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Basa rekugadzira jekiseni rinowanzotsanangurwa sekusatenda. Sekutaura kwaBill Foege, mumwe wevanachiremba vakurusa vezveutano pasi rose, “Hapana achakutendai nekuvaponesa kubva kuchirwere chavasina kumboziva kuti vanacho.

Asi varapi vehutano hweveruzhinji vanopokana kuti kudzoka kwekudyara kwakanyanya nekuti majekiseni anodzivirira kufa nekuremara, kunyanya kuvana. Saka sei tisiri kugadzira mishonga yekudzivirira zvirwere zvakawanda zvinodziviririka? Chikonzero ndechekuti majekiseni anofanirwa kuve anoshanda uye akachengeteka kuitira kuti agone kushandiswa muvanhu vane hutano, izvo zvinoita kuti nzira yekuvandudza yekudzivirira irebe uye yakaoma.

Gore ra2020 risati rasvika, avhareji yenguva kubva pakubata pamuviri kusvika pakupihwa rezenisi rejekiseni yaive makore gumi kusvika gumi nemashanu, nenguva pfupi pfupi yaive makore mana (mumps vaccine). Kugadzira yekudzivirira yeCCIDID-19 mumwedzi gumi neimwe saka chinhu chinoshamisa, chinogoneka nemakore ekutsvagisa kwakakosha pamapuratifomu ekudzivirira, kunyanya mRNA. Pakati pavo, mipiro yaDrew Weissman naDr. Katalin Kariko, vanogamuchira 2021 Lasker Clinical Medical Research Award, inonyanya kukosha.

Nheyo yekudzivirira nucleic acid yakadzika midzi mumutemo wepakati waWatson neCrick wekuti DNA inonyorwa muRNA, uye mRNA inoshandurirwa kuita mapuroteni. Anenge makore makumi matatu apfuura, zvakaratidzwa kuti kuunza DNA kana mRNA musero kana chero chinhu chipenyu chaizoratidza mapuroteni akatemwa ne nucleic acid sequences. Nguva pfupi yapfuura, iyo nucleic acid vaccine pfungwa yakasimbiswa mushure mekunge mapuroteni anoratidzwa ne exogenous DNA akaratidzwa kuti aite inodzivirira immune immune. Nekudaro, mashandisirwo epasirese ejekiseni reDNA akaganhurirwa, pakutanga nekuda kwekunetseka kwekuchengetedza kwakabatana nekubatanidza DNA mujenome remunhu, uye gare gare nekuda kwekuomerwa kwekukwidza kufambiswa kwakanaka kweDNA mukati memukati.

Kusiyana neizvi, mRNA, kunyangwe ichikonzeresa hydrolysis, inoratidzika kunge iri nyore kushandisa nekuti mRNA inoshanda mukati me cytoplasm uye saka haidi kuendesa nucleic acids mukati meiyo nucleus. Makumi emakore ekutsvagisa kwekutanga naWeissman naKariko, pakutanga mulabhu yavo uye gare gare mushure mekupihwa rezenisi kumakambani maviri ebiotechnology (Moderna neBioNTech), zvakaita kuti mushonga wekudzivirira mRNA uve chokwadi. Chii chakaita kuti vabudirire?

Vakakunda zvipingamupinyi zvakawanda. mRNA inozivikanwa ne innate immune system pattern recognition receptors (FIG. 1), kusanganisira nhengo dzeToll-like receptor mhuri (TLR3 uye TLR7/8, iyo inonzwa kaviri-stranded uye imwe-stranded RNA, zvichiteerana) uye retinoic acid inokonzera gene I protein (RIG-1) nzira, iyo inozoita cytoic plasma uye plasmic plasmic kuzvimba. recognition receptor, Inoziva ipfupi kaviri-yakasungwa RNA uye inomutsa mhando I interferon, nekudaro ichiita inogadzirisa immune system). Saka, kubaya mRNA mumhuka kunogona kukonzera kuvhunduka, zvichiratidza kuti huwandu hwemRNA hunogona kushandiswa muvanhu hunogona kuganhurwa kuitira kudzivirira mhedzisiro isingagamuchirwe.

Kutsvaga nzira dzekudzikisa kuzvimba, Weissman naKariko vakatanga kunzwisisa nzira yekucherekedza nzira yekusiyanisa pakati pepathogen-inotorwa RNA neRNA yavo. Ivo vakacherekedza kuti akawanda intracellular Rnas, akadai seakapfuma ribosomal Rnas, akagadziridzwa zvakanyanya uye akafungidzira kuti shanduko idzi dzakabvumira yavo maRnas kutiza kuzivikanwa kwekudzivirira.

Mhedzisiro yakakosha yakauya apo Weissman naKariko vakaratidza kuti kugadzirisa mRNA nepseudouridine pachinzvimbo cheyeduidine kwakaderedza immune activation uku uchichengeta kugona kuvharidzira mapuroteni. Uku kugadziridzwa kunowedzera kugadzirwa kweprotein, kusvika ku1,000 nguva yemRNA isina kuchinjwa, nekuti iyo yakagadziridzwa mRNA inopukunyuka kuzivikanwa neprotein kinase R (sensor inoziva RNA uye ipapo phosphorylates uye inomutsa shanduro yekutanga chinhu eIF-2α, nekudaro ichivhara kushandura mapuroteni). Pseudouridine yakagadziridzwa mRNA ndiyo musimboti wemishonga yekudzivirira mRNA ine rezinesi yakagadziridzwa neModerna nePfizer-Biontech.

Kubudirira kwekupedzisira kwaive kuona nzira yakanakisa yekuisa iyo mRNA isina hydrolysis uye nzira yakanakisa yekuiburitsa mucytoplasm. Multiple mRNA formulations yakaedzwa mumhando dzakasiyana dzekudzivirira mamwe mavhairasi. Muna 2017, humbowo hwekiriniki kubva kumiyedzo yakadai yakaratidza kuti kuvharirwa uye kuendeswa kwemishonga yeMRNA ine lipid nanoparticles yakakwidziridza immunogenicity uku ichichengetedza inochengetedzwa chengetedzo chimiro.

Zvidzidzo zvinotsigira mumhuka zvakaratidza kuti lipid nanoparticles inotarisa antigen-inopa maseru mukudonhedza lymph nodes uye kubatsira mhinduro kuburikidza nekuita activation yemhando dzakasiyana dzefollicular CD4 mubatsiri T masero. Aya masero eT anogona kuwedzera kugadzirwa kweanorwisa utachiona, huwandu hwemaseru eplasma anogara kwenguva refu uye chiyero cheB cell mhinduro. Iwo maviri parizvino ane marezinesi eCCIDID-19 mRNA ekudzivirira ese anoshandisa lipid nanoparticle maumbirwo.

Neraki, kufambira mberi uku mukutsvagisa kwekutanga kwakaitwa denda risati rasvika, zvichibvumira makambani emishonga kuvaka pakubudirira kwavo. MRNA vaccine yakachengeteka, inoshanda uye inogadzirwa-zhinji. Zvinopfuura bhiriyoni imwe yemadhora ekudzivirira mRNA akaiswa, uye kuwedzera kugadzirwa kusvika pamabhiriyoni maviri-4 emadhora muna 2021 na2022 kuchave kwakakosha kuhondo yepasi rose yeCOVID-19. Zvinosuruvarisa, kune kusaenzana kwakakosha mukuwana zvishandiso izvi zvinoponesa hupenyu, nemishonga yemRNA ikozvino inoshandiswa zvakanyanya munyika dzine mari yakawanda; Uye kusvikira kugadzirwa kwejekiseni kwasvika pakakwirira, kusaenzana kunoenderera mberi.

Zvakawanda, mRNA inovimbisa mambakwedza matsva mumunda wevaccinology, ichitipa mukana wekudzivirira zvimwe zvirwere zvinotapukira, sekuvandudza majekiseni efuruu, nekugadzira mishonga yekudzivirira zvirwere zvakaita semarariya, HIV, uye tuberculosis inouraya nhamba huru yevarwere uye isingashande nenzira dzakajairika. Zvirwere zvakaita segomarara, izvo zvaimbonzi zvakaoma kubata nazvo nekuda kwekuderera kwemukana wekuvandudzwa kwejekiseni uye kudiwa kwejekiseni remunhu, zvino zvinogona kutariswa mukugadzirwa kwemishonga. mRNA haingori nezve majekiseni. Mabhirioni emadosi emRNA atakabaya muvarwere kusvika parizvino aratidza kuchengetedzeka kwavo, achigadzira nzira yemamwe marapirwo eRNA akadai seprotein replacement, RNA interference, uye CRISPR-Cas (nguva dzose masumbu e interspaced short palindromic kudzokorora uye inobatanidzwa Cas endonucrenases) gene editing. Kumukira kweRNA kwakanga kuchangotanga.

Zvakaitwa naWeissman naKariko zvesainzi zvakaponesa mamirioni ehupenyu, uye rwendo rwebasa rwaKariko rwuri kufamba, kwete nekuti rwakasiyana, asi nekuti rwuri pasi rose. Mumwe munhuwo zvake aibva kune imwe nyika yekuEastern Europe, akatamira kuUnited States kuti aite zviroto zvake zvesainzi, achingonetsekana neUS tenure system, makore emari yekutsvagisa, uye kuderedzwa. Akatozobvuma kutora pay cut kuti lab irambe ichishanda uye kuenderera mberi netsvagiridzo yake. Rwendo rwesainzi rwaKariko rwave rwakaoma, iro vakadzi vazhinji, vatorwa nevashoma vanoshanda muzvidzidzo vanoziva. Kana wakamboita rombo rakanaka rekusangana naDr. Kariko, anomiririra zvinoreva kuzvininipisa; Anogona kunge ari matambudziko ake ekare anomuchengeta.

Kushanda nesimba uye kubudirira kukuru kwaWeissman naKariko kunomiririra zvese zvesainzi maitiro. Hapana nhanho, hapana mamaira. Basa ravo rakareba uye rakaoma, rinoda kutsungirira, njere uye kuona. Kunyange tisingakanganwe kuti vanhu vazhinji pasirese havasati vawana majekiseni, isu isu tine rombo rakanaka rekubaiwa nhomba yeCOVID-19 tinotenda nemabhenefiti ekudzivirira ekudzivirira. Makorokoto kumasaenzi maviri ekutanga ane basa rakatanhamara raita kuti mRNA vaccine iite chokwadi. Ndinobatana nevamwe vakawanda mukuratidza kutenda kwangu kusingaperi kwavari.