PaMusangano weVaccine uye Hutano, nyanzvi dzakadaidzira kuti "munhu wese anofanirwa kutarisisa majekiseni emRNA, ayo anopa vanhu kufunga kusingagumi."Saka chii chaizvo chinonzi mRNA vaccine?Yakawanikwa sei uye chii kukosha kwayo kwekushandisa?Inogona here kuramba COVID-19 ichipisa pasirese?Nyika yangu yakabudirira kugadzira mRNA yekudzivirira here?Nhasi, ngatidzidzei nezvezvakapfuura uye zvazvino zvemishonga yekudzivirira mRNA.

01
Chii chinonzi mRNA mumRNA vaccine?

mRNA (Nhume RNA), kureva kuti, mutumwa RNA, imhando yeRNA ine tambo imwe chete iyo inonyorwa kubva kune strand yeDNA se template uye inotakura ruzivo rwe genetic inogona kutungamira protein synthesis.Mukutaura kwe layman, mRNA inodzokorora ruzivo rwemajini eimwe tambo yeDNA yakasungwa kaviri munyucleus, yobva yasiya nucleus kuburitsa mapuroteni mucytoplasm.Mune cytoplasm, ribosomes inofamba ichitevedza mRNA, verenga hwaro hwayo kutevedzana, uye inoishandura mune yayo inoenderana amino acid, pakupedzisira ichigadzira puroteni (Mufananidzo 1).

Mufananidzo 1 mRNA kushanda maitiro

02
Chii chinonzi mRNA vaccine uye chii chinoita kuti ive yakasiyana?

MRNA vaccines inounza mRNA encoding chirwere-chaiwo maantigens mumuviri, uye shandisa iyo host cell's protein synthesis nzira kugadzira maantigen, nekudaro zvichikonzera mhinduro yemuviri.Kazhinji, kutevedzana kwemRNA kwemaantigen chaiwo kunogona kuvakwa zvinoenderana nezvirwere zvakasiyana, kutakurwa uye kutakurwa mumaseru nenovel lipid nanocarrier particles, uyezve iyo mRNA sequences yema ribosomes evanhu inoshandiswa kushandura iyo mRNA sequences kugadzira chirwere antigen mapuroteni, ayo anozivikanwa neautoimmune immune system senge yekudzivirira yekudzivirira kwekudzivirira kwemuviri mushure mekuita basa rekudzivirira.

Mufananidzo 2. In vivo mhedzisiro yemRNA vaccine

Saka, chii chakasiyana nezverudzi urwu rwekudzivirira mRNA zvichienzaniswa nemishonga yechinyakare?Mishonga yemRNA ndiyo yakanyanya kucheka-yechitatu-yechitatu yekudzivirira yekudzivirira, uye kumwe kutsvagurudza kunodiwa kusimudzira kugadzikana kwavo, kutonga immunogenicity yavo, uye kugadzira matekinoroji matsva ekutumira.

Chizvarwa chekutanga chemishonga yechinyakare kunyanya inosanganisira majekiseni asina kuvharwa uye majekiseni anorarama attenuated, ayo ndiwo anonyanya kushandiswa.Inactivated vaccines inoreva kutanga kurima mavhairasi kana mabhakitiriya, uye ipapo inactivate navo nokupisa kana makemikari (kazhinji formalin);live attenuated vaccines zvinoreva utachiona hunochinja uye husina simba muchetura mushure mekurapa kwakasiyana siyana.asi ichiri kuchengetedza immunogenicity yayo.Kuiisa mumuviri hakuzokonzerese kuitika kwechirwere, asi hutachiona hunogona kukura nekuwanda mumuviri, huchikonzeresa kuzvidzivirira kwemuviri, uye kuita basa rekuwana kuchengetedzwa kwenguva refu kana kwehupenyu.

Chizvarwa chechipiri chemishonga mitsva inosanganisira subunit vaccine uye recombinant protein vaccine.Subunit vaccine ijekiseni rekudzivirira subunit rakagadzirwa neiyo huru inodzivirira immunogen zvikamu zvepathogenic bacteria, kureva, kuburikidza nekuora kwekemikari kana kudzorwa proteolysis, iyo yakakosha puroteni chimiro chebhakitiriya nemavhairasi inotorwa uye yakaongororwa kunze.Majekiseni akagadzirwa nemmunologically active zvidimbu;recombinant protein vaccines maantigen recombinant mapuroteni anogadzirwa mumasero akasiyana ekutaura masisitimu.

Chizvarwa chechitatu chekucheka-kumucheto chekudzivirira chinosanganisira DNA vaccine uye mRNA vaccine.Iko kuunza zvakananga viral gene fragment (DNA kana RNA) inokodha imwe antigenic protein mumhuka somatic masero (jekiseni rekudzivirira mumuviri wemunhu), uye kuburitsa antigenic protein kuburikidza neprotein synthesis system yesero rinogamuchira, zvichiita kuti muenzi aburitse kusadzivirirwa kune antigenic protein mhinduro kuitira kuzadzisa chinangwa chekudzivirira nekurapa chirwere.Musiyano uripo pakati pezviviri ndewekuti DNA inotanga kunyorwa muRNA uyezve mapuroteni anogadzirwa, nepo mRNA inogadzirwa zvakananga.

03
Nhoroondo yekuwanikwa uye kukosha kwekushandisa kwemRNA vaccine

Kana zvasvika kune mishonga yekudzivirira mRNA, tinofanira kutaura musayendisiti wechikadzi ane mukurumbira, Kati Kariko, akaisa hwaro hwakasimba hwetsvakiridzo yesainzi yekuuya kwemishonga yekudzivirira mRNA.Aive azere nekutsvagisa kufarira mRNA paaidzidza.Mumakore ake anopfuura makumi mana ebasa rekutsvagisa sainzi, akatambura kakawanda, haana kunyorera mari yekutsvagisa sainzi, uye akange asina nzvimbo yakagadzikana yekutsvagisa sainzi, asi agara achisimbirira patsvagiridzo yemRNA.

Kati Karito

Kune matatu akakosha node mukuuya kwemRNA vaccine.

Mudanho rekutanga, akabudirira kugadzira yaidiwa mRNA molecule kuburikidza nesero tsika, asi akasangana nedambudziko mukuita kuti mRNA ishande mumuviri: mushure mekubaya mRNA mugonzo, yaizomedzwa nekudzivirira kwembeva.Akabva asangana naWeissman.Vakashandisa morekuru mu tRNA inonzi pseudouridine kuita kuti mRNA inzvenge mhinduro yemuviri.[2].
Mudanho rechipiri, makore akapoteredza 2000, Prof. Pieter Cullis vakadzidza lipid nanotechnology LNPs ye in vivo kuendesa siRNA yekushandiswa kwemajini ekunyararidza [3][4].Weissman sangano Kariko et al.vakawana kuti LNP inotakura mRNA yakakodzera mu vivo, uye inogona kuva chinhu chakakosha chekuendesa mRNA encoding therapeutic proteins, uye inozosimbiswa mukudzivirira Zika virus, HIV nemamota [5] [6] [7][8].

Mudanho rechitatu, muna 2010 na2013, Moderna neBioNTech vakatevedzana vakawana marezinesi ane hukama nemRNA synthesis kubva kuYunivhesiti yePennsylvania kuti iwedzere budiriro.Katalin akazovewo mutevedzeri wemutungamiri weBioNTech muna 2013 kuti aenderere mberi nekugadzira mishonga yekudzivirira mRNA.

Nhasi, mishonga yeMRNA inogona kushandiswa muzvirwere zvinotapukira, mapundu, uye asthma.Munyaya yeCCIDID-19 iri kutenderera pasirese, mishonga yekudzivirira mRNA inogona kuita basa seyanguard.

04
Iyo tarisiro yekushandisa yemRNA yekudzivirira muCOVID-19

Nedenda repasi rose reCOVID-19, nyika dziri kushanda nesimba kugadzira mushonga wekudzivirira denda iri.Semhando nyowani yekudzivirira, mRNA yekudzivirira yakaita basa rekutungamira mukuuya kwedenda idzva rekorona.Majenari mazhinji epamusoro akataura basa remRNA muSARS-CoV-2 nyowani coronavirus (Mufananidzo 3).

Mufananidzo 3 Chirevo pane mRNA vaccines yekudzivirira coronavirus nyowani (kubva kuNCBI)

Chekutanga pane zvese, masayendisiti mazhinji akataura tsvakiridzo yekudzivirira mRNA (SARS-CoV-2 mRNA) kurwisa iyo coronavirus nyowani mumakonzo.Semuenzaniso: lipid nanoparticle-encapsulated-nucleoside-modified mRNA (mRNA-LNP) jekiseni, jekiseni rimwechete-dose rinoita simba remhando 1 CD4 + T uye CD8 + T cell mhinduro, plasma yenguva refu uye chiyeuchidzo B cell mhinduro, uye yakasimba uye Yakasimudzwa neutralizing neutralizing antibody mhinduro.Izvi zvinoratidza kuti nhomba yekudzivirira mRNA-LNP mumiriri anovimbisa kurwisa COVID-19[9][10].

Chechipiri, mamwe masayendisiti akafananidza mhedzisiro yeSARS-CoV-2 mRNA uye echinyakare vaccin.Kuenzaniswa nemishonga yeprotein inogadziriswa: mishonga yemRNA yakakwirira zvikuru kune mapuroteni ekudzivirira mugerminal center response, Tfh activation, neutralizing antibody production, ndangariro chaiyo B masero, uye masero eplasma anogara kwenguva refu [11].

Zvino, sezvo SARS-CoV-2 mRNA vaccine vaccine vakapinda mumiyedzo yekiriniki, kunetseka kwakasimudzwa nezvenguva pfupi yekudzivirira kwekudzivirira.Masayendisiti akagadzira lipid-encapsulated fomu yenucleoside-yakagadziridzwa mRNA vaccine inonzi mRNA-RBD.Jekiseni rimwe chete rinogona kuburitsa masoja ekudzivirira akasimba uye mhinduro dzemaserura, uye anogona kudzivirira zvakazara mbeva dzemhando dzakatapukirwa ne2019-nCoV, ine huwandu hwakanyanya hwekudzivirira masoja ekudzivirira chirwere anochengetwa kweinenge mwedzi mitanhatu neshanu.Aya data anoratidza kuti dosi rimwe chete remRNA-RBD rinopa dziviriro yenguva refu kubva kuSARS-CoV-2 dambudziko [12].
Kune zvakare masayendisiti ari kushanda kugadzira mishonga mitsva yakachengeteka uye inoshanda kurwisa COVID-19, senge BNT162b yekudzivirira.Akadzivirirwa macaques kubva kuSARS-CoV-2, akadzivirira epasi pekufema turakiti kubva kuhutachiona RNA, akagadzira masoja ekudzivirira chirwere ane simba, uye haana kuratidza zviratidzo zvekuwedzera chirwere.Vaviri vavhoterwa parizvino vari pasi pekuongororwa muchikamu chekutanga miedzo, uye kuongororwa muyedzo yepasi rose II/III iri kuenderera mberi, uye kunyorera kwave pedyo nekona [13].

05
Mamiriro ekudzivirira mRNA munyika

Parizvino, BioNTech, Moderna uye CureVac vanozivikanwa sevatungamiriri vepamusoro vepasi rose vemRNA therapy.Pakati pavo, BioNTech neModerna vari pamberi pekutsvagisa nekuvandudza kweiyo korona itsva yekudzivirira.Moderna anga achitarisa mukutsvagisa nekuvandudza kwemishonga ine chekuita nemRNA nemishonga yekudzivirira.Iyo COVID-19 phase III yekudzivirira yekudzivirira mRNA-1273 ndiyo kambani iri kukurumidza kukura chirongwa.BioNTech zvakare inotungamira pasi rose mRNA mushonga uye vaccine yekutsvagisa nekusimudzira kambani, ine huwandu hwe19 mRNA mishonga / yekudzivirira, 7 yacho yapinda mukiriniki.CureVac yanga yakatarisana nekutsvagisa nekuvandudzwa kwemRNA mishonga/jekiseni, uye ndiyo kambani yekutanga pasi rose kugadzira GMP-inoenderana neRNA mutsara wekugadzira, yakatarisana nemamota, zvirwere zvinotapukira uye zvirwere zvisingawanzo.

Zvigadzirwa zvinoenderana:RNase Inhibitor
Mazwi akakosha: miRNA vaccine, RNA Isolation, RNA kutorwa, RNase Inhibitor

References:1.K Karikó, Buckstein M , Ni H , et al.Kudzvinyirirwa kweRNA Kuzivikanwa neToll-like Receptors: Iyo Impact yeNucleoside Modification uye Evolutionary Origin yeRNA[J].Immunity, 2005, 23(2):165-175.
2. K Karikó, Muramatsu H , Welsh FA, et al.Kubatanidzwa kwePseudouridine MumRNA Kunobereka Superior Nonimmunogenic Vector Nekuwedzera Kwekushandura Kukwanisa uye Kugadzikana Kwehupenyu[J].Molecular Therapy, 2008.3.Chonn A , Cullis PR .Kufambira mberi kwazvino mu liposome tekinoroji uye mashandisiro azvo e systemic gene delivery[J].Ongororo Yepamusoro Yekupa Mushonga, 1998, 30(1-3):73.4.Kulkarni JA , Witzigmann D , Chen S , et al.Lipid Nanoparticle Technology yeClinical Dudziro yeSiRNA Therapeutics[J].Accounts of Chemical Research, 2019, 52(9).5.Kariko, Katalin, Madden, et al.Tsanangudzo kinetics ye nucleoside-modified mRNA yakaunzwa mu lipid nanoparticles kumakonzo nenzira dzakasiyana [J].Chinyorwa cheKudzorwa Kuburitswa Kwepamutemo Chinyorwa cheiyo Inodzorwa Release Society, 2015.6.Kudzivirirwa kweutachiona hweZika nejekiseni rimwechete rakaderera-nucleoside-modified mRNA [J].Zvisikwa, 2017, 543(7644):248-251.7.Pardi N, Secreto AJ, Shan X, et al.Kudzora kwenucleoside-modified mRNA encoding yakafararira inodzivirira maantibody inodzivirira mbeva dzevanhu kubva kuHIV-1 dambudziko[J].Nature Communications, 2017, 8:14630.8.Stadler CR , B?Hr-Mahmud H , Celik L , et al.Kubviswa kwemamota makuru mumakonzo nemRNA-encoded bispecific antibodies[J].Nature Medicine, 2017.9.NN Zhang, Li XF , Deng YQ , et al.A Thermostable mRNA Vaccine kurwisa COVID-19[J].Sero, 2020.10.D Laczkó, Hogan MJ , Toulmin SA , et al.Kubaiwa Kumwe chete neNucleoside-Modified mRNA Vaccines Inounza Mhinduro Dzakasimba dzeSero uye Humoral Immune kurwisa SARS-CoV-2 muMice - ScienceDirect[J].2020.11.Lederer K , Castao D , Atria DG , et al.SARS-CoV-2 mRNA Vaccines Foster Potent Antigen-Specific Germinal Center Mhinduro Yakabatana neNeutralizing Antibody Generation[J].Immunity, 2020, 53(6):1281-1295.e5.12.Huang Q , Ji K , Tian S , et al.Mushonga mumwe chete wekudzivirira mRNA unopa dziviriro yenguva refu yehACE2 transgenic mbeva kubva kuSARS-CoV-2[J].Kukurukurirana Kwakasikwa.13.Vogel AB , Kanevsky I , Ye C , et al.Immunogenic BNT162b yekudzivirira inodzivirira rhesus macaques kubva kuSARS-CoV-2[J].Zvisikwa, 2021:1-10.