Jump to content

MRNA vaccine

Page extended-protected
From Wikipedia, the free encyclopedia

This is an old revision of this page, as edited by Iztwoz (talk | contribs) at 17:00, 20 December 2020 (→‎History: link). The present address (URL) is a permanent link to this revision, which may differ significantly from the current revision.

See also: DNA vaccine, RNA therapeutics, and Nucleoside-modified messenger RNA

An RNA vaccine or mRNA (messenger RNA) vaccine is a type of vaccine that uses a man-made copy of a natural chemical called messenger RNA (mRNA) to produce an immune response. The vaccine transfects molecules of synthetic RNA into human cells. Once inside the cells, the vaccine's RNA functions as mRNA, causing the cells to build the foreign protein that would normally be produced by a pathogen (such as a virus) or by a cancer cell. These protein molecules stimulate an adaptive immune response which teaches the body how to identify and destroy the corresponding pathogen or cancer cells.[1] The delivery of mRNA is achieved by a co-formulation of the molecule into lipid nanoparticles which protect the RNA strands and helps their absorption into the targeted cells.[2][3]

Reactogenicity, the property of a vaccine of being able to produce common, "expected" adverse reactions, is similar to that of conventional, non-RNA, vaccines.[4] People susceptible to an autoimmune response may have an adverse reaction to RNA vaccines.[4] The advantages of RNA vaccines over traditional protein vaccines are superior design and production speed, lower cost of production,[5][4] and the induction of both cellular as well as humoral immunity.[6] A disadvantage in the Pfizer mRNA vaccine for COVID-19 is that it requires ultracold storage before distribution.[1]

mRNA vaccines have attracted considerable interest as vaccines against COVID-19. By early December 2020, there were two novel mRNA vaccines for COVID-19 that had completed the required eight-week period post-final human trials and were awaiting emergency use authorization as COVID-19 vaccines: mRNA-1273 from Moderna and Tozinameran from a BioNTech/Pfizer partnership.[1][7] On 2 December 2020, the United Kingdom's Medicines and Healthcare products Regulatory Agency (MHRA) became the first medicines regulator to approve an mRNA vaccine, authorizing BioNTech/Pfizer's Tozinameran vaccine for widespread use against COVID-19.[8][9]

The use of RNA in a vaccine has been the basis of substantial misinformation circulated via social media, wrongly claiming that the use of RNA somehow alters a person's DNA, or emphasizing the technology's previously unknown safety record, while ignoring the more recent accumulation of evidence from trials involving tens of thousands of people.[10]

Mechanism

Further information: Immune system
An illustration of the mechanism of action of the RNA vaccine

mRNA vaccines operate in a very different manner from a traditional vaccine. Traditional vaccines stimulate an antibody response by injecting a human with antigens (proteins or peptides), an attenuated virus, or a recombinant antigen-encoding viral vector. These ingredients are prepared and grown outside of the human body.

In contrast, mRNA vaccines insert a synthetically created fragment of the RNA sequence of a virus directly into the human cells (known as transfection).[4] The cell uses its own internal machinery to produce the specific proteins (viral antigens) encoded by the mRNA strand.[4] These antigens produced stimulate an adaptive immune response in an equivalent manner to how direct injection of the antigen protein/peptide would have; that is, via production of new antibodies which bind to the antigen and activate T cells that recognize specific peptides presented on MHC molecules.[11] The original cells present the antigen to other cells in the immune system.[12]

The benefit of using mRNA to have human cells produce the antigen is that mRNA is far easier for vaccine creators to produce than antigen proteins or attenuated virus.[11][13][4] Another benefit is speed of design and production. Moderna designed their MRNA-1273 vaccine for COVID-19 in 2 days.[14] Another advantage of RNA vaccines is that since the antigens are produced inside the cell, they stimulate cellular immunity, as well as humoral immunity.[6][15]

mRNA vaccines do not affect or reprogram DNA inside the cell. The synthetic mRNA fragment is a copy of the specific part of the viral RNA that carries the instructions to build the antigen of the virus (a protein spike, in the case of the main coronavirus mRNA vaccines), and is not related to DNA. This misconception was circulated as the COVID-19 mRNA vaccines came to public prominence, and is a debunked conspiracy theory.[16][17]

The mRNA should degrade in the cells after producing the foreign protein. However, because the specific formulation (including the exact composition of the lipid nanoparticle drug delivery coating) is kept confidential by the manufacturers of the candidate mRNA vaccines, details and timings have not been researched yet by third parties.[18]

Delivery

The method of vaccine delivery can be broadly classified by whether the RNA transfer to cells happens within (in vivo) or outside (ex vivo) the organism.[3]

Ex vivo

Dendritic cells are a type of immune cells that display antigens on their surfaces, leading to interactions with T cells to initiate an immune response. Dendritic cells can be collected from patients and programmed with the desired mRNA. Then, they can be re-administered back into patients to create an immune response.[19]

In vivo

Since the discovery that introducing in vitro transcribed mRNA leads to expression in vivo following direct administration, in vivo approaches have become more and more attractive.[20] They offer some advantages over ex vivo methods, particularly by avoiding the cost of harvesting and adapting dendritic cells from patients, and by imitating a regular infection. There are still obstacles for these methods to overcome for RNA vaccination to be a potent procedure. Evolutionary mechanisms that prevent the infiltration of unknown nucleic material and promote degradation by RNases need to be circumvented in order to initiate translation. In addition, RNA is too heavy to move around on its own inside the cell via diffusion, making it vulnerable to being discovered and eliminated by the host cell.

Naked mRNA injection

A naked injection means that the delivery of the vaccine is simply held in a buffer.[21] This mode of mRNA uptake has been known for over two decades. The first worldwide clinical studies (Tübingen, Germany) used intradermal injections of naked mRNA for vaccination.[22][23]

The use of RNA as a vaccine tool was discovered in the 1990s in the form of self-amplifying mRNA.[24][25] The two main categories of mRNA vaccines are non-amplifying (conventional, viral delivery), and molecular self-amplifiying mRNA (non-viral delivery). When mRNA is delivered non-virally it enters the cell's cytoplasm and can amplify and express the antigenic protein.[26][27]

It has also emerged that the different routes of injection, such as into the skin, blood or to muscles, resulted in varying levels of mRNA uptake, making the choice of administration route a critical aspect of delivery. One study showed, in comparing different routes, that lymph node injection leads to the largest T cell response.[28]

The mechanisms and consequently the evaluation of self-amplifying mRNA may be different, as self-amplifying mRNA is fundamentally different by being a much bigger molecule in size.[3]

Polyplex vector

Cationic polymers can be mixed with mRNA to generate protective coatings called polyplexes. These protect the recombinant mRNA from ribonucleases and assist its penetration in cells. Protamine is a natural cationic peptide and has been used to encapsulate mRNA for vaccination.[non-primary source needed][29]

Lipid nanoparticle vector

The first time the FDA approved the use of lipid nanoparticles as a drug delivery system was in 2018, when the agency approved the first siRNA drug, Onpattro.[30] Encapsulating the mRNA molecule in lipid nanoparticles was a critical breakthrough for producing viable mRNA vaccines, solving a number of key technical barriers in delivering the mRNA molecule into the human cell.[30][31] Principally, the lipid provides a layer of protection against degradation, allowing more robust translational output. In addition, the customization of the lipid's outer layer allows the targeting of desired cell types through ligand interactions. However, many studies have also highlighted the difficulty of studying this type of delivery, demonstrating that there is an inconsistency between in vivo and in vitro applications of nanoparticles in terms of cellular intake.[32] The nanoparticles can be administered to the body and transported via multiple routes, such as intravenously or through the lymphatic system.[30]

Viral vector

Further information: Viral vector

In addition to non-viral delivery methods, RNA viruses have been engineered to achieve similar immunological responses. Typical RNA viruses used as vectors include retroviruses, lentiviruses, alphaviruses and rhabdoviruses, each of which can differ in structure and function.[33] Clinical studies have utilized such viruses on a range of diseases in model animals such as mice, chicken and primates.[34][35][36]

Efficacy of mRNA vaccines for COVID-19

It is unclear why the novel mRNA COVID-19 vaccines from Moderna and BioNTect/Pfizer have shown potential efficacy rates of 90 to 95 percent, when the prior mRNA drug trials on pathogens other than COVID-19 were not so promising and had to be abandoned in the early phases of trials.[37] Physician-scientist Margaret Liu stated that it could be due to the "sheer volume of resources" that went into development, or that the vaccines might be "triggering a nonspecific inflammatory response to the mRNA that could be heightening its specific immune response, given that the modified nucleoside technique reduced inflammation but hasn't eliminated it completely", and that "this may also explain the intense reactions such as aches and fevers reported in some recipients of the mRNA SARS-CoV-2 vaccines". These reactions though severe were transient and another view is that they were believed to be a reaction to the lipid drug delivery molecules.[37]

Unlike DNA molecules, the mRNA molecule is a very fragile molecule that degrades within minutes in an exposed environment, and thus mRNA vaccines need to be transported and stored at very low temperatures.[7] Outside of the human cell, or its drug delivery system, the mRNA molecule is also quickly broken down by the human body.[5] This fragility of the mRNA molecule is a hurdle to the efficacy of any mRNA vaccine due to bulk disintegration before it enters the cells, that could lead people to believe, and act, as if they are immune when they are not.[7][5]

Side effects and risks

Reactogenicity is similar to that of conventional, non-RNA vaccines. However, those susceptible to an autoimmune response may have an adverse reaction to RNA vaccines.[4] The mRNA strands in the vaccine may elicit an unintended immune reaction. To minimize this, mRNA sequences in mRNA vaccines are designed to mimic those produced by human cells.[5]

The drug delivery system holding the mRNA molecule and protecting the fragile mRNA strands from being broken down before they enter the human cell are PEGylated lipid nanoparticles that can trigger their own immune reactions, and cause damage to the liver at higher doses.[38] Strong reactogenic effects were reported in trials of novel COVID-19 RNA vaccines.[39][example needed]

General

Before 2020, no mRNA technology platform (drug or vaccine) had been authorized for use in humans, so there was a risk of unknown effects,[15] both short- and longer-term (such as autoimmune responses or diseases).[better source needed][13][7][40] The 2020 coronavirus pandemic required faster production capability of mRNA vaccines, made them attractive to national health organisations, and led to debate about the type of initial authorization mRNA vaccines should get (including emergency use authorization or expanded access authorization) after the eight-week period of post-final human trials.[41][42]

Storage

Because mRNA is fragile, the vaccine must be kept at very low temperatures to avoid degrading and thus giving little effective immunity to the recipient. The BNT162b2 mRNA vaccine has to be kept at −70 °C (−94 °F).[43] Moderna say their MRNA-1273 vaccine can be stored at −20 °C (−4 °F), which is comparable to a home freezer,[43] and that it remains stable between 2 and 8 °C (36 and 46 °F).[44] In November 2020, Nature reported, "While it’s possible that differences in LNP formulations or mRNA secondary structures could account for the thermostability differences [between Moderna and BioNtech], many experts suspect both vaccine products will ultimately prove to have similar storage requirements and shelf lives under various temperature conditions."[15]

Advantages

Traditional vaccines

RNA vaccines offer specific advantages over traditional protein vaccines.[5][4] Because RNA vaccines are not constructed from an active pathogen (or even an inactivated pathogen), they are non-infectious. In contrast, traditional vaccines require the production of pathogens, which, if done at high volumes, could increase the risks of localized outbreaks of the virus at the production facility.[5] RNA vaccines can be produced faster, more cheaply, and in a more standardized fashion (with fewer error rates in production), which can improve responsiveness to serious outbreaks.[4][5]

DNA vaccines

In addition to sharing the advantages of theoretical DNA vaccines over established traditional protein vaccines, RNA vaccination offers other benefits. The mRNA is translated in the cytosol, so there is no need for the RNA to enter the cell nucleus, and the risk of being integrated to the host genome is averted.[3] Modified nucleosides (for example, pseudouridines, 2'-O-methylated nucleosides) can be incorporated to mRNA to suppress immune response stimulation to avoid immediate degradation and produce a more persistent effect through enhanced translation capacity.[45][46][47] The open reading frame (ORF) and untranslated regions (UTR) of mRNA can be optimized for different purposes (a process called sequence engineering of mRNA), for example through enriching the guanine-cytosine content or choosing specific UTRs known to increase translation.[48]

An additional ORF coding for a replication mechanism can be added to amplify antigen translation and therefore immune response, decreasing the amount of starting material needed.[25][49]

History

Researchers at the Salk Institute, University of California-San Diego, and a US-based biotech company, Vical Incorporated, published work in 1989 demonstrating that mRNA, using a liposomal nanoparticle for drug delivery, could transfect mRNA into a variety of eukaryotic cells.[50] In 1990, Jon A. Wolff et al. at the University of Wisconsin, reported positive results where "naked" (or unprotected) mRNA was injected into the muscle of mice.[3] These studies were the first evidence that in vitro transcribed (IVT) mRNA could deliver the genetic information to produce proteins within living cell tissue.[3]

The use of RNA vaccines goes back to the early 1990s. The in vitro demonstration of mRNA in animals was first reported in 1990,[51] and use as immunization proposed shortly thereafter.[52][53] In 1993, Martinon demonstrated that liposome-encapsulated RNA could stimulate T-cells in vivo, and in 1994, Zhou & Berglund published the first evidence that RNA could be used as a vaccine to elicit both humoral and cellular immune response against a pathogen.[3][54][55]

Hungarian biochemist Katalin Kariko attempted to solve some of the main technical barriers to introducing mRNA into human cells in the 1990s.[1] Kariko partnered with Drew Weissman, and by 2005 they published a joint paper that solved one of the key technical barriers by using modified nucleosides to get mRNA inside human cells without setting off the body's defense system.[3][1] Harvard stem cell biologist Derrick Rossi (then at Stanford) read Kariko and Weissman's paper and recognized that their work was "groundbreaking",[1] and in 2010 founded the mRNA-focused biotech Moderna along with Robert Langer, who also saw its potential in vaccine development.[1][3] Other mRNA-focused biotechs were formed or re-focused, including CureVac and BioNTech, which licensed Kariko and Weissman's work.[1]

Up until 2020, these mRNA biotech companies had poor results testing mRNA drugs for cardiovascular, metabolic and renal diseases; selected targets for cancer; and rare diseases like Crigler–Najjar syndrome, with most finding that the side-effects of mRNA insertion were too serious.[56][57] mRNA vaccines for human use have been developed and tested for the diseases rabies, Zika, cytomegalovirus, and influenza, although none of these mRNA vaccines have been licensed.[58] Many large pharmaceutical companies abandoned the technology,[56] while some biotechs re-focused on the less profitable area of vaccines, where the doses would be at lower levels and side-effects reduced.[56][59]

Before December 2020, no mRNA drug or vaccine had been licensed for use in humans, but both Moderna and Pfizer/BioNTech were close to securing emergency use authorization for their mRNA-based COVID-19 vaccines, which had been funded by Operation Warp Speed (directly in the case of Moderna and indirectly for Pfizer/BioNTech).[1] On 2 December 2020, seven days after its final eight-week trial, the UK's MHRA, became the first global medicines regulator in history to approve an mRNA vaccine, granting "emergency authorization" for BioNTech/Pfizer's B"Verbeke_2019"62b2 COVID-19 vaccine for widespread use.[8][60] MHRA CEO June Raine said "no corners have been cut in approving it",[61] and that, "the benefits outweigh any risk".[62][63]

Culture and society

Further information: Misinformation related to the COVID-19 pandemic and vaccine hesitancy

The use of RNA-based vaccines has been the basis of substantial misinformation circulated in social media, wrongly claiming that the use of RNA somehow alters a person's DNA, or emphasizing the technology's previously unknown safety record, while ignoring the accumulation of recent evidence from trials involving tens of thousands of people.[10] In November 2020, The Washington Post reported on novel mRNA vaccine hesitancy amongst healthcare professionals in the United States, citing surveys that "some did not want to be in the first round, so they could wait and see if there are potential side effects".[64]

See also

References

  1. ^ a b c d e f g h i Garade D (10 November 2020). "The story of mRNA: How a once-dismissed idea became a leading technology in the Covid vaccine race". Stat. Retrieved 16 November 2020.
  2. ^ Kowalski PS, Rudra A, Miao L, Anderson DG (April 2019). "Delivering the Messenger: Advances in Technologies for Therapeutic mRNA Delivery". Mol Ther. 27 (4): 710–728. doi:10.1016/j.ymthe.2019.02.012. PMC 6453548. PMID 30846391.
  3. ^ a b c d e f g h i Verbeke R, Lentacker I, De Smedt SC, Dewitte H (October 2019). "Three decades of messenger RNA vaccine development". Nano Today. 28: 100766. doi:10.1016/j.nantod.2019.100766.
  4. ^ a b c d e f g h i Pardi N, Hogan MJ, Porter FW, Weissman D (April 2018). "mRNA vaccines – a new era in vaccinology". Nature Reviews. Drug Discovery. 17 (4): 261–279. doi:10.1038/nrd.2017.243. PMC 5906799. PMID 29326426.
  5. ^ a b c d e f g PHG Foundation (2019). "RNA vaccines: an introduction". University of Cambridge. Retrieved 18 November 2020.
  6. ^ a b Kramps T, Elders K (2017). "Introduction to RNA Vaccines". RNA Vaccines: Methods and Protocols. Methods in Molecular Biology. Vol. 1499. pp. 1–11. doi:10.1007/978-1-4939-6481-9_1. ISBN 978-1-4939-6479-6. PMID 27987140. Retrieved 18 November 2020.
  7. ^ a b c d Jaffe-Hoffman M (17 November 2020). "Could mRNA COVID-19 vaccines be dangerous in the long-term?". The Jerusalem Post. Retrieved 17 November 2020.
  8. ^ a b Boseley S, Halliday J (2 December 2020). "UK approves Pfizer/BioNTech Covid vaccine for rollout next week". The Guardian. Retrieved 2 December 2020.
  9. ^ "Conditions of Authorisation for Pfizer/BioNTech COVID-19 Vaccine" (Decision). Medicines & Healthcare Products Regulatory Agency. 8 December 2020.
  10. ^ a b Carmichael F, Goodman J (2 December 2020). "Vaccine rumours debunked: Microchips, 'altered DNA' and more" (Reality Check). BBC.
  11. ^ a b "Seven vital questions about the RNA Covid-19 vaccines emerging from clinical trials". Wellcome Trust. 19 November 2020. Retrieved 26 November 2020.
  12. ^ Fiedler K, Lazzaro S, Lutz J, Rauch S, Heidenreich R (2016). "mRNA Cancer Vaccines". Recent Results in Cancer Research. Fortschritte der Krebsforschung. Progres dans les Recherches Sur le Cancer. Recent Results in Cancer Research. 209: 61–85. doi:10.1007/978-3-319-42934-2_5. ISBN 978-3-319-42932-8. PMID 28101688.
  13. ^ a b Roberts J (1 June 2020). "Five things you need to know about: mRNA vaccines". Horizon. Retrieved 16 November 2020.
  14. ^ Neilson S, Dunn A, Bendix A (26 November 2020). "Moderna's groundbreaking coronavirus vaccine was designed in just 2 days". Business Insider. Retrieved 28 November 2020.
  15. ^ a b c Dolgin E (November 2020). "COVID-19 vaccines poised for launch, but impact on pandemic unclear". Nature Biotechnology. doi:10.1038/d41587-020-00022-y. PMID 33239758. S2CID 227176634.
  16. ^ Carmichael F (15 November 2020). "Vaccine rumours debunked: Microchips, 'altered DNA' and more". BBC News. Retrieved 17 November 2020.
  17. ^ Rahman G (30 November 2020). "RNA Covid-19 vaccines will not change your DNA". Full Fact. Retrieved 1 December 2020.
  18. ^ Vallejo J (18 November 2020). "'What is Covid vaccine made of?' trends on Google as Pfizer and Moderna seek FDA approval". The Independent. Retrieved 3 December 2020.
  19. ^ Benteyn D, Heirman C, Bonehill A, Thielemans K, Breckpot K (February 2015). "mRNA-based dendritic cell vaccines". Expert Review of Vaccines. 14 (2): 161–76. doi:10.1586/14760584.2014.957684. PMID 25196947. S2CID 38292712.
  20. ^ Wolff JA, Malone RW, Williams P, Chong W, Acsadi G, Jani A, Felgner PL (March 1990). "Direct gene transfer into mouse muscle in vivo". Science. 247 (4949 Pt 1): 1465–8. Bibcode:1990Sci...247.1465W. doi:10.1126/science.1690918. PMID 1690918.
  21. ^ "Vaccine components". Immunisation Advisory Centre. 22 September 2016. Retrieved 20 December 2020.
  22. ^ Probst J, Weide B, Scheel B, Pichler BJ, Hoerr I, Rammensee HG, Pascolo S (August 2007). "Spontaneous cellular uptake of exogenous messenger RNA in vivo is nucleic acid-specific, saturable and ion dependent". Gene Therapy. 14 (15): 1175–80. doi:10.1038/sj.gt.3302964. PMID 17476302.
  23. ^ Lorenz C, Fotin-Mleczek M, Roth G, Becker C, Dam TC, Verdurmen WP, et al. (July 2011). "Protein expression from exogenous mRNA: uptake by receptor-mediated endocytosis and trafficking via the lysosomal pathway". RNA Biology. 8 (4): 627–36. doi:10.4161/rna.8.4.15394. PMID 21654214.
  24. ^ Zhou X, Berglund P, Rhodes G, Parker SE, Jondal M, Liljeström P (December 1994). "Self-replicating Semliki Forest virus RNA as recombinant vaccine". Vaccine. 12 (16): 1510–4. doi:10.1016/0264-410x(94)90074-4. PMID 7879415.
  25. ^ a b Berglund P, Smerdou C, Fleeton MN, Tubulekas I, Liljeström P (June 1998). "Enhancing immune responses using suicidal DNA vaccines". Nature Biotechnology. 16 (6): 562–5. doi:10.1038/nbt0698-562. PMID 9624688. S2CID 38532700.
  26. ^ Deering RP, Kommareddy S, Ulmer JB, Brito LA, Geall AJ (June 2014). "Nucleic acid vaccines: prospects for non-viral delivery of mRNA vaccines". Expert Opin Drug Deliv. 11 (6): 885–99. doi:10.1517/17425247.2014.901308. PMID 24665982.
  27. ^ Geall AJ, Verma A, Otten GR, Shaw CA, Hekele A, Banerjee K, Cu Y, Beard CW, Brito LA, Krucker T, O'Hagan DT, Singh M, Mason PW, Valiante NM, Dormitzer PR, Barnett SW, Rappuoli R, Ulmer JB, Mandl CW (September 2012). "Nonviral delivery of self-amplifying RNA vaccines". Proc Natl Acad Sci U S A. 109 (36): 14604–9. doi:10.1073/pnas.1209367109. PMC 3437863. PMID 22908294.
  28. ^ Kreiter S, Selmi A, Diken M, Koslowski M, Britten CM, Huber C, et al. (November 2010). "Intranodal vaccination with naked antigen-encoding RNA elicits potent prophylactic and therapeutic antitumoral immunity". Cancer Research. 70 (22): 9031–40. doi:10.1158/0008-5472.can-10-0699. PMID 21045153.
  29. ^ [non-primary source needed]Weide B, Pascolo S, Scheel B, Derhovanessian E, Pflugfelder A, Eigentler TK, Pawelec G, Hoerr I, Rammensee HG, Garbe C (June 2009). "Direct injection of protamine-protected mRNA: results of a phase 1/2 vaccination trial in metastatic melanoma patients". J Immunother. 32 (5): 498–507. doi:10.1097/CJI.0b013e3181a00068. PMID 19609242. S2CID 3278811.
  30. ^ a b c Cooney E (1 December 2020). "How nanotechnology helps mRNA Covid-19 vaccines work". Stat. Retrieved 3 December 2020.
  31. ^ Reichmuth AM, Oberli MA, Jaklenec A, Langer R, Blankschtein D (May 2016). "mRNA vaccine delivery using lipid nanoparticles". Therapeutic Delivery. 7 (5): 319–34. doi:10.4155/tde-2016-0006. PMC 5439223. PMID 27075952.
  32. ^ Paunovska K, Sago CD, Monaco CM, Hudson WH, Castro MG, Rudoltz TG, et al. (March 2018). "A Direct Comparison of in Vitro and in Vivo Nucleic Acid Delivery Mediated by Hundreds of Nanoparticles Reveals a Weak Correlation". Nano Letters. 18 (3): 2148–2157. Bibcode:2018NanoL..18.2148P. doi:10.1021/acs.nanolett.8b00432. PMC 6054134. PMID 29489381.
  33. ^ Lundstrom K (March 2019). "RNA Viruses as Tools in Gene Therapy and Vaccine Development". Genes. 10 (3): 189. doi:10.3390/genes10030189. PMC 6471356. PMID 30832256.{{cite journal}}: CS1 maint: unflagged free DOI (link)
  34. ^ Huang TT, Parab S, Burnett R, Diago O, Ostertag D, Hofman FM, et al. (February 2015). "Intravenous administration of retroviral replicating vector, Toca 511, demonstrates therapeutic efficacy in orthotopic immune-competent mouse glioma model". Human Gene Therapy. 26 (2): 82–93. doi:10.1089/hum.2014.100. PMC 4326030. PMID 25419577.
  35. ^ Schultz-Cherry S, Dybing JK, Davis NL, Williamson C, Suarez DL, Johnston R, Perdue ML (December 2000). "Influenza virus (A/HK/156/97) hemagglutinin expressed by an alphavirus replicon system protects chickens against lethal infection with Hong Kong-origin H5N1 viruses". Virology. 278 (1): 55–9. doi:10.1006/viro.2000.0635. PMID 11112481.
  36. ^ Geisbert TW, Feldmann H (November 2011). "Recombinant vesicular stomatitis virus-based vaccines against Ebola and Marburg virus infections". The Journal of Infectious Diseases. 204 Suppl 3 (suppl_3): S1075-81. doi:10.1093/infdis/jir349. PMC 3218670. PMID 21987744.
  37. ^ a b Kwon D (25 November 2020). "The Promise of mRNA Vaccines". The Scientist. Retrieved 27 November 2020.
  38. ^ Servick K (27 December 2018). "Can a multibillion-dollar biotech prove its RNA drugs are safe for a rare disease?". Science (journal). doi:10.1126/science.aar8088. Retrieved 19 November 2020.
  39. ^ Wadman M (November 2020). "Public needs to prep for vaccine side effects". Science. 370 (6520): 1022. doi:10.1126/science.370.6520.1022. PMID 33243869.
  40. ^ Gu E (21 May 2020). "This is the hard-to-swallow truth about a future coronavirus vaccine (and yes, I'm a doctor)". The Independent. Retrieved 23 November 2020.
  41. ^ Thomas K (22 October 2020). "Experts Tell F.D.A. It Should Gather More Safety Data on Covid-19 Vaccines". New York Times. Retrieved 21 November 2020.
  42. ^ Kuchler H (30 September 2020). "Pfizer boss warns on risk of fast-tracking vaccines". Financial Times. Retrieved 21 November 2020.
  43. ^ a b Simmons-Duffin S. "Why Does Pfizer's COVID-19 Vaccine Need To Be Kept Colder Than Antarctica?". NPR.org. Retrieved 18 November 2020.
  44. ^ "Moderna Announces Longer Shelf Life for its COVID-19 Vaccine Candidate at Refrigerated Temperatures". NPR.org.
  45. ^ Karikó K, Buckstein M, Ni H, Weissman D (August 2005). "Suppression of RNA recognition by Toll-like receptors: the impact of nucleoside modification and the evolutionary origin of RNA". Immunity. 23 (2): 165–75. doi:10.1016/j.immuni.2005.06.008. PMID 16111635.
  46. ^ Karikó K, Muramatsu H, Ludwig J, Weissman D (November 2011). "Generating the optimal mRNA for therapy: HPLC purification eliminates immune activation and improves translation of nucleoside-modified, protein-encoding mRNA". Nucleic Acids Research. 39 (21): e142. doi:10.1093/nar/gkr695. PMC 3241667. PMID 21890902.
  47. ^ Pardi N, Weissman D (17 December 2016). "Nucleoside Modified mRNA Vaccines for Infectious Diseases". RNA Vaccines. Methods in Molecular Biology. Vol. 1499. Springer New York. pp. 109–121. doi:10.1007/978-1-4939-6481-9_6. ISBN 978-1-4939-6479-6. PMID 27987145.
  48. ^ Schlake T, Thess A, Fotin-Mleczek M, Kallen KJ (November 2012). "Developing mRNA-vaccine technologies". RNA Biology. 9 (11): 1319–30. doi:10.4161/rna.22269. PMC 3597572. PMID 23064118.
  49. ^ Vogel AB, Lambert L, Kinnear E, Busse D, Erbar S, Reuter KC, et al. (February 2018). "Self-Amplifying RNA Vaccines Give Equivalent Protection against Influenza to mRNA Vaccines but at Much Lower Doses". Molecular Therapy. 26 (2): 446–455. doi:10.1016/j.ymthe.2017.11.017. PMC 5835025. PMID 29275847.
  50. ^ Malone RW, Felgner PL, Verma IM (August 1989). "Cationic liposome-mediated RNA transfection". Proceedings of the National Academy of Sciences of the United States of America. 86 (16): 6077–81. doi:10.1073/pnas.86.16.6077. PMC 297778. PMID 2762315.
  51. ^ Pardi, N., Hogan, M., Porter, F. et al. (2018). "mRNA vaccines — a new era in vaccinology", Nature Rev. Drug Discov., 17, pp. 261–279
  52. ^ Sahin U, Karikó K, Türeci Ö (October 2014). "mRNA-based therapeutics--developing a new class of drugs". Nature Reviews. Drug Discovery. 13 (10): 759–80. doi:10.1038/nrd4278. PMID 25233993. S2CID 27454546.
  53. ^ Weissman D (February 2015). "mRNA transcript therapy". Expert Review of Vaccines. 14 (2): 265–81. doi:10.1586/14760584.2015.973859. PMID 25359562. S2CID 39511619.
  54. ^ Pascolo S (August 2004). "Messenger RNA-based vaccines". Expert Opinion on Biological Therapy. 4 (8): 1285–94. doi:10.1517/14712598.4.8.1285. PMID 15268662. S2CID 19350848.
  55. ^ Kallen KJ, Theß A (January 2014). "A development that may evolve into a revolution in medicine: mRNA as the basis for novel, nucleotide-based vaccines and drugs". Therapeutic Advances in Vaccines. 2 (1): 10–31. doi:10.1177/2051013613508729. PMC 3991152. PMID 24757523.
  56. ^ a b c Garde D (10 January 2017). "Lavishly funded Moderna hits safety problems in bold bid to revolutionize medicine". Stat. Archived from the original on 16 November 2020. Retrieved 19 May 2020.
  57. ^ Garade D (13 September 2016). "Ego, ambition, and turmoil: Inside one of biotech's most secretive startups". Stat. Archived from the original on 16 November 2020. Retrieved 18 May 2020.
  58. ^ "COVID-19 and Your Health". Centers for Disease Control and Prevention. 11 February 2020.
  59. ^ Kuznia R, Polglase K, Mezzofiore G (1 May 2020). "In quest for vaccine, US makes 'big bet' on company with unproven technology". CNN Investigates. Archived from the original on 16 November 2020. Retrieved 1 May 2020.
  60. ^ Roberts M (2 December 2020). "Covid Pfizer vaccine approved for use next week in UK". BBC News. Retrieved 2 December 2020.
  61. ^ "UK regulator says it did not cut any corners to approve Pfizer vaccine". Reuters. 2 December 2020. Retrieved 2 December 2020.
  62. ^ "The benefits of the Pfizer/BioNTech vaccine "far outweigh any risk", says Dr June Raine from UK regulator MHRA". BBC News Twittter. 2 December 2020. Retrieved 2 December 2020.
  63. ^ Guarascio F (2 December 2020). "EU criticises 'hasty' UK approval of COVID-19 vaccine". Reuters. Retrieved 2 December 2020.
  64. ^ Rowland C (21 November 2020). "Doctors and nurses want more data before championing vaccines to end the pandemic". Washington Post. Retrieved 22 November 2020.

External links

Scholia has a profile for RNA vaccine (Q85795487).
Retrieved from "https://en.wikipedia.org/w/index.php?title=MRNA_vaccine&oldid=995361902"