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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 [[RNA transfection|transfects]] molecules of [[Nucleoside-modified messenger RNA|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, without harming the host cell.<ref name=STAT1/> The mRNA molecule is coated with a [[drug delivery]] vehicle, usually [[PEGylation|PEGylated]] [[solid lipid nanoparticles|lipid nanoparticles]],<ref name=Stat4/> to protect the fragile mRNA strands and aid their absorption into the human cells.<ref name="Verbeke_2019">{{cite journal | vauthors = Verbeke R, Lentacker I, De Smedt SC, Dewitte H |title=Three decades of messenger RNA vaccine development |journal=Nano Today |date=October 2019 |volume=28 |pages=100766 |doi=10.1016/j.nantod.2019.100766 |url=https://biblio.ugent.be/publication/8628303 }}</ref><ref name=Horizon/>
[[Reactogenicity]], the property of a vaccine of being able to produce common, "expected" adverse reactions, is similar to that of conventional, non-RNA, vaccines.<ref name=NAT1/> People susceptible to an [[autoimmunity|autoimmune response]] may have an adverse reaction to RNA vaccines.<ref name=NAT1/> The advantages of RNA vaccines over traditional protein vaccines are superior design and production speed, lower cost of production,<ref name=PHG1/><ref name="NAT1">{{cite journal|vauthors=Pardi N, Hogan MJ, Porter FW, Weissman D|date=April 2018|title=mRNA vaccines – a new era in vaccinology|journal=Nature Reviews. Drug Discovery|volume=17|issue=4|pages=261–279|doi=10.1038/nrd.2017.243|pmc=5906799|pmid=29326426}}</ref> and the induction of both [[cellular immunity|cellular]] as well as [[humoral immunity]].<ref name="bk1">{{cite book|url=https://link.springer.com/protocol/10.1007%2F978-1-4939-6481-9_1|title=RNA Vaccines: Methods and Protocols|vauthors=Kramps T, Elders K|date=2017|isbn=978-1-4939-6479-6|series=Methods in Molecular Biology|volume=1499|pages=1–11|chapter=Introduction to RNA Vaccines|doi=10.1007/978-1-4939-6481-9_1|pmid=27987140|access-date=18 November 2020}}</ref> A disadvantage is that the fragility of the mRNA molecule requires [[cold chain]] distribution and storage, which may impair [[efficacy|effective efficacy]] due to inadequate dosage when the molecule degrades before injection as the cold chain fails.<ref name="STAT1" /><ref name="PHG1" /><ref name="NAT1" />
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 vaccine]]s: [[mRNA-1273]] from [[Moderna]] and [[Tozinameran]] from a [[BioNTech]]/[[Pfizer]] partnership.<ref name=STAT1/><ref name=JP1/> On 2 December 2020, the United Kingdom's [[Medicines and Healthcare products Regulatory Agency]] (MHRA) became the first [[Regulation of therapeutic goods|medicines regulator]] [[Timeline of human vaccines|in history]] to approve an mRNA vaccine, authorizing BioNTech/Pfizer's [[Tozinameran]] vaccine for widespread use against COVID-19.<ref name=guar2/><ref name=mhra-auth>{{cite web |publisher=Medicines & Healthcare Products Regulatory Agency |url=https://www.gov.uk/government/publications/regulatory-approval-of-pfizer-biontech-vaccine-for-covid-19/conditions-of-authorisation-for-pfizerbiontech-covid-19-vaccine |type=Decision |date=8 December 2020 |title=Conditions of Authorisation for Pfizer/BioNTech COVID-19 Vaccine}}</ref>
The use of RNA in a vaccine has been the basis of substantial [[Misinformation related to the COVID-19 pandemic|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.<ref name=bunk/>
==
{{further|Immune system}}
[[File:RNA_vaccine-en.svg|thumb|upright=1.6|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 [[Oligonucleotide synthesis|synthetically created fragment of the RNA sequence]] of a virus directly into the human cells (known as [[RNA transfection|transfection]]).<ref name="NAT1" /> The cell uses its own internal machinery to produce the specific proteins (viral antigens) encoded by the mRNA strand.<ref name="NAT1" /> These antigens produced by the human cells 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 cell|T-cells]] that recognize specific [[peptide]]s presented on [[Major histocompatibility complex|MHC molecules]].<ref name="WEL1" /> The original cells simply [[Antigen presentation|present the antigen]], and are not targeted by antibodies.
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.<ref name="WEL1">{{cite website | url=https://wellcome.org/news/seven-vital-questions-about-rna-covid-19-vaccines-pfizer-biontech-moderna | title=Seven vital questions about the RNA Covid-19 vaccines emerging from clinical trials | date=19 November 2020 | access-date=26 November 2020 | website=[[Wellcome Trust]]}}</ref><ref name="Horizon" /><ref name="NAT1" /> Another benefit is speed of design and production. Moderna designed their [[MRNA-1273]] vaccine for COVID-19 in 2 days.<ref>{{cite website|date=26 November 2020|title=Moderna's groundbreaking coronavirus vaccine was designed in just 2 days|url=https://www.businessinsider.com/moderna-designed-coronavirus-vaccine-in-2-days-2020-11?r=US&IR=T|access-date=28 November 2020|website=[[Business Insider]]|vauthors=Neilson S, Dunn A, Bendix A}}</ref> Another advantage of RNA vaccines is that since the antigens are produced inside the cell, they stimulate [[cellular immunity]], as well as [[humoral immunity]].<ref name="bk1" /><ref name="nature1" />
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]].<ref name=BBC>{{cite website | website=[[BBC News]] | url=https://www.bbc.com/news/54893437 | title=Vaccine rumours debunked: Microchips, 'altered DNA' and more | vauthors = Carmichael F | date=15 November 2020 | access-date=17 November 2020}}</ref><ref>{{cite website | website=[[Full Fact]] | url=https://fullfact.org/online/rna-vaccine-covid/ | title=RNA Covid-19 vaccines will not change your DNA | date=30 November 2020 | access-date=1 December 2020 | vauthors = Rahman G }}</ref>
The mRNA should [[Messenger_RNA#Degradation|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.<ref>{{cite newspaper | newspaper=[[The Independent]] | date=18 November 2020 | access-date=3 December 2020 | url=https://www.independent.co.uk/news/world/americas/covid-vaccine-ingredients-pfizer-moderna-fda-b1729324.html | title='What is Covid vaccine made of?' trends on Google as Pfizer and Moderna seek FDA approval | vauthors = Vallejo J }}</ref>
== Delivery ==
The methods of [[drug delivery]] can be broadly classified by whether the RNA transfer to cells happens within (''[[in vivo]]'') or outside (''[[ex vivo]]'') the organism.<ref name="Verbeke_2019"/>
===
[[Dendritic cell]]s are a type of immune cells that display antigens on their [[Cell surface|surfaces]], leading to interactions with [[T cell]]s to initiate an immune response. Dendritic cells can be collected from patients and be programmed with mRNA. Then, they can be re-administered back into patients to create an immune response.<ref>{{cite journal | vauthors = Benteyn D, Heirman C, Bonehill A, Thielemans K, Breckpot K | title = mRNA-based dendritic cell vaccines | journal = Expert Review of Vaccines | volume = 14 | issue = 2 | pages = 161–76 | date = February 2015 | pmid = 25196947 | doi = 10.1586/14760584.2014.957684 | s2cid = 38292712 }}</ref>
=== ''In vivo'' ===
Since the discovery of ''[[in vitro]]'' transcribed mRNA expression ''in vivo'' following direct administration, ''in vivo'' approaches have become more and more attractive.<ref>{{cite journal | vauthors = Wolff JA, Malone RW, Williams P, Chong W, Acsadi G, Jani A, Felgner PL | title = Direct gene transfer into mouse muscle in vivo | journal = Science | volume = 247 | issue = 4949 Pt 1 | pages = 1465–8 | date = March 1990 | pmid = 1690918 | doi = 10.1126/science.1690918 | bibcode = 1990Sci...247.1465W }}</ref> 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 be overcome for RNA vaccination to be a potent procedure. [[Evolution|Evolutionary mechanisms]] that prevent the infiltration of unknown [[Nucleic acid|nucleic material]] and promote degradation by [[RNase]]s need to be circumvented in order to initiate translation. In addition, the mobility of RNA on its own is dependent on regular cell processes because it is too heavy to [[Diffusion|diffuse]], which is likely to be eliminated, halting translation.
==== Naked mRNA injection ====
This mode of mRNA uptake has been known for over two decades and the worldwide first clinical studies (Tuebingen, Germany) using direct injections of mRNA for vaccination consisted in injections of naked mRNA in the dermis,<ref>{{cite journal | vauthors = Probst J, Weide B, Scheel B, Pichler BJ, Hoerr I, Rammensee HG, Pascolo S | title = Spontaneous cellular uptake of exogenous messenger RNA in vivo is nucleic acid-specific, saturable and ion dependent | journal = Gene Therapy | volume = 14 | issue = 15 | pages = 1175–80 | date = August 2007 | pmid = 17476302 | doi = 10.1038/sj.gt.3302964 | doi-access = free }}</ref><ref>{{cite journal | vauthors = Lorenz C, Fotin-Mleczek M, Roth G, Becker C, Dam TC, Verdurmen WP, Brock R, Probst J, Schlake T | display-authors = 6 | title = Protein expression from exogenous mRNA: uptake by receptor-mediated endocytosis and trafficking via the lysosomal pathway | journal = RNA Biology | volume = 8 | issue = 4 | pages = 627–36 | date = July 2011 | pmid = 21654214 | doi = 10.4161/rna.8.4.15394 | doi-access = free }}</ref> and the use of RNA as a vaccine tool was discovered in the 1990s in the form of self-amplifying mRNA.<ref>{{cite journal | vauthors = Zhou X, Berglund P, Rhodes G, Parker SE, Jondal M, Liljeström P | title = Self-replicating Semliki Forest virus RNA as recombinant vaccine | journal = Vaccine | volume = 12 | issue = 16 | pages = 1510–4 | date = December 1994 | pmid = 7879415 | doi = 10.1016/0264-410x(94)90074-4 }}</ref><ref name = "Berglund_1998">{{cite journal | vauthors = Berglund P, Smerdou C, Fleeton MN, Tubulekas I, Liljeström P | title = Enhancing immune responses using suicidal DNA vaccines | journal = Nature Biotechnology | volume = 16 | issue = 6 | pages = 562–5 | date = June 1998 | pmid = 9624688 | doi = 10.1038/nbt0698-562 | s2cid = 38532700 }}</ref> It has also emerged that the different routes of [[Injection (medicine)|injection]], such as into the [[skin]], [[blood]] or to [[muscle]]s, resulted in varying levels of mRNA uptake, making the choice of administration route a critical aspect of delivery. Kreiter et al. demonstrated, in comparing different routes, that [[lymph node]] injection leads to the largest T cell response.<ref>{{cite journal | vauthors = Kreiter S, Selmi A, Diken M, Koslowski M, Britten CM, Huber C, Türeci O, Sahin U | display-authors = 6 | title = Intranodal vaccination with naked antigen-encoding RNA elicits potent prophylactic and therapeutic antitumoral immunity | journal = Cancer Research | volume = 70 | issue = 22 | pages = 9031–40 | date = November 2010 | pmid = 21045153 | doi = 10.1158/0008-5472.can-10-0699 | doi-access = free }}</ref> The mechanisms and consequently the evaluation of self-amplifying mRNA could be different, as they are fundamentally different by being a much bigger molecule in size.<ref name="Verbeke_2019" />
====
[[Cationic polymerization|Cationic polymer]]s can be mixed with mRNA to generate [[Vectors in gene therapy#Polyplexes|polyplexes]] that protect the recombinant mRNA from [[ribonuclease]]s and assist its penetration in cells. [[Protamine]] is a natural cationic peptide and has been used to complex mRNA for vaccination.{{primary-source inline|date=December 2020}}<ref>{{primary-source inline|date=December 2020}}{{cite journal |vauthors=Weide B, Pascolo S, Scheel B, Derhovanessian E, Pflugfelder A, Eigentler TK, Pawelec G, Hoerr I, Rammensee HG, Garbe C |title=Direct injection of protamine-protected mRNA: results of a phase 1/2 vaccination trial in metastatic melanoma patients |journal=J Immunother |volume=32 |issue=5 |pages=498–507 |date=June 2009 |pmid=19609242 |doi=10.1097/CJI.0b013e3181a00068 |url=}}</ref>
==== Lipid nanoparticles ====
The first time the FDA approved the use of [[solid lipid nanoparticles|lipid nanoparticles]] as a drug delivery system was in 2018, when the agency approved the first [[Small interfering RNA|siRNA]] drug, [[Onpattro]].<ref name=Stat4>{{cite website | website=[[Stat (website)|Stat]] | date=1 December 2020 | access-date=3 December 2020 | url=https://www.statnews.com/2020/12/01/how-nanotechnology-helps-mrna-covid19-vaccines-work/ | title=How nanotechnology helps mRNA Covid-19 vaccines work | vauthors = Cooney E }}</ref> 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.<ref name=Stat4/><ref>{{cite journal | vauthors = Reichmuth AM, Oberli MA, Jaklenec A, Langer R, Blankschtein D | title = mRNA vaccine delivery using lipid nanoparticles | journal = Therapeutic Delivery | volume = 7 | issue = 5 | pages = 319–34 | date = May 2016 | pmid = 27075952 | pmc = 5439223 | doi = 10.4155/tde-2016-0006 }}</ref> Principally, the [[Lipid bilayer|lipid]] provides a layer of protection against degradation, allowing more robust translational output. In addition, the customization of the lipid 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.<ref>{{cite journal | vauthors = Paunovska K, Sago CD, Monaco CM, Hudson WH, Castro MG, Rudoltz TG, Kalathoor S, Vanover DA, Santangelo PJ, Ahmed R, Bryksin AV, Dahlman JE | display-authors = 6 | title = A Direct Comparison of in Vitro and in Vivo Nucleic Acid Delivery Mediated by Hundreds of Nanoparticles Reveals a Weak Correlation | journal = Nano Letters | volume = 18 | issue = 3 | pages = 2148–2157 | date = March 2018 | pmid = 29489381 | pmc = 6054134 | doi = 10.1021/acs.nanolett.8b00432 | bibcode = 2018NanoL..18.2148P }}</ref> The nanoparticles can be administered to the body and transported via multiple routes, such as [[Intravenous therapy|intravenously]] or through the [[lymphatic system]].<ref name=Stat4/>
===
{{further|Viral vector}}
In addition to non-viral delivery methods, [[RNA virus]]es have been [[Biological engineering|engineered]] to achieve similar immunological responses. Typical RNA viruses used as vectors include [[retrovirus]]es, [[lentivirus]]es, [[alphavirus]]es and [[Rhabdoviridae|rhabdoviruses]], each of which can differ in structure and function.<ref>{{cite journal | vauthors = Lundstrom K | title = RNA Viruses as Tools in Gene Therapy and Vaccine Development | journal = Genes | volume = 10 | issue = 3 | pages = 189 | date = March 2019 | pmid = 30832256 | pmc = 6471356 | doi = 10.3390/genes10030189 }}</ref> Clinical studies have utilized such viruses on a range of diseases in [[Model organism|model animals]] such as [[Mouse|mice]], [[chicken]] and [[primate]]s.<ref>{{cite journal | vauthors = Huang TT, Parab S, Burnett R, Diago O, Ostertag D, Hofman FM, Espinoza FL, Martin B, Ibañez CE, Kasahara N, Gruber HE, Pertschuk D, Jolly DJ, Robbins JM | display-authors = 6 | title = Intravenous administration of retroviral replicating vector, Toca 511, demonstrates therapeutic efficacy in orthotopic immune-competent mouse glioma model | journal = Human Gene Therapy | volume = 26 | issue = 2 | pages = 82–93 | date = February 2015 | pmid = 25419577 | pmc = 4326030 | doi = 10.1089/hum.2014.100 }}</ref><ref>{{cite journal | vauthors = Schultz-Cherry S, Dybing JK, Davis NL, Williamson C, Suarez DL, Johnston R, Perdue ML | title = Influenza virus (A/HK/156/97) hemagglutinin expressed by an alphavirus replicon system protects chickens against lethal infection with Hong Kong-origin H5N1 viruses | journal = Virology | volume = 278 | issue = 1 | pages = 55–9 | date = December 2000 | pmid = 11112481 | doi = 10.1006/viro.2000.0635 }}</ref><ref>{{cite journal | vauthors = Geisbert TW, Feldmann H | title = Recombinant vesicular stomatitis virus-based vaccines against Ebola and Marburg virus infections | journal = The Journal of Infectious Diseases | volume = 204 Suppl 3 | issue = suppl_3 | pages = S1075-81 | date = November 2011 | pmid = 21987744 | pmc = 3218670 | doi = 10.1093/infdis/jir349 }}</ref>
==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.<ref name=NS1/> [[Physician-scientist]] [[Margaret A. Liu|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 [[Nucleoside-modified messenger RNA|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 fevers were believed to be reactogenic effects from the lipid drug delivery molecules).<ref name=NS1>{{cite magazine | url=https://www.the-scientist.com/news-opinion/the-promise-of-mrna-vaccines-68202 | title=The Promise of mRNA Vaccines | date=25 November 2020 | access-date=27 November 2020 | vauthors = Kwon D | magazine=[[The Scientist (magazine)|The Scientist]]}}</ref>
In addition to the efficacy of potential mRNA vaccines under clinical trial conditions, the ''effective efficacy'' of distributed mRNA vaccines could also be hard to sustain at high levels.<ref name=NS1/> 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.<ref name=JP1>{{cite newspaper | url=https://www.jpost.com/health-science/could-an-mrna-vaccine-be-dangerous-in-the-long-term-649253 | title=Could mRNA COVID-19 vaccines be dangerous in the long-term? | vauthors = Jaffe-Hoffman M | newspaper=[[The Jerusalem Post]] | date=17 November 2020 | access-date=17 November 2020 }}</ref> Outside of the human cell, or its drug delivery system, the mRNA molecule is also quickly broken down by the human body.<ref name=PHG1/> This fragility of the mRNA molecule is a hurdle to the ''effective 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.<ref name=JP1/><ref name=PHG1/>
== Side effects and risks ==
[[Reactogenicity]] is similar to that of conventional, non-RNA vaccines. However, those susceptible to an [[autoimmunity|autoimmune response]] may have an adverse reaction to RNA vaccines.<ref name=NAT1/> 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.<ref name=PHG1>{{cite web |title=RNA vaccines: an introduction | url=https://www.phgfoundation.org/briefing/rna-vaccines | website=[[University of Cambridge]] | author=PHG Foundation | access-date=18 November 2020 | date=2019}}</ref>
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 [[PEGylation|PEGylated]] [[solid lipid nanoparticles|lipid nanoparticles]] that can be trigger their own immune reactions, and cause damage to the liver at higher doses.<ref>{{cite journal | url=https://www.sciencemag.org/news/2017/12/can-multibillion-dollar-biotech-prove-its-rna-drugs-are-safe-rare-disease | title=Can a multibillion-dollar biotech prove its RNA drugs are safe for a rare disease? | vauthors = Servick K | date=27 December 2018 | access-date=19 November 2020 | journal=[[Science (journal)]] | doi=10.1126/science.aar8088 }}</ref> Strong reactogenic effects were reported in trials of novel COVID-19 RNA vaccines.<ref>{{cite journal | vauthors = Wadman M | title = Public needs to prep for vaccine side effects | journal = Science | volume = 370 | issue = 6520 | pages = 1022 | date = November 2020 | pmid = 33243869 | doi = 10.1126/science.370.6520.1022 }}</ref>{{Example needed|date=December 2020}}
==
Before 2020, no mRNA technology platform (drug or vaccine) had been authorized for use in humans, so there was a risk of unknown effects,<ref name=nature1/> both short- and longer-term (such as autoimmune responses or diseases).{{better source|date=December 2020}}<ref name=Horizon>{{cite magazine | url=https://horizon-magazine.eu/article/five-things-you-need-know-about-mrna-vaccines.html | title=Five things you need to know about: mRNA vaccines | magazine=[[Horizon (online magazine)|Horizon]] | date=1 June 2020 | access-date=16 November 2020 | vauthors = Roberts J }}</ref><ref name=JP1/><ref name=IND1>{{cite newspaper | url=https://www.independent.co.uk/voices/coronavirus-vaccine-covid-19-cure-doctor-moderna-novavax-oxford-a9523091.html | newspaper=[[The Independent]] | title=This is the hard-to-swallow truth about a future coronavirus vaccine (and yes, I'm a doctor) | vauthors = Gu E | author-link1 = Eugene Gu | date=21 May 2020 | access-date=23 November 2020}}</ref> 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 |expanded access authorization]]) after the eight-week period of post-final human trials.<ref name=nyt9>{{cite newspaper | newspaper =[[New York Times]] | url=https://www.nytimes.com/2020/10/22/health/covid-vaccine-fda-advisory-committee.html | title=Experts Tell F.D.A. It Should Gather More Safety Data on Covid-19 Vaccines | vauthors = Thomas K | date=22 October 2020 | access-date=21 November 2020}}</ref><ref name=ft8>{{cite newspaper | newspaper=[[Financial Times]] | url=https://www.ft.com/content/1a91c897-66d5-4bd5-ae9b-0b3be185dac8 | title=Pfizer boss warns on risk of fast-tracking vaccines | vauthors = Kuchler H | date=30 September 2020 | access-date=21 November 2020}}</ref>
===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 {{convert|-70|C|F}}.<ref name = "Simmons-Duffin_2020">{{cite web | vauthors = Simmons-Duffin S |title=Why Does Pfizer's COVID-19 Vaccine Need To Be Kept Colder Than Antarctica? |url=https://www.npr.org/sections/health-shots/2020/11/17/935563377/why-does-pfizers-covid-19-vaccine-need-to-be-kept-colder-than-antarctica |website=NPR.org |access-date=18 November 2020 |language=en}}</ref> Moderna say their [[MRNA-1273]] vaccine can be stored at {{convert|-20|C|F}}, which is comparable to a home freezer,<ref name = "Simmons-Duffin_2020" /> and that it remains stable between {{convert|2|and|8|C}}.<ref>{{cite web |title=Moderna Announces Longer Shelf Life for its COVID-19 Vaccine Candidate at Refrigerated Temperatures |url=https://investors.modernatx.com/news-releases/news-release-details/moderna-announces-longer-shelf-life-its-covid-19-vaccine |website=NPR.org |language=en}}</ref> In November 2020, ''[[Nature (journal)|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."<ref name=nature1>{{cite journal | vauthors = Dolgin E | title = COVID-19 vaccines poised for launch, but impact on pandemic unclear | journal = Nature Biotechnology | date = November 2020 | pmid = 33239758 | doi = 10.1038/d41587-020-00022-y | url = https://www.nature.com/articles/d41587-020-00022-y | s2cid = 227176634 }}</ref>
=== Traditional vaccines ===
RNA vaccines offer specific advantages over traditional [[Vaccine|protein vaccines]].<ref name=PHG1/><ref name=NAT1/> 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.<ref name=PHG1/> 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.<ref name=NAT1/><ref name=PHG1/>
===
In addition to sharing the advantages of theoretical [[DNA vaccine]]s over established traditional [[Vaccine|protein vaccines]], RNA vaccination offers other benefits. The [[Messenger RNA|mRNA]] is [[Translation (biology)|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.<ref name="Verbeke_2019" /> [[Nucleoside analogue|Modified nucleosides]] (for example, [[pseudouridine]]s, 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.<ref>{{cite journal | vauthors = Karikó K, Buckstein M, Ni H, Weissman D | title = Suppression of RNA recognition by Toll-like receptors: the impact of nucleoside modification and the evolutionary origin of RNA | journal = Immunity | volume = 23 | issue = 2 | pages = 165–75 | date = August 2005 | pmid = 16111635 | doi = 10.1016/j.immuni.2005.06.008 }}</ref><ref>{{cite journal | vauthors = Karikó K, Muramatsu H, Ludwig J, Weissman D | title = Generating the optimal mRNA for therapy: HPLC purification eliminates immune activation and improves translation of nucleoside-modified, protein-encoding mRNA | journal = Nucleic Acids Research | volume = 39 | issue = 21 | pages = e142 | date = November 2011 | pmid = 21890902 | pmc = 3241667 | doi = 10.1093/nar/gkr695 }}</ref><ref>{{cite book | vauthors = Pardi N, Weissman D | title = RNA Vaccines | chapter = Nucleoside Modified mRNA Vaccines for Infectious Diseases | series = Methods in Molecular Biology | volume = 1499 | pages = 109–121 | date = 17 December 2016 | pmid = 27987145 | doi = 10.1007/978-1-4939-6481-9_6 | publisher = Springer New York | isbn = 978-1-4939-6479-6 }}</ref> The [[Open reading frame|open reading frame (ORF)]] and [[Untranslated region|untranslated regions (UTR)]] of mRNA can be optimized for different purposes (a process called sequence engineering of mRNA), for example through enriching the [[GC-content|guanine-cytosine content]] or choosing specific UTRs known to increase translation.<ref>{{cite journal | vauthors = Schlake T, Thess A, Fotin-Mleczek M, Kallen KJ | title = Developing mRNA-vaccine technologies | journal = RNA Biology | volume = 9 | issue = 11 | pages = 1319–30 | date = November 2012 | pmid = 23064118 | pmc = 3597572 | doi = 10.4161/rna.22269 }}</ref>
An additional ORF coding for a [[RNA replication|replication]] mechanism can be added to amplify antigen translation and therefore immune response, decreasing the amount of starting material needed.<ref name = "Berglund_1998" /><ref>{{cite journal | vauthors = Vogel AB, Lambert L, Kinnear E, Busse D, Erbar S, Reuter KC, Wicke L, Perkovic M, Beissert T, Haas H, Reece ST, Sahin U, Tregoning JS | display-authors = 6 | title = Self-Amplifying RNA Vaccines Give Equivalent Protection against Influenza to mRNA Vaccines but at Much Lower Doses | journal = Molecular Therapy | volume = 26 | issue = 2 | pages = 446–455 | date = February 2018 | pmid = 29275847 | pmc = 5835025 | doi = 10.1016/j.ymthe.2017.11.017 }}</ref>
==History==
Researchers at the [[Salk Institute for Biological Studies|Salk Institute]], [[University of California, San Diego|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 [[RNA transfection|transfect]] mRNA into a variety of [[eukaryotic cell]]s.<ref>{{cite journal | vauthors = Malone RW, Felgner PL, Verma IM | title = Cationic liposome-mediated RNA transfection | journal = Proceedings of the National Academy of Sciences of the United States of America | volume = 86 | issue = 16 | pages = 6077–81 | date = August 1989 | pmid = 2762315 | pmc = 297778 | doi = 10.1073/pnas.86.16.6077 }}</ref> 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.<ref name="Verbeke_2019"/> These studies were the first evidence that in vitro transcribed (IVT) mRNA could deliver the genetic information to produce proteins within living cell tissue.<ref name="Verbeke_2019"/>
The use of RNA vaccines goes back to the early 1990s. The ''in vitro'' demonstration of mRNA in animals was first reported in 1990,<ref name=Pardi2018>Pardi, N., Hogan, M., Porter, F. ''et al.'' (2018). "[https://doi.org/10.1038/nrd.2017.243https://www.nature.com/articles/nrd.2017.243 mRNA vaccines — a new era in vaccinology"], ''Nature Rev. Drug Discov., 17'', pp. 261–279</ref> and use as immunization proposed shortly thereafter.<ref name="pmid25233993">{{cite journal | vauthors = Sahin U, Karikó K, Türeci Ö | title = mRNA-based therapeutics--developing a new class of drugs | journal = Nature Reviews. Drug Discovery | volume = 13 | issue = 10 | pages = 759–80 | date = October 2014 | pmid = 25233993 | doi = 10.1038/nrd4278 }}</ref><ref name="pmid25359562">{{cite journal | vauthors = Weissman D | title = mRNA transcript therapy | journal = Expert Review of Vaccines | volume = 14 | issue = 2 | pages = 265–81 | date = February 2015 | pmid = 25359562 | doi = 10.1586/14760584.2015.973859 }}</ref> In 1993, Martinon demonstrated that lipsome-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.<ref name="Verbeke_2019" /><ref>{{cite journal | vauthors = Pascolo S | title = Messenger RNA-based vaccines | journal = Expert Opinion on Biological Therapy | volume = 4 | issue = 8 | pages = 1285–94 | date = August 2004 | pmid = 15268662 | doi = 10.1517/14712598.4.8.1285 | s2cid = 19350848 }}</ref><ref>{{cite journal | vauthors = Kallen KJ, Theß A | title = A development that may evolve into a revolution in medicine: mRNA as the basis for novel, nucleotide-based vaccines and drugs | journal = Therapeutic Advances in Vaccines | volume = 2 | issue = 1 | pages = 10–31 | date = January 2014 | pmid = 24757523 | pmc = 3991152 | doi = 10.1177/2051013613508729 }}</ref>
[[Hungarians|Hungarian]] [[biochemist]] [[Katalin Kariko]] attempted to solve some of the main technical barriers to introducing mRNA into human cells in the 1990s.<ref name=STAT1>{{cite website | website=[[Stat (website)|Stat]] | date=10 November 2020 | access-date=16 November 2020 | vauthors = Garade D | url=https://www.statnews.com/2020/11/10/the-story-of-mrna-how-a-once-dismissed-idea-became-a-leading-technology-in-the-covid-vaccine-race/ | title=The story of mRNA: How a once-dismissed idea became a leading technology in the Covid vaccine race}}</ref> Kariko partnered with [[Drew Weissman]], and by 2005 they published a joint paper that solved one of the key technical barriers by using [[Nucleoside analogue|modified nucleosides]] to get mRNA inside human cells without setting off the body's defense system.<ref name="Verbeke_2019"/><ref name=STAT1/> In 2005, [[Harvard]] [[stem cell]] biologist [[Derrick Rossi]] stated that their paper was "groundbreaking" and that they deserved the [[Nobel Prize in Chemistry]].<ref name=STAT1/> In 2010, Rossi founded the mRNA-focused biotech [[Moderna]], along with [[Robert S. Langer|Robert Langer]], who saw its potential in vaccine development.<ref name=STAT1/><ref name="Verbeke_2019"/> Other mRNA-focused biotechs were formed or re-focused, including [[CureVac]] and [[BioNTech]], which licensed Kariko and Weissman's work.<ref name=STAT1/>
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.<ref name=ST1/><ref name=ST>{{cite website | url=https://www.statnews.com/2016/09/13/moderna-therapeutics-biotech-mrna/ | title=Ego, ambition, and turmoil: Inside one of biotech's most secretive startups | vauthors = Garade D | date=13 September 2016 | access-date=18 May 2020 | website=[[Stat (website)|Stat]] | archive-date=16 November 2020 | archive-url= https://web.archive.org/web/20201116154313/https://www.statnews.com/2016/09/13/moderna-therapeutics-biotech-mrna/ | url-status=live }}</ref> mRNA vaccines for human use have been developed and tested for the diseases [[rabies]], [[Zika]], [[cytomegalovirus]], and [[influenza]], although none of these had previously been adopted for widespread use.<ref>{{cite web | vauthors = Fiore K | date = 3 December 2020 | title = Want to Know More About mRNA Before Your COVID Jab? — A primer on the history, scope, and safety of mRNA vaccines and therapeutics | url = https://www.medpagetoday.com/infectiousdisease/covid19/89998 | work = Medpagetoday.com }}</ref> Many large pharmaceutical companies abandoned the technology,<ref name=ST1/> while some biotechs re-focused on the less profitable area of vaccines, where the doses would be at lower levels and side-effects reduced.<ref name=ST1>{{cite website | url=https://www.statnews.com/2017/01/10/moderna-trouble-mrna/ | title=Lavishly funded Moderna hits safety problems in bold bid to revolutionize medicine | vauthors = Garde D | website=[[Stat (website)|Stat]] | date=10 January 2017 | access-date=19 May 2020 | archive-date=16 November 2020 | archive-url=https://web.archive.org/web/20201116154151/https://www.statnews.com/2017/01/10/moderna-trouble-mrna/ | url-status=live }}</ref><ref name=CNN>{{cite web | vauthors = Kuznia R, Polglase K, Mezzofiore G |title=In quest for vaccine, US makes 'big bet' on company with unproven technology |url=https://edition.cnn.com/2020/05/01/us/coronavirus-moderna-vaccine-invs/index.html |access-date=1 May 2020 |website=CNN Investigates |date=1 May 2020 |archive-date=16 November 2020 |archive-url=https://web.archive.org/web/20201116154315/https://edition.cnn.com/2020/05/01/us/coronavirus-moderna-vaccine-invs/index.html |url-status=live }}</ref>
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).<ref name=STAT1/> On 2 December 2020, seven days after its final eight-week trial, the UK's [[Medicines and Healthcare products Regulatory Agency|MHRA]], became the first global medicines regulator [[Timeline of human vaccines|in history]] to approve an mRNA vaccine, granting "emergency authorization" for BioNTech/Pfizer's B"Verbeke_2019"62b2 COVID-19 vaccine for widespread use.<ref name=guar2>{{cite newspaper | newspaper=[[The Guardian]] | url=https://www.theguardian.com/society/2020/dec/02/pfizer-biontech-covid-vaccine-wins-licence-for-use-in-the-uk | title=UK approves Pfizer/BioNTech Covid vaccine for rollout next week | vauthors = Boseley S, Halliday J | date=2 December 2020 | access-date=2 December 2020}}</ref><ref name=BBC7>{{Cite news|date=2 December 2020|title=Covid Pfizer vaccine approved for use next week in UK|language=en-GB|work=BBC News|url= https://www.bbc.com/news/health-55145696|access-date=2 December 2020 | vauthors = Roberts M }}</ref> MHRA CEO [[June Raine]] said "no corners have been cut in approving it",<ref>{{cite website| website=[[Reuters]] | url=https://www.reuters.com/article/uk-health-coronavirus-britain-vaccine-re/uk-regulator-says-it-did-not-cut-any-corners-to-approve-pfizer-vaccine-idUSKBN28C1AB | title=UK regulator says it did not cut any corners to approve Pfizer vaccine | date=2 December 2020 | access-date=2 December 2020}}</ref> and that, "the benefits outweigh any risk".<ref name=BBC8>{{cite website| website=BBC News Twittter| url=https://twitter.com/BBCNews/status/1334084332500226049 | title=The benefits of the Pfizer/BioNTech vaccine "far outweigh any risk", says Dr June Raine from UK regulator MHRA | date=2 December 2020 | access-date=2 December 2020}}</ref><ref name=Reuters>{{cite website | website=[[Reuters]] | url=https://www.reuters.com/article/uk-health-coronavirus-britain-eu/eu-lawmaker-warns-of-risks-from-uk-hasty-approval-of-pfizer-covid-vaccine-idUKKBN28C12X | title=EU criticises 'hasty' UK approval of COVID-19 vaccine | vauthors = Guarascio F | date=2 December 2020 | access-date=2 December 2020}}</ref>
==
{{Further|Misinformation related to the COVID-19 pandemic|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.<ref name=bunk>{{cite news |publisher=BBC |type=Reality Check |title=Vaccine rumours debunked: Microchips, 'altered DNA' and more |vauthors=Carmichael F, Goodman J |url=https://www.bbc.co.uk/news/54893437 |date=2 December 2020}}</ref> 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".<ref name=WP4>{{cite newspaper | newspaper=[[Washington Post]] | url=https://www.washingtonpost.com/business/2020/11/21/vaccines-advocates-nurses-doctors-coronavirus/ | title=Doctors and nurses want more data before championing vaccines to end the pandemic | vauthors = Rowland C | date=21 November 2020 | access-date=22 November 2020}}</ref>
==
*[[Arcturus Therapeutics#LUNAR-COV19|LUNAR-COV19]], mRNA vaccine from [[Arcturus Therapeutics]]
*[[CureVac|CVnCoV]], mRNA vaccine from [[CureVac]]
*[[Timeline of human vaccines]]
== References ==
{{Reflist}}
== External links ==
{{scholia}}
* {{cite web | vauthors = Roberts J | url = https://horizon-magazine.eu/article/five-things-you-need-know-about-mrna-vaccines.html | title = Five things you need to know about: mRNA vaccines | work = [[Horizon (online magazine)|Horizon]] | date = June 2020 }}
* {{cite web | url = https://www.phgfoundation.org/briefing/rna-vaccines | title = RNA vaccines: an introduction | work = PHG Foundation | publisher = [[University of Cambridge]] | date = October 2020 |vauthors= Blackburn L |ref=Blackburn }}
* {{cite web | url = https://www.cdc.gov/coronavirus/2019-ncov/vaccines/different-vaccines/mrna.html | title = Understanding mRNA COVID-19 Vaccines] | publisher = [[Centers for Disease Control and Prevention]] | date = November 2020 }}
* {{cite web | url = https://www.gov.uk/government/news/uk-authorises-pfizer-biontech-covid-19-vaccine | title = UK authorises Pfizer/BioNTech COVID-19 vaccine | publisher = [[Department of Health and Social Care]] | date = 2 December 2020 }}
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