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📦 | Todai Seminar "What is an mRNA vaccine?" Online 10/1


Photo IQB Public Lecture "What is an mRNA vaccine?"

Todai Seminar "What is an mRNA vaccine?" Online 10/1

 
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The mRNA vaccine is extremely effective in preventing the infection and aggravation of the new coronavirus infection, and the inoculation rate is also increasing.
 

On October 2021, 10, the University of Tokyo held a seminar "mRNA vaccine ..." for high school students, examinees, university students, and the general public. → Continue reading

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New coronavirus infection

RNA vaccine

RNA vaccine, ま た はmRNA vaccine (messenger RNA vaccine)It is,Messenger RNAUsing an artificial replica of a natural chemical called (mRNA)ImmunologyReactvaccineA kind of.Vaccine is syntheticRNAWhen the molecule is introduced into human cells and enters the cells, the RNA of the vaccine functions as mRNA, and the cells usuallyPathogen(ウ イ ル スEtc.) orcancerMakes foreign proteins that should be produced by cells.These protein molecules remember how to identify and destroy the corresponding pathogen or cancer cell without damaging the host cell.Acquired immunityStimulate[1].

The advantages of RNA vaccines over traditional protein vaccines are superior design, production speed, and reduced production costs.[2][3], Induction of both cell-mediated immunity and humoral immunity[4]..The disadvantage is that it is due to the vulnerability of the mRNA molecule.Cold chainIf the cold chain breaks and the molecules break down prior to injection, the dose may be inadequate and efficacy may be compromised.[1]..Also, because there are "expected" side reactions similar to conventional vaccines, people who are prone to autoimmune reactions may have side reactions to RNA vaccines.[3][2].

mRNA vaccineNew Coronavirus Infection (COVID-19)It is attracting a great deal of attention as a vaccine against. Complete the final clinical trial by early December 2020COVID-19 vaccineThere are two mRNA vaccines waiting for an emergency use authorization (US)ModernaCompanymRNA-1273When,Biontech/PfizerJoint[1][5]Developed in BNT162b2 <Tozinameran>). December 2020, 12, UKDrug and Medical Product Regulatory Agency(MHRA) is the world's first mRNA vaccine (Tozinameran) Was approved for the first time in history[6][7].

The misinterpretation that RNA-based vaccines mutate human DNAVaccine evasionPrinciplesQ AnonBelievers, etc.Conspiracy theoristSpread among, initiallySocial MediaThe hoax was disseminated around.Those involved in the spread of hoax ignored data from the latest clinical trials involving tens of thousands of people and claimed it was an unknown technology with unconfirmed safety.[8].

mechanism

RNA vaccine is conventionalvaccineWorks in a very different way.Conventional vaccinesantigen(Protein orpeptide),Attenuated virus, The antibody reaction is induced by injecting a viral vector, which is an antigen having a recombinant code, into a human.These components are regulated outside the human body.In contrast, mRNA vaccines are made by chemically synthesizing the RNA sequence of a virus and inserting (transfecting) the fragment into human cells.[3]..The internal function in the cell produces a specific protein (antigen) encoded by the incorporated mRNA chain.[3]..Those antigens produced by human cells elicit the same immune response as injections of antigens that are proteins or peptides.[9].. Cells injected with mRNA are safe because they merely present the antigen and are not targets for the antibody.

The advantage of using mRNA to produce antigens in human cells is that it is much easier to produce antigens in human cells than antigen proteins or attenuated viruses.[9][10][3]..Design and manufacturing speed is also an important advantage.ModernaThe company is for COVID-2 in just two daysmRNA-1273Vaccine designed[11]..In addition, because the antigen is produced intracellularlyHumoral immunityだ け で な く,Cellular immunityAlso induces stimulation[12][13].

The mRNA molecule protects the fragile mRNA strand and helps its absorption into human cells.Drug delivery system(NormallyPEGChemicalLipid nanoparticles) Is coated[14][10] .

As a safety measure, the mRNA vaccine does not affect or reprogram intracellular DNA.The synthesized mRNA fragment is a copy of a particular portion of viral RNA that carries instructions for constructing viral antigens and is independent of DNA.The misconception that mRNA vaccines against the new coronavirus are protein "types" and affect cellsConspiracy theoryJust[15][16].

After producing a foreign protein, the mRNA should be degraded intracellularly.However, the details and mechanism have not yet been investigated by a third party, as the specific formulation is kept secret by the manufacturer.[17].

Efficacy of mRNA vaccine against COVID-19

COVID-19Prior mRNA drug trials for pathogens other than were not very promising and were urgently developed despite having to give up early in the trial.ModernaBiontech/PfizerIt is unclear why the novel mRNA COVID-19 vaccine in Japan has a potential efficacy rate of 90-95%.[18]..Medical researcher(English editionSuggests that "the amount of resources devoted to development" may be the cause.Vaccines are also "non-specific to mRNAs that may enhance a specific immune response.Inflammatory reactionMay be inducingNucleosideWe reviewed and reduced inflammation from the immune response, but we have not completely eliminated it. "Clinical trialReactions such as fever and pain in some vaccine subjects seen in[19]Pointed out that this may be the reason (these causes arePEGylationWas thought to be a drug reaction)[18].

COVID-2020 in March 3PandemicIt is unknown about the long-term side effects that occur very rarely because it was put into practical use and commercialized in an unusually short time within just one year after it was declared.[20][21].

In addition to the potential for high effectiveness, the difficulty of handling is also regarded as a problem.[18].. RNA vaccines need to be transported and stored at very low temperatures, as mRNA molecules are highly degradable and degrade within minutes in exposed environments.[5]..In addition, extracellularly in human cells, or outside of its drug delivery system, mRNA molecules are rapidly degraded by the human body.[2]..The brittleness of these mRNAs is also a barrier to ensuring the effectiveness of the vaccine.[5][2].

Side effects and risks

People who are prone to autoimmune reactions may have side effects on RNA vaccines, as common "expected" side effects are similar to traditional non-RNA vaccines.[3][2]..Also, the mRNA strand of the vaccine can provoke an unintended immune response, and to minimize this, fragments of the mRNA vaccine gene sequence are designed to mimic antibody proteins produced in human cells. Is[2].

To prevent the mRNA chain from being degraded or destroyed before it is inserted into human cellsDrug delivery systemAsPEGLipid nanoparticles are used, which can cause an immune response that can cause liver damage at high doses.[22].. actuallyNew coronavirus infectionStrong response reported in vaccine clinical trials[19].

General

Before 2020, there was no technology platform for mRNA drugs, and unknown effects (autoimmune reactions, diseases, etc.), including short-term and long-term, were concerns.[13], There was no permission to use for humans[10][5][23].. But in 2020Global pandemic of new coronavirus infectionsHealth agencies in each country have noticed the rapid productivity of mRNA vaccines and discussed what initial approvals (including emergency use approvals and extended access approvals) should be given to vaccines after final clinical trials. Led to[24][25].

Storage and storage and transportation

Since mRNA is easily fragmented, it is kept at a very low temperature so as not to deteriorate the performance until the inoculation scene.Pfizer's vaccine requires freezing at -60-80 ° C, and Moderna's vaccine also requires storage at -20 ° C, which is said to be effective for 2 days even at 8-30 ° C.[26]..Science magazineNatureThe magazine reported that many experts believe that it will eventually prove to have similar storage requirements and shelf life under different temperature conditions.[13]..For airlift vaccinesdry iceIs used.

Superiority

Comparison with conventional vaccines

RNA vaccines have some advantages over traditional protein vaccines[2][3]..First, it is non-infectious at the time of inoculation because the vaccine is not constructed from pathogens.On the other hand, for conventional vaccine productionPathogenMay increase the risk of local virus outbreaks in production facilities if mass production takes place[2].. RNA vaccines are more serious because they can be manufactured faster, cheaper, by more standardized methods, and with less defect rates in the manufacturing process.OutbreakCan respond to (virus spread)[3][2].

Comparison with DNA vaccine

mRNA does not require RNA to enter the cell nucleus and is translated into the cytosol, avoiding the risk of integration into the gene to be inoculated.[14]..Also modified nucleosides (eg Pseudouridine 2'-O-Incorporation of methylated nucleoside) into mRNA suppresses immune response stimulation, avoids immediate mRNA degradation, and improves translation ability for sustained effects.[27][28][29]..In addition, on the mRNA sequenceOpen reading frame(ORF) andUntranslated region(UTR) can also be optimized for a variety of purposes, such as enriching GC content or selecting specific UTRs known to increase translation.[30].

Mechanism for replicating proteinsOpen reading frameAdd (code) the procedure to (ORF) andGolgi apparatusIt is possible to produce a large amount of antigen during translation by and amplify the immune responsiveness.It says that it can reduce the amount of material used for duplication at the beginning.[31][32].

History

University of CaliforniaSan DiegoSalk InstituteIn 1989, researchers at Baikal, a U.S.-based biotechnology company, demonstrated that liposome nanoparticles could be used for drug delivery to transfer mRNA into a variety of eukaryotic cells. Published the study[33].. 1990,University of WisconsinJohn A. Wolff and others reported injecting raw mRNA (not protected by coatings, etc.) into mouse muscle with positive drug delivery.[14]..These studies demonstrate for the first time that mRNA can be transcribed in vitro (IVT) to provide the genetic information for producing proteins in living cell tissues.[14].

The use of RNA vaccines dates back to the early 1990s, and in vitro demonstrations of mRNA in animals were first reported in 1990.[34]Shortly thereafter, the vaccine was proposed for use as a vaccination.[35][36].. In 1993 MartinnonLiposomesRNA encapsulated in the bodyT cellsIn 1994, Elephant and Bergland published the first evidence that RNA could be used as a vaccine to elicit both a moist humoral immune response to a pathogen and a cellular immune response.[14][37][38].

HungarianBiochemistKariko CatalinAttempted to solve some of the technical challenges needed to introduce mRNA into human cells in the 1990s.[1]..KarikoUniversity of PennsylvaniaIn collaboration with Drew Wessaman, 2005 was modified without activating the body's original defense system.NucleosideAs a joint paper, we announced that we solved one of the technical problems by incorporating mRNA into human cells using[14][1].. In 2005, Harvard Stem Cell Biologist Derrick Rossy said their treatise was comparable to the Nobel Prize in Chemistry as "overturning the roots."[1].. In 2010, RossyRobert LangerAlong with, a biotechnology company focusing on mRNA, discovering the potential of vaccine developmentModernaEstablished a company[1][14]..Other mRNA-focused biotech companies, including Cureback, have licensed Calico and Wessaman research technologies.BiontechThe company also focused on the development of mRNA vaccines, etc.[1].

By 2020, these mRNA biotechnology companies willCardiovascular disease,, and among kidney diseases,cancerAndRare diseaseAs a result of testing mRNA as a drug focusing on (Crigler-Najer syndrome), it was found that the side effects of incorporating mRNA into cells are often too serious, resulting in inadequate results.[39][40]..RNA vaccine for humans has been developedRabies,Zika fever,Cytomegalovirus,andinfluenzaTested against viruses but not widely used[41], Many major pharmaceutical companies have abandoned technology using this mRNA[39]..Among them, some biotech companies continued to focus again on reducing side effects to low levels with the dose of mRNA vaccine, ignoring profitability.[39][42].

Prior to December 2020, no mRNA vaccine was approved for use in humans,ModernaWith the company (direct technical license enjoyment)Pfizer/BiontechCompany (enjoying indirect technology license)Operation Warp SpeedWe raised funds from the company and started the development of a new type of mRNA-based corona vaccine (COVID-19 vaccine) in an emergency with the permission of clinical trials.[1].. December 2020, 12, 2 days after 8 weeks of final clinical trial,英国 OfMHRABecame the first drug regulator in the world to approve the use of the mRNA vaccine, granting an "emergency use authorization" to two vaccines developed by BioNTech and Pfizer.[6][43].MHRA"There is no point to withdraw approval," said June Rain, a director of the company.[44]At the same time, "the benefits of vaccine use outweigh all risks."[45][46]Said.

Introduction into and out of cells (drug delivery)

The drug delivery procedure is internal to cellular RNA transfer (In vivo) Or externally (Ex vivo) Is roughly classified according to what happens[14].

RNA translocation outside the cell (Ex vivo)

Dendritic cellsIs a type of immune cell that shows the type of antigen on the cell surface,T cellsInteracts with and initiates an immune response.Dendritic cells can be collected from the patient and incorporated into mRNA, which can then be re-administered to the patient to provoke an immune response.[47].

RNA transfer inside the cell (in vivo)

The discovery of transcription and expression mechanisms (antigen synthesis) by direct administration of mRNA has made their insights (approaches) even more attractive to pharmaceutical companies.[48]..Since standard infections can be assumed, the cost and introduction of collecting patient dendritic cells can be avoided. As RNA vaccination is a better method, there are still areas to overcome.Required to stop translationRibonucleaseAnd unknownNucleic acidInnovative mechanisms have been discovered to prevent material wetting, and RNA mobility relies on standard cell cycle models.This is because the RNA numerator is too large to diffuse inside the cell and is either removed or translation is stopped.

About infusion of untreated mRNA

The world's first direct injection of live mRNA vaccineClinical research TheGermany OfTubingenThis method has been known for over 20 years[49][50].. For vaccines using RNA, self-amplifying mRNA was discovered in the 1990s.[51][31].皮膚,blood(Blood),筋肉It has also been clarified that the selection of the administration route is an important point of delivery (gene drug delivery) because the mRNA uptake level is different when the injection route to the site is different. By comparing different routes by Kreiter and othersT cellsTo maximize the responseLymph nodeHas been shown to be effective[52].. The mechanism of mRNA self-amplification and the resulting evaluation of RNA as a much larger molecule may be fundamentally different.[14]

About Polyplex

Cationic polymers help cell penetration and at the same time recombined mRNARibonucleaseCan be protected from and mixed with mRNA.Protamine is naturalCationsexpeptideHas been used to assemble mRNA for vaccination[Non-primary materials required][53].

About lipid nanoparticles

US Food and Drug Administration (FDA) Approved the use of lipid nanoparticles as a drug delivery system (drug delivery system) for the first time in 2018.FDAIs the firstsiRNAIt was when I approved the drug using[54]..Encapsulating mRNA molecules with lipid nanoparticles was a breakthrough in an important way to produce mRNA vaccines, solving the technical challenges of delivering mRNA to human cells.[54][55]..Lipids act as a protective layer from RNA degradation, allowing for more robust translational output (producing antibody proteins).In addition, by customizing the outer layer of lipidsLigandThe target cell can be captured through the interaction of (matching of gene fragments and their sequences).However, many studies have also emphasized the difficulty of studying this type of delivery (drag delivery), and the application of nanoparticles in the uptake of mRNA into cells is in vitro experiments. And in vivo have been shown to be inconsistent[56]..When nanoparticles are administered into the body,lymphTransported by multiple routes through system systems, etc.[54].

Viral vector

In addition to non-viral delivery (drag delivery) methods such as the use of E. coli, pre-designed RNA viruses (which use viruses to carry RNA to cells) cause an immune response.Typical RNA viruses used as viral vectors include retroviruses, lentiviruses, alphaviruses, and labedviruses, each with a different structure and working style.[57]..In clinical studies, such viruses are used for diseases of typical animals such as mice, chickens, and primates.[58][59][60].

Self-amplified RNA

Self-amplifying RNA (saRNA) is a technique similar to mRNA, but saRNA, like mRNA, produces multiple copies of itself within the cell before producing a protein.This uses less and has potential benefits[61][62].. SaRNA vaccines are being studied, including the development of malaria vaccines.

footnote

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