Jump to content

MRNA vaccine: Difference between revisions

From Wikipedia, the free encyclopedia
Browse history interactively
← Previous editNext edit →
Content deleted Content added
VisualWikitext
→top: summarize some
Line 9: Line 9:
The fragility of the mRNA molecule requires [[cold chain]] distribution and storage, which may impair [[efficacy|effective efficacy]] due to inadequate dosage (i.e molecule degrades before injection).<ref name="STAT1" /><ref name="PHG1" /><ref name="NAT1" />
The fragility of the mRNA molecule requires [[cold chain]] distribution and storage, which may impair [[efficacy|effective efficacy]] due to inadequate dosage (i.e molecule degrades before injection).<ref name="STAT1" /><ref name="PHG1" /><ref name="NAT1" />


{{asof|December 2020}}, there were two novel mRNA vaccines awaiting [[emergency use authorization]] as [[COVID-19 vaccine]]s (having completed the required eight-week period post final human trials) – [[mRNA-1273]] from [[Moderna]], and [[BNT162b2]] from a [[BioNTech]]/[[Pfizer]] partnership.<ref name=STAT1/><ref name=JP1/>
{{asof|December 2020}}, there were two novel mRNA vaccines awaiting [[emergency use authorization]] as [[COVID-19 vaccine]]s (having completed the required eight-week period post final human trials) – [[mRNA-1273]] from [[Moderna]], and [[BNT162b2]] 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 COVID-19 vaccine for "widespread use".<ref name=guar2/><ref name=mhra-auth>{{cite web |publisher=Medicines &amp; 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 has been the basis of [[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 tens of thousands of people.<ref name=bunk/>
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 COVID-19 vaccine for "widespread use".<ref name=guar2/><ref name=mhra-auth>{{cite web |publisher=Medicines &amp; 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>


==Efficacy==
==Efficacy==

Revision as of 05:50, 10 December 2020

See also: DNA vaccine, RNA therapeutics, and Nucleoside-modified messenger RNA
An illustration of the mechanism of action of the RNA vaccine

An RNA vaccine or mRNA (messenger RNA) vaccine is a type of vaccine that transfects molecules of synthetic RNA into human cells. Once inside the cells, the RNA functions as mRNA, and the cells then make the foreign protein that would normally be produced by the pathogen (e.g. a virus), or by cancer cells. These protein molecules then stimulate an adaptive immune response that teaches the body to destroy any pathogen, or cancer cells, with the protein.[1] The mRNA molecule is coated with a drug delivery vehicle, usually PEGylated lipid nanoparticles,[2] to protect the fragile mRNA strands, and aid their absorption into the human cells.[3][4]

The advantages of RNA vaccines over traditional protein vaccines are design and production speed, low cost of production,[5][6] and the induction of cellular immunity as well as humoral immunity.[7] Autoimmunity, and reactogenicity (mainly from the lipid nanoparticles), have been highlighted as possible side-effects.[6]

The fragility of the mRNA molecule requires cold chain distribution and storage, which may impair effective efficacy due to inadequate dosage (i.e molecule degrades before injection).[1][5][6]

As of December 2020, there were two novel mRNA vaccines awaiting emergency use authorization as COVID-19 vaccines (having completed the required eight-week period post final human trials) – mRNA-1273 from Moderna, and BNT162b2 from a BioNTech/Pfizer partnership.[1][8] On 2 December 2020 the United Kingdom's Medicines and Healthcare products Regulatory Agency (MHRA), became the first medicines regulator in history to approve an mRNA vaccine, authorizing BioNTech/Pfizer's COVID-19 vaccine for "widespread use".[9][10]

The use of RNA has been the basis of 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 tens of thousands of people.[11]

Efficacy

Scientists were also not clear as to why the novel mRNA COVID-19 vaccines from Moderna and BioNTect/Pfizer have shown potential high efficacy rates of 90 to 95 percent (from their November press releases), when the prior mRNA drug trials on other pathogens (i.e. other than COVID-19), were not so promising and had to be abandoned in the early phases of trials.[12] Virologist 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 fevers were believed to be reactogenic effects from the lipid drug delivery molecules).[12]

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.[12] 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.[8] 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 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.[8][5]

Mechanism

Theory

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), or an attenuated virus, or a recombinant antigen-encoding viral vector. These ingredients are prepared and grown outside of the human body, which takes time, and even when they are injected into the bloodstream, they do not enter the human cell. In contrast, mRNA vaccines transfect a synthetically created fragment of the RNA sequence of a virus directly into the human cells (known as transfection), which causes the cells to produce their own viral antigens, which then stimulate an adaptive immune response, resulting in the production of new antibodies which bind to the antigen and activate T-cells that recognize specific peptides presented on MHC molecules.[13] In addition, mRNA is not grown, but can be designed and manufactured quicker in a biochemical synthesis.[13][4][6]

mRNA vaccines do not affect or reprogram the DNA inside the cell – the synthetic mRNA fragment is a copy of the specific part of the virus RNA that carries the instructions to build the antigen of the virus (a protein spike, in the case of the main coronavirus mRNA vaccines); this misconception became a debunked conspiracy theory regarding mRNA vaccines, as the COVID-19 mRNA vaccines came to public prominence.[14][15]

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) are held confidential by the manufacturers of the candidate mRNA vaccines, such details and timings remain to be confirmed by further study.[16]

Speed of design and production is an important advantage of mRNA vaccines; Moderna designed their MRNA-1273 vaccine in 2 days.[17] Another advantage of RNA vaccines is that since the antigens are produced inside the cell, they stimulate cellular immunity, as well as humoral immunity.[7][18]

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.[3]

Ex vivo

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

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.[20] They offer some advantages over ex vivo methods, particularly by avoiding the cost of harvesting and adapting DCs 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. 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, the mobility of RNA on its own is dependent on regular cell processes because it is too heavy to 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 https://pubmed.ncbi.nlm.nih.gov/18481387/ https://pubmed.ncbi.nlm.nih.gov/21189474/,[21][22] and the use of RNA as a vaccine tool was discovered in the 1990s in the form of self-amplifying mRNA.[23][24] 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. Kreiter et al. demonstrated, in comparing different routes, that lymph node injection leads to the largest T cell response.[25] 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.[3]

Polyplexes

Cationic polymers can be mixed with mRNA to generate polyplexes that protect the recombinant mRNA from RNases and assist its penetration in cells. Protamine is a natural cationic peptide and was used to complex mRNA for vaccination. One of the first clinical study using direct injection of mRNA used mRNA-Protamine complexes https://pubmed.ncbi.nlm.nih.gov/19609242/.

Lipid nanoparticles

In 2018, the first siRNA drug, Onpattro, was approved by the FDA to use lipid nanoparticles as the drug delivery system for the first time.[2] Encapsulating the mRNA molecule in lipid nanoparticles was a critical breakthrough for producing viable mRNA vaccines, solving a number of key techical barriers in delivering the mRNA molecule into the human cell.[2][26] Principally, the 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.[27] The nanoparticles can be administered to the body and transported via multiple routes, such as intravenously or through the lymphatic system.[2]

Viral vectors

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.[28] Clinical studies have utilized such viruses on a range of diseases in model animals such as mice, chicken and primates.[29][30][31]

Side effects and risks

Specific

  • mRNA strands in the vaccine may elicit an unintended immune reaction; to minimize this, mRNA vaccine sequences are designed to mimic those produced by mammalian cell (i.e. human cells).[5]
  • The drug delivery system holding the mRNA molecule (protecting the fragile mRNA strands from being broken down before they enter the human cell), are PEGylated lipid nanoparticles that can be reactogenic, triggering their own immune reactions, and causing damage to the liver at higher doses.[32] Strong reactogenic effects were reported in trials of novel COVID-19 RNA vaccines.[33]

General

Before 2020, no mRNA technology platform (drug or vaccine) had ever been authorized for use in humans, and thus there was the risk of unknown effects,[18] both short-term and longer-term (e.g. autoimmune responses or diseases).[4][8][34] The 2020 coronavirus pandemic required the faster production capability of mRNA vaccines, and 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 post final human trials.[35][36]

Storage

mRNA is fragile, and thus the vaccine has to be kept at very low temperatures to avoid degrading and thus giving little effective immunity to the recipient; for example, the BNT162b2 mRNA vaccine has to be kept at -70 degrees Celsius,[37] although Moderna say their MRNA-1273 vaccine can be stored at -20 degrees Celsius (comparable to a home freezer),[37] and remains stable at 2 to 8 degrees Celsius.[38] In November 2020, Nature reported that "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".[18]

Advantages

Traditional vaccines

RNA vaccines offer a number of specific advantages over traditional protein vaccines:[5][6]

  • As 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 (i.e. fewer error rates in production), which can improve responsiveness to serious outbreaks.[6][5]

DNA vaccines

In addition to sharing the advantages of theoretical DNA vaccines over established traditional protein vaccines, RNA vaccination offers further benefits, including:

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.[24][43]

History

Using mRNA as a novel therapeutic drug class was first demonstrated in 1989, when a US-based biotech, Vical Incorporated, published work demonstrating that mRNA, using a liposomal nanoparticle for drug delivery, could transfect mRNA into a variety of eukaryotic cells.[3] In 1990, Jon A. Wolff et al. at the University of Wisconsin, reported on their 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 go back to the early 1990s. 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.[3][44][45]

Hungarian biochemist Katalin Kariko, spent the 1990s attempting to solve some of the main technical barriers to introducing mRNA into human cells.[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]

In 2005, Harvard stem cell biologist Derrick Rossi read their paper, which he recognized as "groundbreaking", and for which he told Stat, Karikó and Weissman deserve the Nobel Prize in Chemistry.[1] In 2010, Rossi founded the mRNA-focused biotech Moderna, along with Robert Langer, who saw its potential in vaccine development.[1][3] Various other mRNA-focused biotechs were also formed or re-focused (e.g. CureVac), including BioNTech, which was founded in Germany and licensed Kariko and Weissman's work, with both joining the board of BioNtech in 2013.[1]

Up until 2020, the mRNA biotechs had poor results testing mRNA drugs against various therapeutic areas including cardiovascular, metabolic and renal diseases, and selected targets for cancer, and rare diseases (e.g. Crigler–Najjar syndrome), with most finding that the side-effects of mRNA insertion were still too serious.[46][47] Many big pharmaceuticals abandoned the technology,[46] however, some biotechs re-focused on the lower margin (i.e. less profitable) area of vaccines, where the doses would be at lower levels, and side-effects reduced; Rossi decided to leave Moderna post their strategic refocus.[46][48]

By December 2020, no mRNA drug or vaccine had still yet to be licensed for use in humans, however, both Moderna and Pfizer/BioNTech were close to securing emergency use authorization for their mRNA-based COVID-19 vaccines, which had been funded directly and indirectly respectively, by Operation Warp Speed.[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".[9][49] MHRA CEO June Raine said "no corners have been cut in approving it",[50] and that, "the benefits outweigh any risk".[51][52]

Culture and society

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

In November 2020, The Washington Post reported on vaccine hesitancy amongst healthcare professionals in the United States to the novel mRNA vaccines, citing surveys which reported that: "some did not want to be in the first round, so they could wait and see if there are potential side effects",[53] and that "doctors and nurses want more data before championing vaccines to end the pandemic".[53]

The use of RNA has been the basis of 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 tens of thousands of people.[11]

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. ^ a b c d Cooney E (1 December 2020). "How nanotechnology helps mRNA Covid-19 vaccines work". Stat. Retrieved 3 December 2020.
  3. ^ a b c d e f g h i j 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 Roberts J (1 June 2020). "Five things you need to know about: mRNA vaccines". Horizon. Retrieved 16 November 2020.
  5. ^ a b c d e f g h PHG Foundation (2019). "RNA vaccines: an introduction". University of Cambridge. Retrieved 18 November 2020.
  6. ^ a b c d e f 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.
  7. ^ 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.
  8. ^ 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.
  9. ^ 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.
  10. ^ "Conditions of Authorisation for Pfizer/BioNTech COVID-19 Vaccine" (Decision). Medicines & Healthcare Products Regulatory Agency. 8 December 2020.
  11. ^ a b Carmichael F, Goodman J (2 December 2020). "Vaccine rumours debunked: Microchips, 'altered DNA' and more" (Reality Check). BBC.
  12. ^ a b c Kwon D (25 November 2020). "The Promise of mRNA Vaccines". The Scientist. Retrieved 27 November 2020.
  13. ^ a b "Seven vital questions about the RNA Covid-19 vaccines emerging from clinical trials". Wellcome Trust. 19 November 2020. Retrieved 26 November 2020.
  14. ^ Carmichael F (15 November 2020). "Vaccine rumours debunked: Microchips, 'altered DNA' and more". BBC News. Retrieved 17 November 2020.
  15. ^ Rahman G (30 November 2020). "RNA Covid-19 vaccines will not change your DNA". Full Fact. Retrieved 1 December 2020.
  16. ^ 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.
  17. ^ 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.
  18. ^ 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.
  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. ^ 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.
  22. ^ 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.
  23. ^ 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.
  24. ^ 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.
  25. ^ 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.
  26. ^ 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.
  27. ^ 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.
  28. ^ 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)
  29. ^ 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.
  30. ^ 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.
  31. ^ 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.
  32. ^ 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.
  33. ^ 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.
  34. ^ Eugene Gu (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.
  35. ^ 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.
  36. ^ Kuchler H (30 September 2020). "Pfizer boss warns on risk of fast-tracking vaccines". Financial Times. Retrieved 21 November 2020.
  37. ^ 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.
  38. ^ "Moderna Announces Longer Shelf Life for its COVID-19 Vaccine Candidate at Refrigerated Temperatures". NPR.org.
  39. ^ 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.
  40. ^ 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.
  41. ^ Pardi N, Weissman D (2016-12-17). "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.
  42. ^ 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.
  43. ^ 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.
  44. ^ 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.
  45. ^ 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.
  46. ^ 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.
  47. ^ 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.
  48. ^ 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.
  49. ^ Roberts M (2 December 2020). "Covid Pfizer vaccine approved for use next week in UK". BBC News. Retrieved 2 December 2020.
  50. ^ "UK regulator says it did not cut any corners to approve Pfizer vaccine". Reuters. 2 December 2020. Retrieved 2 December 2020.
  51. ^ "The benefits of the Pfizer/BioNTech vaccine "far outweigh any risk", says Dr June Raine from UK regulator MHRA". BBC News. 2 December 2020. Retrieved 2 December 2020.
  52. ^ Guarascio F (2 December 2020). "EU criticises 'hasty' UK approval of COVID-19 vaccine". Reuters. Retrieved 2 December 2020.
  53. ^ a b Rowland C (21 November 2020). "Doctors and nurses want more data before championing vaccines to end the pandemic". Washington Post. Retrieved 22 November 2020.
Scholia has a profile for RNA vaccine (Q85795487).
Retrieved from "https://en.wikipedia.org/enwiki/w/index.php?title=MRNA_vaccine&oldid=993362884"