressed antigens against the respiratory syncytial virus (RSV), human cytomegalovirus (hCMV), and human immunodeficiency virus (HIV), respectively. 2014; Van Lint et al. When co-delivering several antigen-encoding mRNAs, one challenge is to elicit potent specific immune responses to every antigen. 2019; Sebastian et al. Front Immunol 9:884–84, Iavarone C, O’Hagan DT, Yu D et al (2017) Mechanism of action of mRNA-based vaccines. These cyclic amino head groups directly bound the STING (stimulator of interferon genes) protein and triggered the downstream signaling pathway, leading to an elevated innate response. 2012; Bialkowski et al. As the most efficient APCs, dendritic cells (DCs) can present antigens processed from various sources, for example, the captured microorganisms, virus-infected cells, and tumor cells (Wculek et al. RNA Biol 8:627–636, Lorenzi JC, Trombone AP, Rocha CD et al (2010) Intranasal vaccination with messenger RNA as a new approach in gene therapy: use against tuberculosis. 2010). In: Clinical procedures for safer patient care. Cancer Res 59:3340–3345, Eisenhauer EA, Therasse P, Bogaerts J et al (2009) New response evaluation criteria in solid tumours: revised RECIST guideline (version 1.1). The PEG-lipid conjugates could stabilize the nanoparticles during preparation and provide a hydrophilic outer layer that prolongs the circulation time after in vivo administration (Ambegia et al. First, the development process of an mRNA vaccine can be much faster than conventional protein vaccines (DeFrancesco 2017). 2012; Kose et al. We conducted a systematic review of the content and measurement properties of such tools. Both buffers contain calcium which was suggested to trigger the uptake of mRNA into human cells via a calcium-dependent route (Probst et al. 2017). Besides encoding proteins of interest, self-amplifying mRNAs encode replication machinery consisting of several viral non-structural proteins (nsPs) to replicate themselves. Their results showed ID vaccination by a needle-free device could induce better antibody response than IM injection. 2017; Sayers et al. TriMix mRNAs encoding CD40L, CD70, and TLR4; another mRNA encoding a fusion peptide with different epitopes, Express antigen while providing adjuvant activity, RNActive: free mRNA and protamine-mRNA complex, Add free mRNA after protamine-mRNA complex formation, Routes: ID intradermal, SC subcutaneous, IV instantaneous, IM intramuscular and IN intranodal administration, aIndicates the mass ratio of the three TriMix mRNAs. On January 9, Angeli was arrested and... brought up on U.S. federal charges of "knowingly entering or remaining in any restricted building or grounds without lawful authority, and with violent entry and disorderly conduct on Capitol grounds". 2010; Bialkowski et al. There are many co-delivery options. 2019), intratracheal (Tiwari et al. It is noteworthy that the absorption rate in the SC area is slow, which may cause unintended degradation of the mRNA vaccine (Gradel et al. 2015; Batich et al. Adv Drug Deliv Rev 144:90–111, Pepini T, Pulichino A-M, Carsillo T et al (2017) Induction of an IFN-mediated antiviral response by a self-amplifying RNA vaccine: implications for vaccine design. Secondly, the protamine-mRNA complex has adjuvant activity. (2017), Guevara et al. The tumor antigen-specific CD8+ and CD4+ T-cell response were also detected in peripheral blood and skin biopsies (Van Nuffel et al. For example, chemical modifications of RNA using nucleotide analogs, such as pseudouridine, dramatically increased protein production in vivo by diminishing the translation inhibition triggered by the unmodified nucleotides (Kariko et al. Human Vaccines Immunotherapeutics 10:3146–3152, Reche P, Flower DR, Fridkis-Hareli M et al (2018) Peptide-Based Immunotherapeutics and Vaccines 2017. J Appl Toxico Int J 21:15–23, Diken M, Kreiter S, Selmi A et al (2011) Selective uptake of naked vaccine RNA by dendritic cells is driven by macropinocytosis and abrogated upon DC maturation. 2005; Cheng and Lee 2016; Kowalski et al. Therefore, clinical trials are of paramount importance for assessing the efficacy of mRNA vaccines in humans. Current delivery technologies often deliver mRNA vaccines indistinguishably into many different cell types at the injection site, many of which contribute little to immune stimulation (Veiga et al. 2018; Li et al. 2015; Alberer et al. After SC injection of an antigen-coding mRNA encapsulated by such LNP into mice, the researchers observed the upregulation of antigen-specific T cells and inhibition of tumor growth (Miao et al. However, the obstacles might be partially alleviated by local administration of naked mRNA vaccines via intramuscular (Ying et al. 2008; Warren et al. 2019; Patel et al. DC-based mRNA vaccines have been tested in many clinical trials and have shown acceptable safety profiles (Garg et al. 2018). Cell Stem Cell 7:618–30, Wculek SK, Cueto FJ, Mujal AM et al (2019) Dendritic cells in cancer immunology and immunotherapy. This approach comprises a mAb conjugated to the cytotoxic payload via a chemical linker that directed toward a target antigen expressed on the cancer cell surface, reducing systemic exposure and therefore toxicity. Therapeutic vaccination needs to effectively elicit the body’s adaptive immunity. 2019b). One possible force is the hydrostatic pressure formed after fast injection of a relatively large volume into small mammals. 1c). RNases are present ubiquitously throughout the body to degrade exogenous RNAs (Gupta et al. Immunity 23:165–175, Karikó K, Muramatsu H, Ludwig J et al (2011) Generating the optimal mRNA for therapy: HPLC purification eliminates immune activation and improves translation of nucleoside-modified, protein-encoding mRNA. The tumor-bearing mice were then vaccinated with such mRNA-pulsed DCs and were protected against the subsequent challenge of OVA-expressing tumor cells (Boczkowski et al. 2019). 2017). Besides cationic polymer materials, anionic polymers, such as PLGA, were also used to deliver mRNA vaccines. 2018). The large size makes efficient encapsulation and delivery more challenging than other payloads, such as small molecules, siRNAs, and antisense oligonucleotides (ASOs). Therefore, detailed characterizations are necessary for each specific naked mRNA vaccine (Pardi et al. The two self-amplifying mRNAs were formulated by CNE independently and mixed before simultaneous intramuscular injection to mice. In the presence of a storage reagent, such as 10% trehalose, freeze-dried naked RNA remains stable in the refrigerator temperature (4 ℃) for up to 10 months (Jones et al. 1990). Nat Rev Mater 2:17056, Hartmann AF, Senn MJ (1932) Studies in the metabolism of sodium r-lactate. 2019). Human vaccines & immunotherapeutics 9:2263–2276, Kang Z, Meng Q, Liu K (2019) Peptide-based gene delivery vectors. J Immunol Res 2018:2, Redka DS, Gütschow M, Grinstein S et al (2018) Differential ability of proinflammatory and anti-inflammatory macrophages to perform macropinocytosis. 2017b). The third challenge is the safety of the delivery vehicles. As the delivery methods and the vaccine formulations further advance, mRNA vaccines will become an important class of medicine to effectively tackle diverse health issues, such as infectious diseases and cancers. Sci Rep 7:3286, Liang F, Lindgren G, Lin A et al (2017) Efficient targeting and activation of antigen-presenting cells in vivo after modified mRNA vaccine administration in rhesus macaques. The resulting nanoparticle induced innate and specific immune responses in primary human DC upon in vitro delivery. 2016; Guardo et al. Get all of Hollywood.com's best Celebrities lists, news, and more. 2019). Mol Ther 27:2080–2090, Miao L, Li L, Huang Y et al (2019) Delivery of mRNA vaccines with heterocyclic lipids increases anti-tumor efficacy by STING-mediated immune cell activation. 2018; Kose et al. Mol Ther Nucleic Acids 3:e173, Melo M, Porter E, Zhang Y et al (2019) Immunogenicity of RNA replicons encoding HIV Env immunogens designed for self-assembly into nanoparticles. 2017a, b; Thran et al. Among the mucosal administration routes, intranasal and intravaginal administrations were utilized to deliver mRNA vaccines (Lorenzi et al. The resulting ex vivo DC-based mRNA vaccine showed prophylactic anticancer efficacy and inhibited the growth of OVA-expressing cancer cells in mice (Tateshita et al. 2012; Calabro et al. Antibodies, such as immunoglobulin G (IgG), and some antigens are assembled from more than one single-chain protein subunits. J Biol Chem 287:13959–13971, Batich KA, Reap EA, Archer GE et al (2017) Long-term survival in glioblastoma with cytomegalovirus pp65-targeted vaccination. 2018; Qiu et al. This formulation delivered OVA-mRNA and delayed OVA-expressing lymphoma growth in mice after IV injection (Fan et al. 2019). 2016; Guardo et al. 2004; Li et al. Hepatitis C is the most commonly reported bloodborne infection in the United States (1), and surveys conducted during 2013–2016 indicated an estimated 2.4 million persons (1.0%) in the nation were living with hepatitis C (2).Percutaneous exposure is the most efficient mode of hepatitis C virus (HCV) transmission, and injection drug use (IDU) is the … 2018). Peptides themselves are also a large class of vaccine agents, which have been reviewed in the literature (Li et al. 2019). J Transl Med 15:1, Eggert AA, Schreurs MW, Boerman OC et al (1999) Biodistribution and vaccine efficiency of murine dendritic cells are dependent on the route of administration. 2009; Morse et al. However, there are two challenges for VRP-based mRNA vaccines. ... 2018 . Several methods were used to co-deliver multiple nucleic acids into the same cell. 2010; Gerna et al. Although some approaches have been explored to reduce cytotoxicity, such as using biodegradable materials (Zhang et al. Oncotarget 5, Joe PT, Christopoulou I, van Hoecke L et al (2019) Intranodal administration of mRNA encoding nucleoprotein provides cross-strain immunity against influenza in mice. 2013; Sayers et al. 2012; Bialkowski et al. In this chapter, we summarize the routes of administrations for mRNA vaccines, discuss mRNA delivery carriers and their corresponding formulation methods, and overview the challenges and future development of mRNA vaccines. 433 Followers, 2 Following, 140 Posts - See Instagram photos and videos from @lampeetlumiere.fr 2019) boost innate and/or adaptive immunity. mRNA has demonstrated its potential as a vaccine platform. 2018; Sato et al. Download PDF. 2016; Sedic et al. Eur J Immunol 23:1719–1722, Maruggi G, Chiarot E, Giovani C et al (2017) Immunogenicity and protective efficacy induced by self-amplifying mRNA vaccines encoding bacterial antigens. 2019a). The fourth challenge is the applicability to human. To develop an anti-hCMV vaccine, six conventional mRNAs encoding five subunits of the hCMV pentameric complex (PC) and one glycoprotein, respectively, were co-delivered by LNP in equal mass (John et al. This mRNA solution expressed the antigen and stimulated innate response by triggering cellular RNA sensors in mouse models and primary human peripheral blood mononuclear cells (PBMC) (Edwards et al. Antigen-encoding self-amplifying mRNAs formulated by PAMAM dendrimer protected mice from lethal challenge of Ebola, H1N1 influenza, Toxoplasma gondii, respectively, after IM administration (Chahal et al. 2002; Brito et al. The mRNAs were formulated and injected separately through the intradermal route into patients. Intranasal delivery can also apply mRNA to the lung through the trachea. Science (New York, N.Y.) 247:1465–1468, Xiong Q, Lee GY, Ding J et al (2018) Biomedical applications of mRNA nanomedicine. Mol Ther 27:850–865, Sato Y, Hashiba K, Sasaki K et al (2019) Understanding structure-activity relationships of pH-sensitive cationic lipids facilitates the rational identification of promising lipid nanoparticles for delivering siRNAs in vivo. In another report, a truncated 9-aa cationic CPP (N-RKKRRQRRR-C) derived from HIV Tat protein was fused to the C terminus of a tumor epitope antigen Melan-A (sequence: N-ELAGIGILTV-C) (Haenssle et al. Furthermore, protamine-CPP fusion protein combines cationic and cell-penetrating features. The immunostimulatory activity of each antigen may be different. 2020). 2020). However, improvements are still needed to optimize the safety profile and to increase the vaccination efficacy. The amphipathic feature enhanced the endosomal escape of mRNA as RALA peptide selectively disrupted the endosome membrane at low pH (McCarthy et al. Under the optimized condition, the mRNA-loaded DCs should maintain their biological properties, including cell phenotypes, maturation status, cytokine secreting ability, and antigen presentation function (Tuyaerts et al. Nat Commun 9:4493, Verbeke R, Lentacker I, Breckpot K et al (2019a) Broadening the message: a nanovaccine co-loaded with messenger RNA and α-GalCer induces antitumor immunity through conventional and natural killer T cells. In another example, Sahin and colleagues simultaneously delivered two mRNAs encoding a total of ten neo-epitopes from melanoma (Sahin et al. 2017; Sahin et al. However, after co-formulating this mRNA with six additional antigen-encoding mRNAs in equal mass by LNP and simultaneous intramuscular injection, the anti-pp65 response was barely above the negative control. Mol Ther 28:805–819, Liu C, Feng Q, Sun J (2018) Lipid nanovesicles by microfluidics: manipulation, synthesis, and drug delivery. RALA peptide (sequence: N-WEARLARALARALARHLARALARALRACEA-C) is an amphipathic arginine-rich CPP with positively charged arginine residues on one side and neutral leucine residues on the other side (McCarthy et al. 2011; Weissman et al. 2019). Crit Revi Immunol 34:433–54, Current Topics in Microbiology and Immunology, Division of Pharmaceutics & Pharmacology, College of Pharmacy, Department of Chemical and Biomolecular Engineering, The Center for Clinical and Translational Science, The Comprehensive Cancer Center, The Ohio State University, Dorothy M. Davis Heart & Lung Research Institute, Current Challenges and Future Perspectives. When delivering mRNA vaccines, a comparison of several administration routes will help determine the most appropriate injection method and promote efficacy. 2018). Large-scale production of VRPs may require a special manufacturing process (Rauch et al. LNPs represent one of the most advanced platforms among various carriers for mRNA vaccine delivery in vivo. Ann Oncol 24:2686–93, Wolff JA, Malone RW, Williams P et al (1990) Direct gene transfer into mouse muscle in vivo. 2013; Mitchell et al. Self–guided students and classroom learners alike will be delighted by the way they are helped to progress easily from one unit to the next, using a combination of pictures and text to discover for themselves how English works. In one recent clinical trial (NCT00639639), the long-term progression-free survival (PFS) and overall survival (OS) were significantly increased in glioblastoma patients who were injected intradermally with autologous DCs pulsed with an antigen-encoding mRNA(Batich et al. Another amphipathic CPP, LAH4-L1 (sequence: N- KKALLAHALHLLALLALHLAHALKKA-C) facilitated the binding of antigen-encoding mRNA to negatively charged polylactic acid nanoparticle (Coolen et al. Chem Rev 118:7409–7531, Stewart MP, Sharei A, Ding X et al (2016) In vitro and ex vivo strategies for intracellular delivery. Sci Rep 7:252, Chahal JS, Khan OF, Cooper CL et al (2016) Dendrimer-RNA nanoparticles generate protective immunity against lethal Ebola, H1N1 influenza, and Toxoplasma gondii challenges with a single dose. Nature 534:396, Kreiter S, Selmi A, Diken M et al (2010) Intranodal vaccination with naked antigen-encoding RNA elicits potent prophylactic and therapeutic antitumoral immunity. Expert Rev Vaccines 14:161–176, Bernstein DI, Reap EA, Katen K et al (2009) Randomized, double-blind, Phase 1 trial of an alphavirus replicon vaccine for cytomegalovirus in CMV seronegative adult volunteers. CNEs delivered self-amplifying mRNA vaccines against several viral and bacterial infections (Brito et al. Gene Ther 14:1175, Pun SH, Hoffman AS (2013) B.8—nucleic acid delivery. 2019). 2016). 2017). AIDS 32:2533–2545, Lee JA (1981) Sydney Ringer (1834-1910) and Alexis Hartmann (1898-1964). The use of new formulation technologies, such as continuous-flow microfluidic devices, enabled reproducible production of nanoparticles at various scales with controllable sizes (Jahn et al. These lipid materials can be positively charged at a certain pH to encapsulate the negatively charged RNA molecules via electrostatic interactions and help interact with the cell membrane on target cells. Diacetyl (IUPAC systematic name: butanedione or butane-2,3-dione) is an organic compound with the chemical formula (CH 3 CO) 2.It is a yellow or green liquid with an intensely buttery flavor. Based on this co-delivery method, vaccines against various types of viral infection (Petsch et al. Encourage your school to imagine, create and celebrate with Reflections Arts Program. J Controlled Release 295:140–152, Sayers EJ, Peel SE, Schantz A et al (2019) Endocytic profiling of cancer cell models reveals critical factors influencing LNP-mediated mRNA delivery and protein expression. 2018). 2019) or checkpoint inhibitors (NCT03164772). Mol Biol Cell 29:53–65, Reichmuth AM, Oberli MA, Jaklenec A et al (2016) mRNA vaccine delivery using lipid nanoparticles. For example, TT3-LNPs were used to deliver mRNAs encoding the full-length spike protein or its receptor binding domain of SARS-CoV-2. The differences in the immune systems between human and other animal species may lead to distinct immune responses (Shay et al. Ringer’s solution (Ringer 1882) and Ringer’s lactate (Hartmann and Senn 1932; Lee 1981) are two commonly used buffers for dissolving and diluting naked mRNA vaccines before injection. The mechanism study suggested mRNA complex was taken up by phagocytosis and clathrin-dependent endocytosis followed by endosomal escape (Coolen et al. 2016). Eur J Cancer 45:228–247, Ellgaard L, McCaul N, Chatsisvili A et al (2016) Co- and post-translational protein folding in the ER. Adv Mater 31:1805116, Patel S, Athirasala A, Menezes PP et al (2019b) Messenger RNA delivery for tissue engineering and regenerative medicine applications. 2012). 2011), delivery systems with a broad therapeutic index are still in urgent demand. Electroporation disrupted the cell membrane by an electric shock to enable intracellular nucleic acid delivery (Stewart et al. PLOS Negl Tropical Dis 11:e0006108, Taratula O, Garbuzenko O, Savla R et al (2011) Multifunctional nanomedicine platform for cancer specific delivery of siRNA by superparamagnetic iron oxide nanoparticles-dendrimer complexes. 2017; Feldman et al. In recent clinical trials, naked mRNA vaccines were administered via ultrasound-guided intranodal injection (Sahin et al. For example, two influenza virus antigens, nucleoprotein, and matrix protein 1 (M1) were expressed from two self-amplifying mRNAs (Magini et al. Because of these advantages, mRNA vaccines have great potential to be manufactured and deployed in a timely manner in response to rapid infectious disease outbreaks.
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