Ntawm Lub Rooj Sib Tham Tshuaj Tiv Thaiv thiab Kev Noj Qab Haus Huv, cov kws tshaj lij tau hu rau "txhua tus neeg yuav tsum ua tib zoo saib xyuas cov tshuaj tiv thaiv mRNA, uas muab kev xav rau tib neeg tsis muaj kev txwv."Yog li dab tsi yog qhov tshuaj tiv thaiv mRNA?Nws nrhiav tau li cas thiab nws daim ntawv thov tus nqi yog dab tsi?Nws puas tuaj yeem tiv thaiv COVID-19 thoob plaws ntiaj teb?Kuv lub tebchaws puas tau tsim tshuaj tiv thaiv mRNA?Hnub no, cia peb kawm txog yav dhau los thiab tam sim no ntawm cov tshuaj tiv thaiv mRNA.

01
mRNA yog dab tsi hauv cov tshuaj tiv thaiv mRNA?

mRNA (Messenger RNA), uas yog, tus tub txib RNA, yog ib hom ntawm ib leeg-stranded RNA uas tau sau los ntawm ib txoj hlua ntawm DNA ua tus qauv thiab nqa cov ntaub ntawv caj ces uas tuaj yeem coj cov protein synthesis.Nyob rau hauv layman cov ntsiab lus, mRNA replicates cov noob caj noob ces cov ntaub ntawv ntawm ib tug strand ntawm ob-stranded DNA nyob rau hauv lub nucleus, thiab ces tawm lub nucleus los tsim cov proteins nyob rau hauv lub cytoplasm.Nyob rau hauv lub cytoplasm, ribosomes txav raws mRNA, nyeem nws lub hauv paus sib lawv liag, thiab txhais nws mus rau hauv nws coj amino acid, thaum kawg tsim ib tug protein (Daim duab 1).

Daim duab 1 mRNA kev ua haujlwm

02
Qhov tshuaj tiv thaiv mRNA yog dab tsi thiab dab tsi ua rau nws txawv?

mRNA tshuaj tiv thaiv qhia mRNA encoding kab mob tshwj xeeb antigens rau hauv lub cev, thiab siv tus tswv tsev cell's protein synthesis mechanism los tsim cov antigens, yog li ua rau lub cev tiv thaiv kab mob.Feem ntau, mRNA cov kab ke ntawm cov antigens tshwj xeeb tuaj yeem tsim tau raws li cov kab mob sib txawv, ntim thiab thauj mus rau hauv cov hlwb los ntawm cov lipid nanocarrier tshiab, thiab tom qab ntawd cov mRNA sequences ntawm tib neeg ribosomes siv los txhais cov mRNA sequences los tsim cov kab mob antigen proteins, uas tau lees paub los ntawm cov kab mob autoimmune tiv thaiv kab mob tom qab kev tiv thaiv kab mob. 2).

Daim duab 2. Hauv vivo cov tshuaj tiv thaiv mRNA

Yog li, dab tsi yog qhov tshwj xeeb ntawm hom tshuaj tiv thaiv mRNA piv rau cov tshuaj tiv thaiv ib txwm muaj?Cov tshuaj tiv thaiv mRNA yog cov tshuaj tiv thaiv thib peb tshaj plaws, thiab xav tau kev tshawb fawb ntxiv los txhim kho lawv txoj kev ruaj ntseg, tswj lawv cov kev tiv thaiv kab mob, thiab tsim cov thev naus laus zis tshiab.

Thawj tiam ntawm cov tshuaj tiv thaiv ib txwm muaj feem ntau suav nrog cov tshuaj tiv thaiv tsis muaj zog thiab cov tshuaj tiv thaiv muaj sia nyob, uas yog siv dav tshaj plaws.Cov tshuaj tiv thaiv tsis muaj zog xa mus rau thawj kab mob los yog kab mob, thiab tom qab ntawd inactivating lawv nrog kub los yog tshuaj (feem ntau yog formalin);Cov tshuaj tiv thaiv kab mob muaj sia nyob hais txog cov kab mob uas hloov pauv thiab ua rau lawv cov tshuaj lom tsis muaj zog tom qab ntau yam kev kho mob.tab sis tseem khaws nws cov immunogenicity.Inoculating nws mus rau hauv lub cev yuav tsis ua rau tshwm sim ntawm tus kab mob, tab sis cov kab mob tuaj yeem loj hlob thiab sib npaug hauv lub cev, ua rau lub cev tiv thaiv kab mob, thiab ua lub luag haujlwm kom tau txais kev tiv thaiv mus ntev lossis kev tiv thaiv lub neej.

Lub cim thib ob ntawm cov tshuaj tiv thaiv tshiab suav nrog cov tshuaj tiv thaiv subunit thiab cov tshuaj tiv thaiv kab mob sib xyaw ua ke.Cov tshuaj tiv thaiv subunit yog cov tshuaj tiv thaiv subunit uas ua los ntawm cov tshuaj tiv thaiv kab mob tseem ceeb ntawm cov kab mob pathogenic, uas yog, los ntawm cov tshuaj tua kab mob los yog kev tswj hwm proteolysis, cov qauv protein tshwj xeeb ntawm cov kab mob thiab cov kab mob raug rho tawm thiab tshuaj xyuas.Cov tshuaj tiv thaiv ua los ntawm cov khoom siv tshuaj tiv thaiv kab mob;recombinant protein vaccines yog antigen recombinant proteins uas tsim nyob rau hauv txawv cell qhia systems.

Lub cim thib peb ntawm cov tshuaj tiv thaiv kab mob suav nrog cov tshuaj tiv thaiv DNA thiab tshuaj tiv thaiv mRNA.Nws yog los qhia ncaj qha rau cov kab mob gene fragment (DNA lossis RNA) encoding ib co antigenic protein rau hauv cov tsiaj somatic hlwb (cov tshuaj txhaj rau hauv tib neeg lub cev), thiab tsim cov antigenic protein los ntawm cov protein synthesis system ntawm tus tswv tsev cell, inducing tus tswv tsev los tsim kev tiv thaiv rau antigenic protein teb nyob rau hauv thiaj li yuav ua tiav lub hom phiaj ntawm kev tiv thaiv thiab kev kho mob ntawm tus kab mob.Qhov sib txawv ntawm ob yog DNA yog thawj transcribed rau hauv mRNA thiab ces protein yog synthesized, thaum mRNA yog ncaj qha synthesized.

03
Kev tshawb pom keeb kwm thiab daim ntawv thov tus nqi ntawm cov tshuaj tiv thaiv mRNA

Thaum nws los txog rau cov tshuaj tiv thaiv mRNA, peb yuav tsum hais txog ib tus poj niam kws tshawb fawb zoo tshaj plaws, Kati Kariko, uas tau tso lub hauv paus kev tshawb fawb txog kev tshawb fawb rau qhov tshwm sim ntawm cov tshuaj tiv thaiv mRNA.Nws tau tag nrho ntawm kev tshawb fawb txaus siab rau mRNA thaum nws kawm.Hauv nws ntau tshaj 40 xyoo ntawm kev tshawb fawb txog kev tshawb fawb, nws raug kev txom nyem ntau dua, tsis tau thov rau cov nyiaj tshawb fawb tshawb fawb, thiab tsis muaj txoj haujlwm tshawb fawb ruaj khov, tab sis nws ib txwm hais rau kev tshawb fawb mRNA.

Kev Karito

Muaj peb qhov tseem ceeb hauv qhov tshwm sim ntawm cov tshuaj tiv thaiv mRNA.

Hauv thawj kauj ruam, nws tau ua tiav hauv kev tsim cov mRNA molecule uas xav tau los ntawm kab lis kev cai ntawm tes, tab sis nws tau ntsib teeb meem hauv kev ua mRNA hauv lub cev: tom qab txhaj mRNA rau hauv tus nas, nws yuav nqos los ntawm tus nas lub cev tiv thaiv kab mob.Tom qab ntawd nws tau ntsib Weissman.Lawv siv cov molecule hauv tRNA hu ua pseudouridine los ua mRNA evade lub cev tiv thaiv kab mob.[2].
Nyob rau theem thib ob, nyob ib ncig ntawm 2000, Prof. Pieter Cullis tau kawm txog lipid nanotechnology LNPs rau hauv vivo xa ntawm siRNA rau gene silencing applications [3][4].Weissman lub koom haum Kariko et al.pom tias LNP yog ib qho tsim nyog tus neeg nqa khoom ntawm mRNA hauv vivo, thiab tuaj yeem dhau los ua cov cuab yeej tseem ceeb rau kev xa tawm mRNA encoding cov proteins kho, thiab tom qab ntawd tau txheeb xyuas hauv kev tiv thaiv tus kab mob Zika, HIV thiab qog nqaij hlav [5] [6][7][8].

Hauv theem thib peb, hauv 2010 thiab 2013, Moderna thiab BioNTech tau ua tiav tau txais daim ntawv tso cai patent ntsig txog mRNA synthesis los ntawm University of Pennsylvania rau kev txhim kho ntxiv.Katalin kuj tau los ua tus lwm thawj coj ntawm BioNTech hauv 2013 txhawm rau tsim cov tshuaj tiv thaiv mRNA ntxiv.

Niaj hnub no, cov tshuaj tiv thaiv mRNA tuaj yeem siv rau hauv cov kab mob sib kis, qog, thiab mob hawb pob.Hauv qhov xwm txheej ntawm COVID-19 thoob plaws ntiaj teb, cov tshuaj tiv thaiv mRNA tuaj yeem ua lub luag haujlwm ua tus saib xyuas.

04
Daim ntawv thov kev cia siab ntawm cov tshuaj tiv thaiv mRNA hauv COVID-19

Nrog rau kev sib kis thoob ntiaj teb ntawm COVID-19, cov tebchaws tau ua haujlwm hnyav los tsim cov tshuaj tiv thaiv los tiv thaiv tus kabmob sib kis.Raws li hom tshuaj tiv thaiv tshiab, tshuaj tiv thaiv mRNA tau ua lub luag haujlwm tseem ceeb hauv kev tshwm sim ntawm tus kabmob tshiab.Ntau cov ntawv xov xwm saum toj kawg nkaus tau tshaj tawm lub luag haujlwm ntawm mRNA hauv SARS-CoV-2 tus kabmob tshiab tshiab (Daim duab 3).

Daim duab 3 Qhia txog cov tshuaj tiv thaiv mRNA los tiv thaiv tus kabmob tshiab (los ntawm NCBI)

Ua ntej tshaj plaws, ntau tus kws tshawb fawb tau tshaj tawm cov kev tshawb fawb ntawm mRNA tshuaj tiv thaiv (SARS-CoV-2 mRNA) tiv thaiv tus kabmob tshiab hauv cov nas.Piv txwv li: lipid nanoparticle-encapsulated-nucleoside-modified mRNA (mRNA-LNP) tshuaj tiv thaiv, ib koob txhaj tshuaj induces muaj zog hom 1 CD4+ T thiab CD8+ T cell teb, ntev-plasma thiab nco B cell teb, thiab robust thiab Sustained neutralizing antibody teb.Qhov no qhia tau hais tias cov tshuaj tiv thaiv mRNA-LNP yog ib tus neeg sib tw ua tau zoo tiv thaiv COVID-19[9][10].

Qhov thib ob, qee cov kws tshawb fawb tau piv cov teebmeem ntawm SARS-CoV-2 mRNA thiab cov tshuaj tiv thaiv ib txwm muaj.Piv nrog cov tshuaj tiv thaiv kab mob sib xyaw ua ke: cov tshuaj tiv thaiv mRNA yog qhov zoo tshaj plaws rau cov tshuaj tiv thaiv kab mob hauv cov kab mob hauv nruab nrab cov lus teb, Tfh activation, neutralizing antibody ntau lawm, lub cim xeeb B hlwb, thiab cov plasma cell nyob ntev [11] .

Tom qab ntawd, raws li SARS-CoV-2 mRNA cov neeg sib tw tshuaj tiv thaiv tau nkag mus rau kev sim tshuaj, kev txhawj xeeb tau tshwm sim txog lub sijhawm luv luv ntawm kev tiv thaiv tshuaj tiv thaiv.Cov kws tshawb fawb tau tsim cov lipid-encapsulated daim ntawv ntawm nucleoside-hloov mRNA tshuaj tiv thaiv hu ua mRNA-RBD.Ib qho kev txhaj tshuaj ib zaug tuaj yeem tsim cov tshuaj tiv thaiv tsis zoo thiab cov lus teb ntawm tes, thiab tuaj yeem tiv thaiv tus qauv nas kis tus kabmob 2019-nCoV, nrog rau qib siab ntawm cov tshuaj tiv thaiv kab mob tiv thaiv tsawg kawg 6.5 lub hlis.Cov ntaub ntawv no qhia tias ib koob tshuaj mRNA-RBD muab kev tiv thaiv mus sij hawm ntev tiv thaiv SARS-CoV-2 kev sib tw [12].
Tseem muaj cov kws tshawb fawb ua haujlwm los tsim cov tshuaj tiv thaiv tshiab muaj kev nyab xeeb thiab siv tau zoo tiv thaiv COVID-19, xws li tshuaj tiv thaiv BNT162b.Kev tiv thaiv macaques los ntawm SARS-CoV-2, tiv thaiv cov kab mob hauv nruab nrog cev los ntawm tus kab mob RNA, tsim cov tshuaj tiv thaiv zoo heev, thiab tsis pom muaj cov tsos mob ntawm kev txhim kho kab mob.Ob tus neeg sib tw tam sim no nyob rau hauv kev ntsuam xyuas hauv theem I sim, thiab kev ntsuam xyuas hauv ntiaj teb theem II / III kev sim kuj tseem tab tom ua, thiab daim ntawv thov tsuas yog nyob ib ncig ntawm lub ces kaum [13].

05
Cov xwm txheej ntawm cov tshuaj tiv thaiv mRNA hauv ntiaj teb

Tam sim no, BioNTech, Moderna thiab CureVac yog lub npe hu ua lub ntiaj teb sab saum toj peb mRNA cov thawj coj kho mob.Ntawm lawv, BioNTech thiab Moderna yog qhov ua ntej ntawm kev tshawb fawb thiab kev tsim cov tshuaj tiv thaiv kab mob tshiab.Moderna tau tsom mus rau kev tshawb fawb thiab kev tsim kho ntawm mRNA ntsig txog tshuaj thiab tshuaj tiv thaiv.COVID-19 theem III sim tshuaj tiv thaiv mRNA-1273 yog lub tuam txhab txoj haujlwm loj tshaj plaws.BioNTech tseem yog lub ntiaj teb ua lag luam mRNA tshuaj thiab tshuaj tiv thaiv kev tshawb fawb thiab kev tsim kho lub tuam txhab, nrog rau tag nrho ntawm 19 mRNA tshuaj / tshuaj tiv thaiv, 7 ntawm uas tau nkag mus rau theem kho mob.CureVac tau tsom mus rau kev tshawb fawb thiab kev tsim kho mRNA tshuaj / tshuaj tiv thaiv, thiab yog thawj lub tuam txhab hauv ntiaj teb los tsim cov kab ntau lawm GMP-raws li RNA, tsom rau cov qog nqaij hlav, kab mob sib kis thiab kab mob tsawg.

Yam khoom:RNase Inhibitor
Cov lus tseem ceeb: tshuaj tiv thaiv miRNA, RNA Isolation, RNA rho tawm, RNase Inhibitor

Cov ntaub ntawv: 1.K Karikó, Buckstein M, Ni H, et al.Kev Tiv Thaiv ntawm RNA Kev Pom Zoo los ntawm Tus Xov Tooj Zoo Li Tus Txais: Qhov cuam tshuam ntawm Nucleoside Modification thiab Evolutionary Origin ntawm RNA [J].Kev tiv thaiv, 2005, 23(2:165-175.
2. K Karikó, Muramatsu H, Welsh FA, et al.Kev koom ua ke ntawm Pseudouridine rau hauv mRNA Yields Superior Nonimmunogenic Vector Nrog Cov Lus Txhais Lus Ntxiv thiab Kev Nyab Xeeb Kev Nyab Xeeb [J].Molecular Therapy, 2008.3.Chonn A, Cullis PR.Kev nce qib tsis ntev los no hauv liposome thev naus laus zis thiab lawv cov ntawv thov rau kev xa cov noob noob [J].Advanced Drug Delivery Reviews, 1998, 30(1-3): 73.4.Kulkarni JA, Witzigmann D, Chen S, et al.Lipid Nanoparticle Technology rau Kev Kho Mob Kev Txhais Lus ntawm siRNA Therapeutics [J].Cov Nyiaj Txiag ntawm Kev Tshawb Fawb Tshuaj, 2019, 52(9.5.Kariko, Katalin, Madden, et al.Kev nthuav qhia kinetics ntawm nucleoside-hloov mRNA xa hauv lipid nanoparticles rau nas los ntawm ntau txoj kev [J].Phau ntawv Journal of Controlled Release Official Journal of the Controlled Release Society, 2015.6.Kev tiv thaiv tus kab mob Zika los ntawm ib koob tshuaj qis nucleoside-hloov tshuaj tiv thaiv mRNA[J].Xwm, 2017, 543(7644):248-251.7.Pardi N, Secreto AJ, Shan X, et al.Kev tswj hwm ntawm nucleoside-hloov mRNA encoding broad neutralizing antibody tiv thaiv tib neeg nas los ntawm HIV-1 kev sib tw [J].Xwm Txheej Taug Kev, 2017, 8:14630.8.Stadler CR, B?Hr-Mahmud H, Celik L, et al.Kev tshem tawm cov qog loj hauv cov nas los ntawm mRNA-encoded bispecific antibodies[J].Xwm Txheej, 2017.9.NN Zhang, Li XF, Deng YQ, et al.Tshuaj tiv thaiv mRNA Thermostable tiv thaiv COVID-19[J].Khob, 2020.10.D Laczkó, Hogan MJ, Toulmin SA, et al.Kev txhaj tshuaj ib zaug nrog Nucleoside-Modified mRNA Vaccines Elicits Strong Cellular and Humoral Immune Responses against SARS-CoV-2 in Mice - ScienceDirect[J].2020.11.Lederer K, Castao D, Atria DG, et al.SARS-CoV-2 mRNA Vaccines Foster Potent Antigen-Specific Germinal Center Responses Associated with Neutralizing Antibody Generation[J].Kev tiv thaiv, 2020, 53(6): 1281-1295.e5.12.Huang Q, Ji K, Tian S, et al.Ib koob tshuaj mRNA ib zaug muab kev tiv thaiv mus sij hawm ntev rau hACE2 transgenic nas los ntawm SARS-CoV-2[J].Nature Communications.13.Vogel AB, Kanevsky I, Ye C, et al.Immunogenic BNT162b vaccines tiv thaiv rhesus macaques los ntawm SARS-CoV-2[J].Xwm Txheej, 2021:1-10.