2018). Advances in recent years made mRNA a promising vaccine platform. 2019). Bioconjug Chem 30:461–475, Lundstrom K (2016) Replicon RNA viral vectors as vaccines. 2010). 2018), potentially lowering the logistical requirement and reducing the vaccine cost. Second, the naked antigen-coding mRNA was mixed with the complexed mRNA in a 1:1 mass ratio. The first challenge is the instability of mRNA mostly due to enzymatic degradation by RNases. 2018). Cationic polymers, such as polyethylenimine (PEI), polyamidoamine (PAMAM) dendrimer, and polysaccharide, condensed and delivered negatively charged RNA molecules (McCullough et al. 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. Methods Mol Biol 969:43–54, Weng Y, Li C, Yang T et al (2020) The challenge and prospect of mRNA therapeutics landscape. Therefore, detailed characterizations are necessary for each specific naked mRNA vaccine (Pardi et al. Protamine possesses two features beneficiary for mRNA vaccines. 2019). Antibody–drug conjugates (ADC) are one of the fastest growing anticancer drugs. Tissue Eng Part A 25:91–112, Patel S, Kim J, Herrera M et al (2019c) Brief update on endocytosis of nanomedicines. What does the Steelers loss mean for the Chiefs? Several mRNAs can be delivered naked or formulated, complexed together or individually, and injected through different routes at different times. 2020). Wiley Interdisc Rev Nanomed Nanobiotechnol 11:e1530, Li W, Joshi MD, Singhania S et al (2014) Peptide vaccine: progress and challenges. 2014). Electroporation disrupted the cell membrane by an electric shock to enable intracellular nucleic acid delivery (Stewart 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. Vaccine 30:4341–4348, Oberli MA, Reichmuth AM, Dorkin JR et al (2016) Lipid nanoparticle assisted mRNA delivery for potent cancer immunotherapy. 2017; Zhang 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. Nanoemulsion can be induced by various methods, such as vigorous agitation, ultrasound, and microfluidics. 2012). Ther Deliv 7:319–334, Richner JM, Himansu S, Dowd KA et al (2017a) Modified mRNA vaccines protect against Zika virus infection. 2019). Appropriate delivery materials and formulation methods often boost the vaccine efficacy which is also influenced by the selection of a proper administration route. 2010). 2018; Liu et al. The activated APCs can be recruited to the injection site to process the mRNA vaccine. Sci Transl Med 11: eaaw1565, Kose N, Fox JM, Sapparapu G et al (2019) A lipid-encapsulated mRNA encoding a potently neutralizing human monoclonal antibody protects against chikungunya infection. Expert Rev Vaccines 14:221–234, Mitchell DA, Batich KA, Gunn MD et al (2015) Tetanus toxoid and CCL3 improve dendritic cell vaccines in mice and glioblastoma patients. 2019; Verbeke et al. 1999). 2017) or sonoporation (Dewitte et al. Such a delivery enabled PC expression in vitro and induced specific anti-PC antibody production in mice and monkeys after IM injection. Different routes of administration may exhibit different DCs distribution patterns in vivo. This method dissolves mRNA into a buffer and then injects the mRNA solution directly. 1999; Fleeton et al. 2009). Even though PEI formulation showed in vivo efficacy, the potential toxicity may impede its development (Kowalski et al. 1a). In addition, the larger injection volume may compensate for the less efficient draining activity in this layer of skin (Johansen and Kündig 2015). 2017) or intratumoral (Jeught et al. 2005; Heyes et al. 2001; De Temmerman et al. Cell 170:273–83.e12, Riley RS, June CH, Langer R et al (2019) Delivery technologies for cancer immunotherapy. J Virol 84:1005, Magini D, Giovani C, Mangiavacchi S et al (2016) Self-amplifying mRNA vaccines expressing multiple conserved influenza antigens confer protection against homologous and heterosubtypic viral challenge. (2016). 2014; Brazzoli et al. In summary, protamine was the only peptide carrier evaluated in clinical trials of mRNA vaccines. 2019). 2019). Nat Rev Mater 2:17056, Hartmann AF, Senn MJ (1932) Studies in the metabolism of sodium r-lactate. 2018). 2018). 2019), reducing the effective amount of RNA reaching the cytosol. 2011; Selmi et al. 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. 2005; Cheng and Lee 2016; Kowalski et al. 2019b; Pardi et al. 2018). Gene Ther 14:1175, Pun SH, Hoffman AS (2013) B.8—nucleic acid delivery. DC-based mRNA vaccines have been tested in many clinical trials and have shown acceptable safety profiles (Garg et al. Virol J 10:185–85, Valencia PM, Farokhzad OC, Karnik R et al (2012) Microfluidic technologies for accelerating the clinical translation of nanoparticles. 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. 2017a, b; Thran et al. Besides cationic polymer materials, anionic polymers, such as PLGA, were also used to deliver mRNA vaccines. 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. Mol Ther 16:1833–1840, Kashem SW, Haniffa M, Kaplan DH (2017) Antigen-presenting cells in the skin. 2016), direct mixing (Borrego et al. Science (New York, N.Y.) 349:739, McCarthy HO, McCaffrey J, McCrudden CM et al (2014) Development and characterization of self-assembling nanoparticles using a bio-inspired amphipathic peptide for gene delivery. Thus, local injections were utilized to deliver most LNP encapsulated antigen-encoding mRNA vaccines (see examples in Table 2). 1989; Martinon et al. 2019). After SC injection, no radioactivity was observed in the draining lymph nodes. This vaccine was formulated in two steps (Fotin-Mleczek et al. In the presence of protamine, antigen-encoding mRNA was more resistant to RNase degradation, suggesting better stability in vitro (Hoerr et al. 1998; Diehl et al. 2014; Alberer et al. 2017). mRNA vaccines have become a versatile technology for the prevention of infectious diseases and the treatment of cancers. 2010; Bialkowski et al. Polymer-lipid nanoparticles for systemic delivery of mRNA to the lungs. 2002; Brito et al. 2017). 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. When delivered to the cytosol, this type of mRNA is translated until its degradation without additional replication. Electroporation delivered into K562 cells two mRNAs each of which encoding half of an engineered IgG against a tumor-associated antigen, the tight-junction proteins claudin 6 (Stadler et al. We value excellent academic writing and strive to provide outstanding essay writing service each and every time you place an order. Secondly, efficient intracellular delivery of mRNA is another challenge owing to the negative charge and large size of mRNA molecules. Additionally, dendritic cells were loaded with mRNA vaccines ex vivo and transferred to the hosts (Benteyn et al. 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. ... 2018 . Springer New York, New York, pp 261–86, John S, Yuzhakov O, Woods A et al (2018) Multi-antigenic human cytomegalovirus mRNA vaccines that elicit potent humoral and cell-mediated immunity. Intravenous (IV) injection delivers mRNA vaccines into the systemic circulation (Fig. 2016; Guardo et al. The vascular and lymphatic vessels in this layer of skin also help transport mRNA vaccines and APCs to the draining lymph nodes to activate T and B cells (Kashem et al. 2012; Billingsley et al. Curr Top Microbiol Immunol 405:145–164, Guardo AC, Joe PT, Miralles L et al (2017) Preclinical evaluation of an mRNA HIV vaccine combining rationally selected antigenic sequences and adjuvant signals (HTI-TriMix). Biomater Sci 6:3009–3018, Feldman RA, Fuhr R, Smolenov I et al (2019) mRNA vaccines against H10N8 and H7N9 influenza viruses of pandemic potential are immunogenic and well tolerated in healthy adults in phase 1 randomized clinical trials. 2013; Iavarone et al. Sci Rep 6:22509, Billingsley MM, Singh N, Ravikumar P et al (2020) Ionizable lipid nanoparticle-mediated mRNA delivery for human CAR T cell engineering. 2018), and proteins with immunostimulatory activity (Bonehill et al. 2014). Nat Biotechnol 37:1174–1185, Midoux P, Pichon C (2015) Lipid-based mRNA vaccine delivery systems. This method utilizes one antigen-encoding mRNA: 50% was naked in Ringer’s lactate to express an antigen and 50% was complexed with protamine as an adjuvant (Kallen et al. Three major types of proteins are encoded by mRNA vaccines: antigens (Grunwitz and Kranz 2017; Zhang et al. In these trials, the protamine-mRNA complex and a naked mRNA were injected simultaneously via ID or IM routes (Rausch et al. Chapter 7 of this book reviews the clinical development of mRNA vaccines in details. 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. 2008; Van Lint et al. 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. 2012) and granulocyte-macrophage colony-stimulating factor (GM-CSF) (Manara et al. 1c). J Control Release: Official J Control Release Soc 194:28–36, Diehl KH, Hull R, Morton D et al (2001) A good practice guide to the administration of substances and removal of blood, including routes and volumes. In the vaccination process, mRNA formulation and delivery strategies facilitate effective expression and presentation of antigens, and immune stimulation. Over 10 million scientific documents at your fingertips. In summary, the biological features of different administration routes may impact the safety and efficacy of vaccination. 2014). J Immunother (Hagerstown, Md. Conventional mRNAs are similar to endogenous mRNAs in mammalian cells, consisting of a 5’ cap, 5’ UTR, coding region, 3’ UTR, and a polyadenylated tail (Pardi et al. Cationic peptides contain many lysine and arginine residues that provide positively charged amino groups, therefore enabling complexing with nucleic acids through electrostatic interactions (Grau et al. 2016) were developed. 2015). PLoS ONE 11:e0161193, Malone RW, Felgner PL, Verma IM (1989) Cationic liposome-mediated RNA transfection. 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. 2014). Intranodal (IN) injection directly introduces mRNA vaccines to the peripheral lymphoid organs where APCs and primed T or B cells interact (Fig 1e). Front Immunol 9:2286, Chahal JS, Fang T, Woodham AW et al (2017) An RNA nanoparticle vaccine against Zika virus elicits antibody and CD8+ T cell responses in a mouse model. In: Katze MG, Korth MJ, Law GL, Nathanson N (eds) Viral pathogenesis, 3rd edn. Int J Pharm 572:118813, Lorenz C, Fotin-Mleczek M, Roth G et al (2011) Protein expression from exogenous mRNA: uptake by receptor-mediated endocytosis and trafficking via the lysosomal pathway. The total amount of protein produced via IV administration is often the highest compared to other routes (Pardi 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. 2014; Van Lint et al. 2014). (2017), Liang et al. New Engl J Med, Lv H, Zhang S, Wang B et al (2006) Toxicity of cationic lipids and cationic polymers in gene delivery. In that trial, naked personalized mRNA vaccines were diluted in Ringer’s solution, injected into patients’ lymph nodes, and induced antigen-specific T-cell response (Sahin et al. 2010). ACS Appl Mater Interfaces 9:25481–87, Zhou W-Z, Hoon D, Huang S et al (1999) RNA melanoma vaccine: induction of antitumor immunity by human glycoprotein 100 mRNA immunization. In the clinical trial evaluating RNActive mRNA vaccine against rabies virus, the needle-free injection induced neutralizing antibody titers in some participates, while needle-syringe injection was not effective. With further improvement, LNPs may facilitate the development of more effective mRNA vaccines. One mRNA encoding an antigen was commonly mixed with the three mRNAs and administered simultaneously to initiate specific immunity. 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. 2017). mRNA vaccines have become a versatile technology for the prevention of infectious diseases and the treatment of cancers. The exogenous RNAs could be detected by RNA sensors, such as TLRs, RIG-I, PKR, IFIT1, leading to activation of NF‑κB and type I interferon signaling pathways, and release of cytokines (Schlee and Hartmann 2016). 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. Expert Opin Drug Deliv 16:1205–1226, Inaba K, Metlay JP, Crowley MT et al (1990) Dendritic cells pulsed with protein antigens in vitro can prime antigen-specific, MHC-restricted T cells in situ. This ability is attributed to the fact that viruses have evolved to internalize and release their genomes into cells via many different pathways with high efficiency (Vázquez-Calvo et al. Various delivery strategies have been investigated to address these obstacles with different delivery materials, formulation methods, and routes of administrations. AIDS 32:2533–2545, Lee JA (1981) Sydney Ringer (1834-1910) and Alexis Hartmann (1898-1964). 2015; Hong et al. In this chapter, we overview the recent progress and existing challenges in the formulation and delivery technologies of mRNA vaccines with perspectives for future development. Two or more independent antigen-coding mRNAs can be co-delivered to enhance and broaden immune responses. ADCs are complex molecules that require careful attention to various components. 2018). 1990). 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. The large size makes efficient encapsulation and delivery more challenging than other payloads, such as small molecules, siRNAs, and antisense oligonucleotides (ASOs). Adv Healthc Mater 6, Usme-Ciro JA, Campillo-Pedroza N, Almazán F et al (2013) Cytoplasmic RNA viruses as potential vehicles for the delivery of therapeutic small RNAs. The first challenge is delivery efficiency. These results suggested IV and ID were superior to SC for administering mRNA-loaded DCs (Morse et al. 2015). (2017), Sienkiewicz and Palmunen (2017), 4, Johansen and Kundig (2014), Reichmuth et al. 2019). Additional clinical trials against cancers combined the RNActive mRNA vaccine with other therapies, such as radiation therapy (Sebastian et al. Cationic cell-penetrating peptides (CPPs) can complex with RNA. 2013), could stimulate interferon-mediated immune responses (Pepini et al. 2016). 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. Nat Biotechnol 28:172–176, Senti G, Kündig TM (2015) Intralymphatic Immunotherapy. mRNA vaccines have been delivered in various formats: encapsulation by delivery carriers, such as lipid nanoparticles, polymers, peptides, free mRNA in solution, and ex vivo through dendritic cells. ACS Nano 13:1655–1669, Verbeke R, Lentacker I, De Smedt SC et al (2019b) Three decades of messenger RNA vaccine development. 2015), while other VRPs only engage in one cycle of transduction because the genetic regions encoding envelope and capsid proteins necessary for the viral infection are absent from the self-amplifying mRNAs (Lundstrom 2016). J Exp Med 172:631–640, Islam MA, Xu Y, Tao W et al (2018) Restoration of tumour-growth suppression in vivo via systemic nanoparticle-mediated delivery of PTEN mRNA. J Control Release 79:1–5, Papachristofilou A, Hipp MM, Klinkhardt U et al (2019) Phase Ib evaluation of a self-adjuvanted protamine formulated mRNA-based active cancer immunotherapy, BI1361849 (CV9202), combined with local radiation treatment in patients with stage IV non-small cell lung cancer. 1d). 2015; Hong et al. Methods We searched for potentially relevant articles in Ovid MEDLINE, Ovid Embase, Ovid PsycINFO and … Blood 98:49–56, Vázquez-Calvo Á, Saiz J-C, McCullough KC et al (2012) Acid-dependent viral entry. Mol Ther, Kranz LM, Diken M, Haas H et al (2016) Systemic RNA delivery to dendritic cells exploits antiviral defence for cancer immunotherapy.
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