A taron alluran rigakafi da kiwon lafiya, masana sun yi kira da "kowa ya kamata ya mai da hankali ga allurar mRNA, wanda ke ba 'yan adam tunani mara iyaka."To menene ainihin maganin mRNA?Ta yaya aka gano shi kuma menene ƙimar aikace-aikacen sa?Shin zai iya tsayayya da tashin hankalin COVID-19 a duniya?Shin ƙasata ta sami nasarar samar da rigakafin mRNA?A yau, bari mu koyi game da baya da na yanzu na rigakafin mRNA.

01
Menene mRNA a cikin rigakafin mRNA?

mRNA (Manzo RNA), wato manzo RNA, wani nau'in RNA ne mai dunƙule guda ɗaya wanda aka rubuta daga sigar DNA azaman samfuri kuma yana ɗaukar bayanan kwayoyin halitta waɗanda zasu iya jagorantar haɗin furotin.A cikin sharuddan layman, mRNA yana maimaita bayanan kwayoyin halitta na jigon DNA guda biyu a cikin tsakiya, sannan ya bar tsakiya don samar da sunadarai a cikin cytoplasm.A cikin cytoplasm, ribosomes suna motsawa tare da mRNA, karanta jerin tushen sa, kuma suna fassara shi zuwa amino acid daidai da shi, suna samar da furotin (Hoto 1).

Hoto 1 tsarin aiki na mRNA

02
Menene rigakafin mRNA kuma menene ya sa ya zama na musamman?

Magungunan mRNA suna gabatar da mRNA suna ɓoye takamaiman antigens na cuta a cikin jiki, kuma suna amfani da tsarin haɗin furotin na rundunar don samar da antigens, ta haka yana haifar da amsawar rigakafi.Yawancin lokaci, jerin mRNA na takamaiman antigens za a iya gina su bisa ga cututtuka daban-daban, kunshe da kuma jigilar su cikin sel ta hanyar novel lipid nanocarrier particles, sa'an nan kuma ana amfani da jerin mRNA na ribosomes na mutum don fassara jerin mRNA don samar da sunadaran antigen na cuta, wanda tsarin autoimmune ya gane bayan ɓoyewa don haifar da amsawar rigakafi (Figure 2).

Hoto 2. In vivo tasirin rigakafin mRNA

Don haka, menene na musamman game da irin wannan nau'in rigakafin mRNA idan aka kwatanta da na gargajiya?Magungunan mRNA sune mafi yanke-yanke-baki na ƙarni na uku, kuma ana buƙatar ƙarin bincike don haɓaka kwanciyar hankali, daidaita yanayin rigakafi, da haɓaka sabbin fasahohin bayarwa.

Farko na farko na maganin alurar riga kafi sun haɗa da alluran rigakafin da ba a kunna ba da kuma allurar rigakafin da aka rage, waɗanda aka fi amfani da su.Magungunan da ba a kunna ba suna nufin fara al'ada ƙwayoyin cuta ko ƙwayoyin cuta, sannan kuma ba su kunna su da zafi ko sinadarai (yawanci formalin);allurar rigakafi masu rai suna nufin ƙwayoyin cuta waɗanda ke canzawa da raunana su bayan jiyya daban-daban.amma har yanzu yana riƙe da immunogenicity.Shigar da shi a cikin jiki ba zai haifar da kamuwa da cuta ba, amma ƙwayoyin cuta na iya girma da yawa a cikin jiki, haifar da amsawar rigakafi, da kuma taka rawa wajen samun kariya ta dogon lokaci ko ta rayuwa.

Ƙarni na biyu na sababbin alluran rigakafi sun haɗa da alluran rigakafi na subunit da magungunan furotin na sake haɗuwa.Subunit maganin alurar riga kafi ne da aka yi da babban kayan kariya na rigakafi na ƙwayoyin cuta, wato, ta hanyar lalata sinadarai ko sarrafa proteolysis, tsarin furotin na musamman na ƙwayoyin cuta da ƙwayoyin cuta ana fitar da su tare da tantance su.Alurar rigakafin da aka yi da gutsuttsura masu aiki na rigakafi;Magungunan furotin da aka sake haɗawa sune sunadaran antigen recombinant da aka samar a cikin tsarin maganganun salula daban-daban.

Ƙarni na uku na ƙananan ƙwayoyin cuta sun haɗa da allurar DNA da rigakafin mRNA.Shi ne kai tsaye gabatar da kwayar cutar kwayar cutar kwayar cuta (DNA ko RNA) da ke sanya wani sunadarin antigenic a cikin sel somatic dabba (alurar rigakafi a cikin jikin mutum), da kuma samar da furotin na antigenic ta hanyar tsarin furotin na kwayar halitta, yana haifar da mai watsa shiri don samar da rigakafi ga amsawar furotin na antigenic don cimma manufar rigakafi da maganin cututtuka.Bambancin da ke tsakanin su biyun shi ne, an fara rubuta DNA zuwa cikin mRNA sannan a haxa furotin, yayin da mRNA ke haɗa kai tsaye.

03
Tarihin ganowa da ƙimar aikace-aikacen rigakafin mRNA

Idan ana maganar allurar mRNA, dole ne mu ambaci wata fitacciyar ƙwararriyar masaniyar kimiyyar mata, Kati Kariko, wadda ta kafa ƙwaƙƙwaran ginshiƙin bincike na kimiyya don zuwan rigakafin mRNA.Ta kasance cike da sha'awar bincike akan mRNA yayin da take karatu.A cikin fiye da shekaru 40 na aikin binciken kimiyya, ta fuskanci koma baya akai-akai, ba ta nemi kudaden bincike na kimiyya ba, kuma ba ta da tsayayyen matsayin binciken kimiyya, amma ta dage kan binciken mRNA.

Kati Karito

Akwai mahimman nodes guda uku a cikin zuwan rigakafin mRNA.

A mataki na farko, ta yi nasarar samar da kwayoyin halittar mRNA da ake so ta hanyar al’adar tantanin halitta, amma ta fuskanci matsala wajen sanya mRNA aiki a cikin jiki: bayan allurar mRNA a cikin linzamin kwamfuta, tsarin rigakafi na linzamin zai hadiye shi.Sai ta sadu da Weissman.Sun yi amfani da kwayoyin halitta a cikin tRNA da ake kira pseudouridine don sa mRNA ya guje wa amsawar rigakafi.[2].
A mataki na biyu, a kusa da 2000, Farfesa Pieter Cullis yayi nazarin lipid nanotechnology LNPs don in vivo isar da siRNA don aikace-aikacen shiru na kwayoyin halitta [3] [4].Kungiyar Weissman Kariko et al.an gano cewa LNP shine mai ɗaukar hoto mai dacewa na mRNA a cikin vivo, kuma yana iya zama kayan aiki mai mahimmanci don isar da mRNA mai ɓoye sunadaran warkewa, kuma daga baya an tabbatar da shi a cikin rigakafin cutar Zika, HIV da ciwace-ciwace [5] [6] [7] [8].

A mataki na uku, a cikin 2010 da 2013, Moderna da BioNTech a jere sun sami lasisin haƙƙin mallaka mai alaƙa da haɗin gwiwar mRNA daga Jami'ar Pennsylvania don ƙarin haɓakawa.Katalin kuma ya zama babban mataimakin shugaban BioNTech a cikin 2013 don ƙara haɓaka rigakafin mRNA.

A yau, ana iya amfani da allurar mRNA a cikin cututtuka masu yaduwa, ciwace-ciwace, da asma.A cikin yanayin COVID-19 da ke harzuka a duniya, rigakafin mRNA na iya taka rawa a matsayin mai gadi.

04
Hasashen aikace-aikacen rigakafin mRNA a cikin COVID-19

Tare da annobar COVID-19 a duniya, ƙasashe suna aiki tuƙuru don samar da allurar rigakafin cutar.A matsayin sabon nau'in maganin alurar riga kafi, rigakafin mRNA ya taka rawa wajen zuwan sabuwar annobar kambi.Yawancin manyan jaridu sun ba da rahoton rawar mRNA a cikin sabon SARS-CoV-2 sabon coronavirus (Hoto na 3).

Hoto 3 Rahoto kan allurar rigakafin mRNA don hana sabon coronavirus (daga NCBI)

Da farko, masana kimiyya da yawa sun ba da rahoton binciken rigakafin mRNA (SARS-CoV-2 mRNA) game da sabon coronavirus a cikin beraye.Misali: lipid nanoparticle-encapsulated-nucleoside-modified mRNA (mRNA-LNP), alluran allura guda ɗaya yana haifar da nau'in nau'in CD4+ T da CD8+ T mai ƙarfi, martanin plasma na dogon lokaci da ƙwaƙwalwar ƙwayoyin B, da ƙarfi kuma mai dorewa neutralizing martanin antibody.Wannan yana nuna cewa rigakafin mRNA-LNP ɗan takara ne mai ban sha'awa game da COVID-19[9][10].

Na biyu, wasu masana kimiyya sun kwatanta tasirin SARS-CoV-2 mRNA da rigakafin gargajiya.Idan aka kwatanta da maganin rigakafi na furotin na sake haɗawa: maganin rigakafi na mRNA sun fi alluran furotin a cikin amsawar cibiyar germinal, Tfh kunnawa, ƙaddamar da samar da antibody, ƙayyadaddun ƙwayoyin B ƙwaƙwalwar ajiya, da kuma ƙwayoyin plasma na dogon lokaci [11].

Sannan, yayin da 'yan takarar rigakafin SARS-CoV-2 mRNA suka shiga gwaji na asibiti, an taso da damuwa game da ɗan gajeren lokacin rigakafin rigakafin.Masana kimiyya sun kirkiro wani nau'i mai nau'i mai nau'i na lipid-encapsulated nau'i na maganin mRNA da aka gyara na nucleoside mai suna mRNA-RBD.Allura guda ɗaya na iya haifar da ƙwayoyin rigakafi masu ƙarfi da martani na salon salula, kuma kusan kusan suna iya kare ƙirar berayen da suka kamu da 2019-nCoV, tare da manyan matakan rigakafin ƙwayoyin cuta waɗanda aka kiyaye aƙalla watanni 6.5.Waɗannan bayanan sun ba da shawarar cewa kashi ɗaya na mRNA-RBD yana ba da kariya ta dogon lokaci daga ƙalubalen SARS-CoV-2 [12].
Hakanan akwai masana kimiyya da ke aiki don haɓaka sabbin amintattun allurai masu inganci a kan COVID-19, kamar rigakafin BNT162b.Macaques masu kariya daga SARS-CoV-2, sun kare ƙananan hanyoyin numfashi daga kwayar cutar RNA, sun samar da ƙwayoyin rigakafi masu ƙarfi, kuma ba su nuna alamun haɓaka cuta ba.'Yan takara biyu a halin yanzu suna ƙarƙashin kimantawa a cikin gwaje-gwajen lokaci na I, kuma ana kan kimantawa a cikin gwaji na II/III na duniya, kuma aikace-aikacen yana kusa da kusurwa [13].

05
Matsayin rigakafin mRNA a duniya

A halin yanzu, BioNTech, Moderna da CureVac an san su da manyan shugabannin jiyya na mRNA guda uku na duniya.Daga cikin su, BioNTech da Moderna sune kan gaba a cikin bincike da haɓaka sabon maganin kambi.Moderna yana mai da hankali kan bincike da haɓaka magunguna da alluran rigakafin mRNA.Maganin gwaji na COVID-19 na III na mRNA-1273 shine aikin kamfani mafi girma cikin sauri.BioNTech kuma babban kamfani ne na maganin mRNA na duniya da bincike na alurar rigakafi da haɓakawa, tare da jimillar magunguna / alluran rigakafin mRNA guda 19, 7 daga cikinsu sun shiga matakin asibiti.CureVac yana mai da hankali kan bincike da haɓaka magungunan mRNA/alurar rigakafi, kuma shine kamfani na farko a duniya da ya kafa layin samar da RNA mai dacewa da GMP, yana mai da hankali kan ciwace-ciwace, cututtuka da cututtukan da ba a saba gani ba.

Samfura masu alaƙa:Mai hanawa RNase
Mahimman kalmomi: rigakafin miRNA, Warewar RNA, cirewar RNA, Mai hana RNase

Magana:1.K Karikó, Buckstein M, Ni H, et al.Ƙunƙarar Ganewar RNA ta Masu karɓa-kamar Toll: Tasirin Gyaran Nucleoside da Asalin Juyin Halitta na RNA[J].Kariya, 2005, 23 (2): 165-175.
2. K Karikó, Muramatsu H , Welsh FA , et al.Haɗin Pseudouridine A cikin mRNA Yana Haɓaka Babban Nonimmunogenic Vector Tare da Ƙarfafa Ƙarfin Fassara da Kwanciyar Halittu[J].Magungunan Kwayoyin Halitta, 2008.3.Chonn A, Cullis PR.Ci gaban kwanan nan a cikin fasahar liposome da aikace-aikacen su don isar da kwayoyin halitta [J].Babban Bita na Isar da Magunguna, 1998, 30 (1-3): 73.4.Kulkarni JA , Witzigmann D , Chen S , et al.Fasahar Nanoparticle na Lipid don Fassarar Clinical na siRNA Therapeutics[J].Lissafi na Binciken Kimiyya, 2019, 52 (9.5.Kariko, Katalin, Madden, et al.Bayyanar motsin motsi na nucleoside mRNA wanda aka gyara a cikin nanoparticles na lipid zuwa beraye ta hanyoyi daban-daban[J].Jarida na Sakin Sarrafa Jadawalin Jarida na Jarida na Ƙungiyar Sakin Sarrafa, 2015.6.Kariyar ƙwayar cuta ta Zika ta hanyar allurar mRNA da aka gyaggyara da ƙarancin kashi ɗaya [J].Yanayi, 2017, 543 (7644):248-251.7.Pardi N , Secreto AJ , Shan X , et al.Gudanar da mRNA da aka gyara na nucleoside yana ɓoyewa gabaɗaya kawar da antibody yana kare berayen ɗan adam daga ƙalubalen HIV-1 [J].Sadarwar yanayi, 2017, 8:14630.8.Stadler CR , B?Hr-Mahmud H , Celik L , et al.Kawar da manyan ciwace-ciwace a cikin beraye ta hanyar mRNA-encoded bispecific antibodies[J].Magungunan yanayi, 2017.9.NN Zhang, Li XF, Deng YQ, da dai sauransu.Alurar rigakafin mRNA mai zafi daga COVID-19[J].Cell, 2020.10.D Laczkó, Hogan MJ, Toulmin SA, et al.Rigakafi guda ɗaya tare da Nucleoside-Modified mRNA Vaccines Yana kawar da Amsoshi Mai ƙarfi na Hannu da Humoral Immune akan SARS-CoV-2 a cikin Mice - ScienceDirect[J].2020.11.Lederer K , Castao D , Atria DG , et al.SARS-CoV-2 mRNA Vaccines Foster m Antigen-Specific Cibiyar Germinal Amsoshi Hade da Neutralizing Antibody Generation[J].Kariya, 2020, 53 (6): 1281-1295.e5.12.Huang Q, Ji K, Tian S, et al.Alurar rigakafin mRNA guda ɗaya tana ba da kariya ta dogon lokaci ga berayen transgenic hACE2 daga SARS-CoV-2[J].Sadarwar yanayi.13.Vogel AB, Kanevsky I, Ye C, et al.Immunogenic BNT162b rigakafi yana kare rhesus macaques daga SARS-CoV-2[J].Halitta, 2021: 1-10.