Not logged in Later on, a PEI formulation of self-amplifying mRNA encoding the hemagglutinin antigens from several influenza virus strains stimulated high antibody titer after IM immunization in mice and protected mice against virus challenge (Vogel et al. 2016). Innate immunity 19:86–97, Gurpreet K, Singh S (2018) Review of nanoemulsion formulation and characterization techniques. 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. 2017; Tiwari et al. 2019). J Clin Investig 11:327–335, Harvey TJ, Liu WJ, Wang XJ et al (2004) Tetracycline-inducible packaging cell line for production of flavivirus replicon particles. 2017). It is also necessary to examine whether the antigens expressed from the co-delivered mRNAs interfere with each other. The two self-amplifying mRNAs were formulated by CNE independently and mixed before simultaneous intramuscular injection to mice. 2011). J Immunother Cancer 7:38, Pardi N, Hogan MJ, Pelc RS et al (2017a) Zika virus protection by a single low-dose nucleoside-modified mRNA vaccination. 2016). In response to the pandemic of the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) in 2020, an mRNA vaccine was administrated to the first volunteer in a phase 1 clinical trial within ten weeks after the sequence of the viral genome was revealed (Lurie et al. In recent clinical trials, naked mRNA vaccines were administered via ultrasound-guided intranodal injection (Sahin et al. Introduction. In these studies, every antigen-encoding mRNA was a mixture of its free and protamine-complexed formats. 2010; Gerna et al. Nat Med 5:823–7, Zeng C, Hou X, Yan J et al (2020) Leveraging mRNAs sequences to express SARS-CoV-2 antigens in vivo. Protamine possesses two features beneficiary for mRNA vaccines. Vet Pathol 55:341–354, Selmi A, Vascotto F, Kautz-Neu K et al (2016) Uptake of synthetic naked RNA by skin-resident dendritic cells via macropinocytosis allows antigen expression and induction of T-cell responses in mice. Nat Rev Immunol, Wecker M, Gilbert P, Russell N et al (2012) Phase I safety and immunogenicity evaluations of an alphavirus replicon HIV-1 subtype C gag vaccine in healthy HIV-1-uninfected adults. Sci Immunol 4:eaaw6647, Kowalski PS, Rudra A, Miao L et al (2019) Delivering the messenger: advances in technologies for therapeutic mRNA delivery. 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 … 2016). Electroporation is the most frequently used method for generating DC-based mRNA vaccines due to its high mRNA delivery efficiency (Van Tendeloo et al. This pressure may disrupt the cell membrane and permit cytosolic delivery of nucleic acids (Stewart et al. Table, Lipids, lipid-like compounds, and lipid derivatives have been widely used to formulate lipid and lipid-derived nanoparticles (LNPs) for in vivo delivery of mRNA vaccines (Midoux and Pichon, Taken together, the formulation and delivery of mRNA vaccines have been extensively studied. Similar to functional lipid-based carriers, polymers can also protect RNA from RNase-mediated degradation and facilitate intracellular delivery (Kowalski et al. Nucleic Acids Res 39:e142–e42, Kariko K, Muramatsu H, Welsh FA et al (2008) Incorporation of pseudouridine into mRNA yields superior nonimmunogenic vector with increased translational capacity and biological stability. Mucosal delivery of mRNA vaccines was studied because of the accessible APCs in lymphoid organs at the mucosal sites and their protective roles against various pathogens. It gives beginner English learners easy access to the vocabulary, grammar and functions of English as it is actually used in a comprehensive range of social situations. Adv Mater 29:1606944, Fleeton MN, Chen M, Berglund P et al (2001) Self-replicative RNA vaccines elicit protection against influenza A virus, respiratory syncytial virus, and a tickborne encephalitis virus. 2012). For instance, activated PKR inhibits cap-dependent translation by phosphorylating eukaryotic translation initiation factor 2A (eIF2A) (Anderson et al. Future developments that enhance endosomal escape and reduce exocytosis of nanoparticles would likely improve delivery efficiency. The final mass ratio of free mRNA, complexed mRNA, and protamine was 2:2:1 in Ringer’s lactate. 2015). The advantage of VRPs arises from the efficient cytoplasmic delivery of RNA payload by viral vectors (Usme-Ciro et al. 2016; Patel et al. 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. Such injection enhanced immune cell recruitment to the muscle injection site, expanded the antigen-specific CD8+ T-cell counts and resulted in better survival upon the influenza challenge than other groups receiving a single antigen-encoding self-amplifying mRNA (Manara et al. Methods We searched for potentially relevant articles in Ovid MEDLINE, Ovid Embase, Ovid PsycINFO and … Vaccines 4:39, Lurie N, Saville M, Hatchett R et al (2020) Developing Covid-19 vaccines at pandemic speed. Can Res 59:56–58, Morse MA, Hobeika AC, Osada T et al (2010) An alphavirus vector overcomes the presence of neutralizing antibodies and elevated numbers of Tregs to induce immune responses in humans with advanced cancer. 39 Likes, 2 Comments - Stanford Family Medicine (@stanfordfmrp) on Instagram: “Congratulations to our residents Grace and Jenny on completing their first … 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. Human Vaccines Immunotherapeutics 10:3146–3152, Reche P, Flower DR, Fridkis-Hareli M et al (2018) Peptide-Based Immunotherapeutics and Vaccines 2017. 2013). 2014; Alberer et al. 2010; Wecker et al. Abstract. 2005; Cheng and Lee 2016; Kowalski et al. Front Immunol 9:1963–63, Rausch S, Schwentner C, Stenzl A et al (2014) mRNA vaccine CV9103 and CV9104 for the treatment of prostate cancer. 2009). 2012) and granulocyte-macrophage colony-stimulating factor (GM-CSF) (Manara et al. Nanoemulsion utilizes hydrophobic and hydrophilic surfactants to stabilize the oil core in the aqueous phase, thereby generating particles. 2020). 2015). Cancer Immunol Immunother: CII 64:1461–1473, Son S, Nam J, Zenkov I et al (2020) Sugar-nanocapsules imprinted with microbial molecular patterns for mRNA vaccination. 2018). In addition, DCs can be loaded with various forms of antigens and stimulatory signals and are highly amenable to such modifications (Pardi et al. 2019), neutralizing antibodies (Stadler et al. 2017). The three mRNAs were used in an equal mass ratio in mouse tumor models (Van Lint et al. J Gen Virol 98:2215–2234, Gradel AKJ, Porsgaard T, Lykkesfeldt J et al (2018) Factors affecting the absorption of subcutaneously administered insulin: effect on variability. Nat Biotechnol 37:1174–1185, Midoux P, Pichon C (2015) Lipid-based mRNA vaccine delivery systems. 2016). Download Full PDF Package. Proc Natl Acad Sci U S A 86:6077–6081, Manara C, Brazzoli M, Piccioli D et al (2019) Co-administration of GM-CSF expressing RNA is a powerful tool to enhance potency of SAM-based vaccines. No additional formulation is needed. 2017). Gene Ther 18:702–708, Dimitriadis GJ (1978) Translation of rabbit globin mRNA introduced by liposomes into mouse lymphocytes. Self-amplifying mRNA encoding nucleoprotein; self-amplifying mRNA encoding murine GM-CSF, Formulated separately, mixed before injection. 2019). The typical size is 1–5 k nucleotides. High-performance liquid chromatography (HPLC) purification further increased the purity and translation capability of mRNA by removing the byproducts from in vitro transcription, such as dsRNA, which could induce inhibition of mRNA translation (Karikó et al. Lipid and lipid-derived nanoparticles (LNPs) were previously used to deliver small molecule drugs and siRNAs (Brito et al. The total amount of protein produced via IV administration is often the highest compared to other routes (Pardi et al. 2016). 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. 2008; Valencia et al. 2012; Kose et al. Nat Biotechnol 23:1407–1413, DeFrancesco L (2017) The ‘anti-hype’ vaccine. 2016). 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. The authors are experienced English language teachers with strong backgrounds in language analysis and language learning. (2016), Gradel et al. Nat Biotechnol 30:1210, Podda A, Del Giudice G (2003) MF59-adjuvanted vaccines: increased immunogenicity with an optimal safety profile. Mol Ther 28:805–819, Liu C, Feng Q, Sun J (2018) Lipid nanovesicles by microfluidics: manipulation, synthesis, and drug delivery. 2014). Therefore, IV injection is often used to deliver mRNAs encoding antibodies when the high functional concentration of neutralizing antibodies is required in the bloodstream (Kose et al. Nat Biotechnol 35:193–197, Derdelinckx J, Berneman ZN, Cools N (2016) GMP-grade mRNA electroporation of dendritic cells for clinical use In: Synthetic mRNA. J Control Release Official J Control Release Soc 314:102–115, Rauch S, Jasny E, Schmidt KE et al (2018) New vaccine technologies to combat outbreak situations. 2017). Biotechnol Adv 40:107534, White LJ, Sariol CA, Mattocks MD et al (2013) An alphavirus vector-based tetravalent dengue vaccine induces a rapid and protective immune response in macaques that differs qualitatively from immunity induced by live virus infection. 2018). (2019), Kose et al. 2016). Mol Ther 22:2118–2129, Brito LA, Kommareddy S, Maione D et al (2015) Self-amplifying mRNA vaccines. It was the first classified as a high-severity season for all age groups, with high levels of outpatient clinic and emergency department visits for influenza-like illness, high rates of influenza-related hospitalization, and high mortality. Based on this co-delivery method, vaccines against various types of viral infection (Petsch et al. (2019), Roth et al. Important electrical characteristics, such as voltage, capacitance, and resistance, were adjusted to improve the delivery efficiency (Van Tendeloo et al. Biomaterials 195:23–37, Corthésy B, Bioley G (2018) Lipid-based particles: versatile delivery systems for mucosal vaccination against infection. For example, a cationic lipid, N-bis(2-hydroxyethyl)-N-methyl-N-(2-cholesteryloxy-carbonyl aminoethyl) ammonium bromide (BHEM-Chol), was mixed with a block copolymer poly(ethylene glycol)-block-poly(lactic-co-glycolic acid) (PEG-b-PLGA) and PLGA to form a lipid–polymer hybrid emulsion for mRNA delivery (Fan et al. Vaccine 30:1388–96, Vogel AB, Lambert L, Kinnear E et al (2018) Self-amplifying RNA vaccines give equivalent protection against influenza to mRNA vaccines but at much lower doses. https://cloud.mail.ru/public/AvHh/hPhA15cvF, Book Clubs as a Tool for Community Building and Language Enhancement.pdf, Teaching Technique. The two self-amplifying mRNAs were mixed in an equal amount, formulated together by LNP and delivered into mice intramuscularly. Background Several scales, checklists and domain-based tools for assessing risk of reporting biases exist, but it is unclear how much they vary in content and guidance. Cationic polymers, such as polyethylenimine (PEI), polyamidoamine (PAMAM) dendrimer, and polysaccharide, condensed and delivered negatively charged RNA molecules (McCullough et al. Polymer-lipid nanoparticles for systemic delivery of mRNA to the lungs. in English) 55:13808–13812, Kallen K-J, Heidenreich R, Schnee M et al (2013) A novel, disruptive vaccination technology: self-adjuvanted RNActive(®) vaccines. J Infect Dis 183:1395–1398, Fooks AR, Banyard AC, Ertl HCJ (2019) New human rabies vaccines in the pipeline. 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). 2019). Several mRNAs can be delivered naked or formulated, complexed together or individually, and injected through different routes at different times. 2018). Therefore, they were conjugated to positively charged polymers which served as scaffolds for RNA encapsulation. The LNPs usually contain one or more of the functional lipid components that are crucial for the intracellular RNA delivery described above (Midoux and Pichon 2015; Kowalski et al. NPJ Vaccines 3:38, O’Hagan DT, Ott GS, De Gregorio E et al (2012) The mechanism of action of MF59—an innately attractive adjuvant formulation. Before administration, the naked mRNA vaccine only needs to be dissolved into a buffer. Mol Ther 27:757–772, Marzi A, Robertson SJ, Haddock E et al (2015) VSV-EBOV rapidly protects macaques against infection with the 2014/15 Ebola virus outbreak strain. 2004; Li et al. 2016; Joe et al. Methods Mol Biol 969:43–54, Weng Y, Li C, Yang T et al (2020) The challenge and prospect of mRNA therapeutics landscape. Jones & Bartlett Learning, Burlington, MA, Singer DF, Linderman JJ (1990) The relationship between antigen concentration, antigen internalization, and antigenic complexes: modeling insights into antigen processing and presentation. Cationic cell-penetrating peptides (CPPs) can complex with RNA. 2012). To stabilize the formulation and improve the safety profile, structural modification of polymer materials, such as incorporating lipid chains, hyperbranched groups, and biodegradable subunits, has been explored (Dong et al. Intranasal delivery can also apply mRNA to the lung through the trachea. Nature 274:923–924, Dong Y, Dorkin JR, Wang W et al (2016) Poly(glycoamidoamine) brushes formulated nanomaterials for systemic siRNA and mRNA delivery in vivo. 2015; Sebastian et al. 2017). 2012). Biotechniques 43:675–681, Kaczmarek JC, Patel AK, Kauffman KJ et al. More recently, a PEI-based formulation with mRNAs encoding HIV-1 Gag and Pol proteins induced specific CD8+ and CD4+ T-cell responses against HIV infections upon IM vaccination in mice (Moyo 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. Vaccines 2:515–536, Li M, Li Y, Peng K et al (2017a) Engineering intranasal mRNA vaccines to enhance lymph node trafficking and immune responses. When an irrelevant β-galactosidase mRNA was complexed with protamine and injected into glioblastoma tumor, the anti-tumor effect rivalled two uncomplexed nucleic acid adjuvants (CpG ssDNA and polyI:C dsRNA). During the delivery process, a large portion of RNA-loaded carriers is trapped in endosome/lysosome or recycled out of cells by exocytosis (Sahay et al. 2019). AIDS 32:2533–2545, Lee JA (1981) Sydney Ringer (1834-1910) and Alexis Hartmann (1898-1964). However, no DCs were found in local lymph nodes. Sci Immunol 4:eaaw7083, Bahl K, Senn JJ, Yuzhakov O et al (2017) Preclinical and clinical demonstration of immunogenicity by mRNA vaccines against H10N8 and H7N9 influenza viruses. New Engl J Med, Lv H, Zhang S, Wang B et al (2006) Toxicity of cationic lipids and cationic polymers in gene delivery. Academic Press, pp 179–233, Calabro S, Tritto E, Pezzotti A et al (2013) The adjuvant effect of MF59 is due to the oil-in-water emulsion formulation, none of the individual components induce a comparable adjuvant effect. The feasibility of naked RNA delivery in vivo was reported in an early effort in which a naked mRNA was delivered to mice by intramuscular injection (Wolff et al. When developing naked mRNA vaccines, the buffer is an essential component to be chosen carefully. 2015; Ickenstein and Garidel 2019). 2017–2018 and 2018–2019 Influenza Seasons. Nat Commun 8:14630, Pardi N, Hogan MJ, Porter FW et al (2018) mRNA vaccines—a new era in vaccinology. 2014). Active in vivo targeting to specific cell types of interest, e.g., dendritic cells, macrophages, B cells, and T cells, have the potential to enhance immunization efficacy (Fenton et al. Furthermore, the structure–activity relationship of the lipids head and tail for RNA delivery and endosomal escape was studied (Sato et al. Sustain Chem Pharm 6:37–56, Garg AD, Coulie PG, Van den Eynde BJ et al (2017) Integrating next-generation dendritic cell vaccines into the current cancer immunotherapy landscape. Подробности в лс, 'English Made Easy' Learning English through Pictures, Projects with Young Learners (Resource Books for Teachers). Next, an anionic peptide, named GALA (sequence: N-WEAALAEALAEALAEHLAEALAEALEALAA-OH-C), was conjugated to the azide groups on pHDPA by click chemistry through a BCN-PEG linker. Eur J Immunol 34:537–547, Scheel B, Teufel R, Probst J et al (2005) Toll-like receptor-dependent activation of several human blood cell types by protamine-condensed mRNA. This vaccine was formulated in two steps (Fotin-Mleczek et al. 2017). 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. From then on, preclinical and clinical studies began testing DC-based mRNA vaccines against infectious diseases and cancers. 7 of this book for clinical development, Five mRNAs encoding five subunits of pentameric complex, Two mRNAs each encoding half of an engineered IgG, Express multiple antigens against the same pathogen/cancer, Six self-amplifying mRNAs encoding antigens, Two mRNAs encoding ten cancer neo-antigens, No mixing, injected into separate lymph nodes, Develop multivalent vaccine against multiple pathogen strains, Three self-amplifying mRNAs encoding hemagglutinins from three Influenza strains, Express antigen and immunostimulatory protein (s). Obes Rev 11:11–18, Ickenstein LM, Garidel P (2019) Lipid-based nanoparticle formulations for small molecules and RNA drugs. 2019). 2017). The resident APCs in the skin, muscle, and lymph node can process the expressed antigens and capture mRNA nanoparticles (Moyer et al. 1d). 2018; Li et al. 2009). 2018) or intranasal (Lorenzi et al. We would like to show you a description here but the site won’t allow us. Intramuscular (IM) injection delivers the vaccine into muscles, a deeper tissue under the dermal and subcutaneous layer (Fig. While many carriers are effective in delivering mRNA vaccines in preclinical studies and clinical trials, there are still challenges to be addressed. The routes for administration of mRNA-loaded DCs mainly include ID, SC, IV, and IN injections (Benteyn et al. One possible force is the hydrostatic pressure formed after fast injection of a relatively large volume into small mammals. 2019). 1999). In: Clinical procedures for safer patient care. 2018), and proteins with immunostimulatory activity (Bonehill et al. This four-level American English reading course uses carefully selected reading texts to help students read effectively. Download. MF59 is an FDA-approved oil-in-water nanoemulsion adjuvant used with inactivated Flu vaccine for elders (Vesikari 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. 2020). The immunostimulatory activity of each antigen may be different. The first challenge is the instability of mRNA mostly due to enzymatic degradation by RNases. 2009; Morse et al. 2017; Sayers et al. 2012; Schnee et al. Traffic 17:615–638, Engmann L, Shaker A, White E et al (1998) Local side effects of subcutaneous and intramuscular urinary gonadotropins for ovarian stimulation in in vitro fertilization: a prospective, randomized study 11 supported by Organon, Cambridge, United Kingdom. 2017; Pardi et al. It condensed a modified OVA-mRNA into nanocomplex, transfected dendritic cells and induced OVA-specific cytotoxic T-cell activation upon intradermal injection into mice (Udhayakumar et al. UCSF Faculty: Miles Conrad, MD, MPH (interventional); Rita Freimanis, MD (breast); Travis Henry, MD (thoracic); Priyanka Jha, MD (abdominal); Kimberly Kallianos, MD (thoracic); Jared Narvid, MD (neuro); Ramya Srinivasan, MD (skeletal); Emily … 2016; Guardo et al. Nano Lett 20:1578–1589, Blakney AK, Abdouni Y, Yilmaz G et al (2020) Mannosylated poly(ethylene imine) copolymers enhance saRNA uptake and expression in human skin explants. The three self-amplifying mRNAs expressed antigens against the respiratory syncytial virus (RSV), human cytomegalovirus (hCMV), and human immunodeficiency virus (HIV), respectively. In particular, numerous mRNA vaccines are being developed to tackle infectious diseases and various types of cancer, with many advancing to different stages of clinical trials (Pardi et al. Proc Natl Acad Sci 115:E9153–E9161, Haenssle HA, Riedl P, Buhl T et al (2010) Intracellular delivery of major histocompatibility complex class I-binding epitopes: dendritic cells loaded and matured with cationic peptide/poly(I:C) complexes efficiently activate T cells. 2018). Effective immunization observed in preclinical animal studies may or may not be applied to human. The resulting nanoparticle induced innate and specific immune responses in primary human DC upon in vitro delivery. And using the needle-free injection, the ID route performed better than the IM route (Alberer et al. Regardless of the delivery formats, carrier materials, and administration routes, our knowledge is limited regarding the factors and pathways responsible for cellular uptake, cytosolic release, endosomal escape, lysosomal degradation, and exocytotic recycling of mRNA vaccines. 2016; Guardo et al. In addition, the larger injection volume may compensate for the less efficient draining activity in this layer of skin (Johansen and Kündig 2015). 2013). Second, in vitro transcription reaction is easy to conduct, has a high yield, and can be scaled up (Pardi et al. 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. C.Zhang acknowledges the support from the Professor Sylvan G. Frank Graduate Fellowship. (2019) Nucleoside-modified mRNA encoding HSV-2 glycoproteins C, D, and E prevents clinical and subclinical genital herpes. 2012; Dewitte et al. Unmodified RNA was considered a strong stimulator of TLR3/7/8 (Kariko et al. AIDS 31:321–332, Guevara ML, Jilesen Z, Stojdl D et al (2019) Codelivery of mRNA with α-galactosylceramide using a new lipopolyplex formulation induces a strong antitumor response upon intravenous administration. In the vaccination process, mRNA formulation and delivery strategies facilitate effective expression and presentation of antigens, and immune stimulation. MF59 nanoemulsion enhances the efficacy of vaccines through MyD88-mediated release of cytokines/chemokines and recruitment of immune cells, without triggering TLRs (Seubert et al. The three proteins encoded by the mRNAs were CD40 ligand, constitutive active TLR4 and CD70. A short CPP called Xentry (sequence: N-LCLRPVG-C) was fused to truncated protamine (sequence: N-RSQSRSRYYRQRQRSRRRRRRS-C) and delivered a protein-coding mRNA into several human cell lines in vitro (Bell et al. The delivery formats and delivery materials described above have advanced to various stages of preclinical and clinical studies. 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. Nanoemulsion can be induced by various methods, such as vigorous agitation, ultrasound, and microfluidics. 2019). 2018) and immature dendritic cells (Kreiter et al. The mRNAs were formulated and injected separately through the intradermal route into patients. Such a delivery enabled PC expression in vitro and induced specific anti-PC antibody production in mice and monkeys after IM injection. However, the formulation of polymer-based mRNA nanoparticles tends to have high polydispersity (Kowalski 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. J Gene Med 6:1014–1022, Doyle G, McCuteheon J (2015) Intravenous medications by direct IV route. It is a vicinal diketone (two C=O groups, side-by-side) with the molecular formula C 4 H 6 O 2.Diacetyl occurs naturally in alcoholic beverages and is added to some foods to impart its buttery flavor. 2019b). 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. 1999). 2011). Fourth, transportation and storage of mRNA may be easier than protein-based vaccines, since RNA, if protected properly against ribonucleases (RNases), is less prone to degradation compared to proteins (Stitz et al. In one study, ionizable lipid-based LNPs were used to deliver tumor antigen OVA-mRNA into DCs. Give students confidence in their abilities to explore ideas and learn through the arts in the areas of dance choreography, film production, literature, music composition, photography and visual arts. 2015). J Control Release 217:345–351, Patel AK, Kaczmarek JC, Bose S et al (2019a) Inhaled nanoformulated mRNA polyplexes for protein production in lung epithelium. In the vaccination process, mRNA formulation and delivery strategies facilitate effective expression and presentation of antigens, and immune stimulation. Mol Ther Methods Clin Dev 12:32–46, Nelson CS, Herold BC, Permar SR (2018) A new era in cytomegalovirus vaccinology: considerations for rational design of next-generation vaccines to prevent congenital cytomegalovirus infection. Repeated IN injection of naked mRNAs was well-tolerated and induced a various degree of specific immune responses against tumor or HIV-1 (Sahin et al. These results suggested IV and ID were superior to SC for administering mRNA-loaded DCs (Morse et al. Download full-text PDF Download full-text PDF Download full-text PDF Read full-text. 2017; Sabari et al. 2018). 1a). Content may be subject to copyright. 2017) or intratumoral (Jeught et al. 2015). For example, previous studies found IV injection of mRNA vaccine targeted spleen DCs and induced immune response against tumors in mice (Kranz et al. 2004). Third, mRNA vaccine enables the synthesis of antigen proteins in situ, eliminating the need for protein purification and long-term stabilization which are challenging for some antigens. 2014). 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. 2019). The matured DC activated co-cultured antigen-specific lymphocytes from human donors (Haenssle et al. The other feature of the naked mRNA vaccine, especially those made of unmodified nucleotides, is its intrinsic immunogenicity, which serves as a double-edged sword. 2019). For example, a recent vaccine study against influenza A virus employed two self-amplifying mRNAs: one encoding the influenza A virus nucleoprotein antigen and the other encoding murine immunostimulatory GM-CSF (Manara et al. Mechanism of action studies suggested the GALA peptide facilitated the cell uptake and release of mRNA into the cytosol through binding to sialic acid groups on the DC surface (Lou et al.