Adaptive Immune Responses To SARS-CoV-2.

Xav paub ntau ntxiv plz hu raudavid.wan@wecistanche.com

Txij li thaum Lub Ib Hlis 2020 Elsevier tau tsim COVID-19 chaw pabcuam nrog cov ntaub ntawv pub dawb ua lus Askiv thiab lus Mandarin ntawm tus tshiabkhaus laus nas vais lavCOVID- 19. Lub chaw muab kev pab cuam COVID-19 yog nyob rau ntawm Elsevier Connect, lub tuam txhab xov xwm pej xeem thiab xov xwm lub vev xaib. Elsevier ntawm no tso cai rau ua tag nrho nwsCOVID-19-Txoj kev tshawb fawb ntsig txog uas muaj nyob rau ntawm COVID-19 chaw muab kev pab - suav nrog cov ntsiab lus tshawb fawb no - tam sim ntawd muaj nyob hauv PubMed Central thiab lwm qhov chaw khaws nyiaj txiag rau pej xeem, xws li WHO COVID database nrog cov cai rau kev tshawb fawb tsis txwv rov siv thiab tshuaj xyuas hauv ib daim ntawv lossis los ntawm ib qho kev lees paub ntawm qhov chaw. Cov kev tso cai no tau tso cai pub dawb los ntawm Elsevier ntev npaum li COVID-19 chaw muab kev pabcuam tseem ua haujlwm.

Kab lus keeb kwm: Tau txais 13 Kaum Ob Hlis 2020, Kho dua 7 Lub Ob Hlis 2021, Txais 10 Lub Ob Hlis 2021, Muaj online 18 Lub Ob Hlis 2021 

Ntsiab lus: SARS-CoV-2, Antibody,T hlwb,Kev tiv thaiv kab mob,Epitopes, Neutralization

Nyem qhov no kom paub ntau ntxiv txog Cistanche

paub daws teeb meem:Qhov no tshuaj xyuas tsom ntawm yoog raws tiv thaiv kab mob teb tawm tsam SARS-CoV-2, tus khaus laus nas vais lav uas ua rauCOVID-19. A zoo heev deal ntawm ua haujlwm muaj ua ua tiav hauv a heev luvlub sij hawm rau piav adaptive tiv thaiv kab mob teb thiab rau paub meej lawv luag hauj lwm hauv kev txiav txim tus chav kawm ntawm kab mob. Raws li nrog lwm yam kis kab mob, SARS-CoV-2 elicits ob leeg tshuaj tiv thaiv thiab T-cell teb. Qhov twg tshuaj tiv thaiv teb yog tej zaum yuav siv tau hauv tiv thaiv kab mob thiab muaj koom hauv tswj kab mob ib zaug tsim tawm, nws yog tsawg dua seb los yog tsis yog lawv ua si a luag hauj lwm hauv pathogenesis. T hlwb yog tej zaum koom nrog hauv tswj tsim kab mob, tab sis a kab mob luag hauj lwm yog kuj ua tau. Ntev mus ntev kev soj ntsuam yog tsim nyog rau txiav txim lub durability ntawm tiv thaiv tiv thaiv kab mob teb.

1. Taw qhia

Qhov kev tshuaj xyuas no feem ntau yuav tsom mus rau kev tiv thaiv kev tiv thaivSARS-CoV-2thiab yuav npog lub luag haujlwm uas muaj peev xwm ntawm T hlwb thiab cov tshuaj tiv thaiv kab mob hauv pathogenesis thiab rov qab los ntawm kev kis kab mob.

1. 1. T-cell responses against SARS-CoV-2.1. 1. 1. Lymphopenia thaum lub sij hawm COVID- 19

COVID-19 feem ntau tshwm sim los ntawm lymphopenia, tshwj xeeb tshaj yog nyob rau hauv cov mob hnyav dua, nrog txo qis hauv CD8 ntxiv thiab CD4 ntxiv rau T hlwb [1–5]. Kev txo qis ntawm CD8 ntxiv rau T hlwb tuaj yeem ua rau CD4: CD8 piv [5–7]. Tsis tas li ntawd, kev ua haujlwm tsis zoo thiab kev nthuav qhia ntawm kev ua kom muaj zog thiab / lossis kev ua kom tsis muaj zog tau raug sau tseg [8–12]. Lymphopenia thaum kawg daws nrog kev rov zoo los ntawm kev kis kab mob [13].

1. 1.2. T hlwb thiab COVID- 19 pathogenesis

Seb tus T-cell teb yog cuam ​​tshuam nrog kab mob pathogenesis, rov qab los los ntawm kab mob, los yog ob leeg seem tsis meej. Ntau-dhau, kev kawm muaj concentrated ntawm txawv yam ntawm tus T-cell teb ntawm cov neeg mob ntawm txawv sij hawm thaum kab mob,   kev ua a   tsis muaj ntawm loj-duab kev meej.  Cov  T-cell teb hauv tseem ceeb cov neeg mob yog pom rau feem ntau ua muaj zog thiab piv los yog superior rau uas ntawm tsis yog-tseem ceeb cov neeg mob [14]. Hauv ntxiv,kab mob vais lav tshem tawm thiab ciaj sia tau tsis yog cuam ​​tshuam nrog T-cell kinetics los yog qhov loj ntawm teb [14]. Qhia ntawm a kab mob luag hauj lwm rau T hlwb, siab dua CD4 plus ibthiab CD8 plus ibT-cell teb, ob leeg hauv nqe lus ntawm qhov dav thiab qhov loj, tau pom hauv mob hnyav rooj plaub thaum piv rau mob me rooj plaub [15]. Txawm li cas los, a siab dua kev faib ua feem ntawm tus T-cell teb rau SARS-CoV-2 tus qauv cov proteins tau pab txhawb los ntawm CD8 plus ibT hlwb hauv mob me rooj plaub piv rau mob hnyav rooj plaub, qhia tias cov CD8 plus ibT-cell teb muaj peev xwm ua zooficial, hos tus CD4 plus ibT-cell teb muaj peev xwm ua si a luag hauj lwm hauv pathogenesis [15]. Ntawm tus lwm tes, Oja, thiab al., pom uas thuam mob ICU cov neeg mob muaj a poob CD4 plus ibT-cell teb hauv nqe lus ntawm tus lej thiab zoo raws li ntsuas los ntawm tus tshuaj cytokine profile [2]. Lwm pab pawg hais txog qhov luag hauj lwm ntawm T hlwb pom uas hauv kho siab cov neeg mob >21 hnub tom qab pib, nyob ntawd tau siab dua interferon c (IFN-c) teb rau nucleo-capsid (N) los yog ntsia hlau loj (S) cov proteins hauv mob me piv nrog mob hnyav rooj plaub[16].  Lwm tus pom ntau muaj zog T-cell ua kom,  tshwj xeeb hauv CD8 plus ibT hlwb, hauv poj niam cov neeg mob piv rau txiv neej cov neeg mob thiab pom uas T-cell ua kom tsis zoo kev sib raug zoo nrog hnub nyoog thiab, hauv cov txiv neej nkaus xwb,  yog cuam ​​tshuam nrog phem dua kab mob qhov tshwm sim  [17].Txawm li cas los, Moderbacher, thiab al. qhia uas SARS-CoV-2-tshwj xeebfic cd4 plus ibthiab CD8 plus ibT-cell teb tau cuam ​​tshuam nrog me ntsis tsis yooj yim, tab sis uas kev cuam tshuam ntawm koom tes T-cell teb hauv cov neeg >65 xyoo ntawm hnub nyoog ua tau pab txhawb rau phem dua qhov tshwm sim [18].

Siv Cov ntawv sau tseg tsom xam ntawm ntshav lymphocytes,  nws tau tshaj tawm uas  SARS-CoV-2-reactive  CD8 plus ibT  hlwb nrog ib  ''ex-haus" profile tau nce hauv zaus thiab nthuav tawm qis cytotoxicity thiab hauvflammatory nta hauv mob me piv nrog mob hnyav rooj plaub [19]. Cov hlwb hauv tus tsis yog-sab sab subset ntawm cov neeg mob nrog mob hnyav kab mob tau txhawb nqa rau cov ntawv sau tseg txuas rau co-stimulation, pro-ciaj sia NFkB teeb liab, thiab tiv thaiv-apoptotic txoj kev, qhia muaj zog CD8 plus ibT nco teb hauv tus hnyav dua cov neeg mob. Qhov no ntxiv qhia uas tus qhov loj thiab zoo ntawm tus CD8 plus ibT-cell teb muaj ua tseem ceeb hauv txwv cov ntaub so ntswg kev puas tsuaj. Cov kawm kuj qhia qhov tseem ceeb sib txawv hauv CD8 plus ibT hlwb reactive rau cov khaus laus nas vais lav piv nrog cov reactive rau hauvflua los yog RSV [19].

Ntawm tus ntaub so ntswg qib hauv tus tsis muaj ntawm kab mob, neeg nyob CD8 plus ib T-cell tus lej kev sib raug zoo inversely nrog ACE2 mRNA hauvtuslub ntsws [20].Thaum kab mob,  CD8 plus ibT  hlwb tau ntau ntau hauv  BAL  hauv me me los yog nruab nrab cuam ​​tshuam piv rau mob hnyav rooj plaub [20]. Ib yam li ntawd, nruab nrab rooj plaub tau qhia rau muaj siab dua qib ntawm CD8 plus ibT hlwb tshaj mob hnyav rooj plaub, thiab tus CD8 plus ibT hlwb tau ntau clonally nthuav hauv tus nruab nrab rooj plaub [21]. Cov no kev soj ntsuam xav tias hauv zos  CD8 plus ibT  hlwb ua tau ua ua si a  zooficial luag hauj lwm hauv COVID-19 kab mob. Hauv ntxiv, cov no fintus qhia uas cov neeg nrog siab dua ACE2 kev qhia thiab nws cuam ​​tshuam qis CD8 plus ib T-cell tus lej hauv tus lub ntsws ua ntej-kab mob muaj ua tshwj xeeb raug mob rau mob hnyav kab mob. Ib tsom xam ntawm rhesus macaques sim tau kis kab mob nrog SARS-CoV-2 pom uas ob leeg Th1 thiab Th2hlwb hauv lub ntsws ntaub so ntswg nce thaum tus lig theem ntawm kab mob,thiab tus cov kws sau ntawv ntaus nqi lub ntsws pathogenesis rau qhov no hauv zos T-cell teb. Txawm li cas los, txawm tsiaj txhu nrog mob hnyav mob ntsws o ua qauv qhia ceev kev txhim kho [22].

Nrog tshwj xeeb saib rau CD4 plus ibT hlwb thiab pathogenesis, Laing,thiab al. pom hnyav heev ploj lawm cd T hlwb raws li zoo raws li CD4 plus ibTh17 cell thiab Th1 hlwb, tshwj xeeb hauv mob hnyav cov neeg mob [23]. Hauv ntxiv, CD4 plus ib T hlwb, nyiam CD8 plus ibT hlwb, muaj txo tshuaj tiv thaiv kab mob tshuaj cytokine ntau lawm[11]. Siab dua CD4 plus ibT-cell ua kom muaj peev xwm ua cuam ​​tshuam nrog phem duaoutcomes  [6],  whereas higher  IFN-c-producing ells have been associated with better outcomes [1,24]. Patients who died were more likely to show no response. Patient age and comorbidity cor- related to the frequency of interleukin-2-secreting CD4+ T cells but lower IFN-c-secreting cells [25]. In patients with a mild infection, CD4+ SARS-CoV-2-specific cells were Th1 and predominantly central memory (Tcm) with robust helper function and persisted for >2 lub hlis [26]. Thaum kawg, tus kab mob COVID-19 hnyav tau tshwm sim hauv ib txoj kev tshawb fawb los ntawm kev npaj txhij txog Th2- kho lub cev tiv thaiv kab mob [27].

Ntau qhov kev tshawb fawb tau txuam nrog T hlwb, tshwj xeeb tshaj yog ncig T follicular helper cells (Tfh) nrog SARS-CoV-2-specific antibody level [15,28–30]. Gong, et al. pom tias cov tib neeg muaj kev cuam tshuam loj dua muaj ntau zaus ntawm T-effector nco hlwb (Tem) thiab Tfh-em hlwb, tab sis tsawg zaus ntawm Tcm, circulating Tfh-cm thiab Tnaive hlwb [28]. Circulating Tfh-em hlwb sib cuam tshuam nrog cov ntshav O2 qis, uas yuav piav qhia txog qhov sib piv ntau dua ntawm chav kawm hloov cov tshuaj tiv thaiv kab mob hauv qhov mob hnyav dua COVID-19 [28]. Txawm li cas los xij, SARS-CoV-2-reactive cytotoxic Tfh cells, uas tuaj yeem tua B hlwb, cuam tshuam tsis zoo nrog cov tshuaj tiv thaiv qib [29]. Hauv lwm txoj kev tshawb fawb, qhov qis qis ntawm kev ncig ntawm CCR6 ntxiv rau CXCR3- Tfh hlwb tau cuam tshuam nrog plasma neutralizing antibody kev ua haujlwm [30].Nws yog ib qho tseem ceeb uas yuav tsum nco ntsoov tias cov ntaub ntawv ntev, qhov uas lawv tau tshaj tawm, feem ntau yog raws li cov qauv me me. qhov ntau thiab tsawg [11,31]. Tsis tas li ntawd, lub sij hawm los ntawm kev kis kab mob tsis paub thiab hnub uas cov tsos mob tshwm sim yog qhov sib txawv ntawm cov kev kawm. Yog li, yuav tsum tau ceev faj txog kev txhais cov txiaj ntsig cuam tshuam nrog cov yam ntxwv ntawm T cell thiab pathogenesis, thiab tag nrho, seb T cells puas muaj txiaj ntsig, muaj teeb meem, lossis ob qho tib si (nyob ntawm tus neeg) tseem tsis meej. Txawm li cas los xij, zoo li muaj ntau yam qauv ntawm CD8 ntxiv rau T-cell cov lus teb hauv COVID-19 cov neeg mob, thiab cov txiaj ntsig yuav nyob ntawm T-cell lossis tag nrho kev tiv thaiv kab mob [6,18].

1.2. T cell tiv thaiv kab mob thiab antigen tshwj xeeb

SARS-CoV-2-specific CD8 plus T cells yog induced nyob rau hauv 1 lub lis piam ntawm tus kab mob thiab muaj nyob rau hauv 70– 100 feem pua ​​ntawm cov neeg mob [7,14,15,18,32–34]. Ib txoj kev tshawb nrhiav pom tias CD4 ntxiv rau T cell cov lus teb tau qhia tawm tsam matrix (M), N, thiab S cov proteins, nrog rau qhov sib piv, kev loj hlob, thiab kev faib ua feem ntawm cov neeg mob teb, txawm hais tias anti-N hlwb tsis tshua muaj peev xwm tsim IFN-c, IFN. -b, and TNF-a [25]. Lwm cov neeg tshawb nrhiav pom tias SARS-CoV{19}} tshwj xeeb CD4 ntxiv rau T cells feem ntau yog Tcm hlwb thiab qhia CXCR5, ib qho cim ntawm kev ncig Tfh cells [26]. CD8 ntxiv rau T hlwb tau tshaj tawm tias yog pre-dominantly RA45 ntxiv rau effector nco [Temra] hlwb [26]. Ntxiv thiab, CD8 ntxiv rau T cell teb tau tsav los ntawm ob peb cov tshuaj tiv thaiv kab mob, HLA-txheej txheem epitopes. T hlwb tau nce siab ntawm 1- 2 lub lis piam tom qab kis kab mob thiab tseem tuaj yeem kuaj tau ntau lub hlis [35]. Qhov tseem ceeb, T-cell nco yuav tshwm sim, raws li CD4 ntxiv thiab CD8 ntxiv rau T hlwb tau pom nyob rau hauv 100 thiab 70 feem pua, raws li, ntawm cov neeg mob uas zoo lawm [32]. M, S, thiab N txhua tus suav txog 11– 27 feem pua ​​​​ntawm tag nrho CD4 ntxiv cov lus teb, nrog nsp3, nsp4, orf3a, thiab orf8 pab txhawb thiab. S thiab M thiab ntau lwm cov proteins orf tau lees paub los ntawm CD8 ntxiv rau T hlwb. Ib yam li ntawd, qhov kev tshawb pom siab ntawm SARS- CoV-2-T cells tshwj xeeb tau pom los ntawm Karen, thiab al. [34], dua feem ntau rau sab hauv thiab tsis yog cov qauv kab mob cov kab mob. CD4 ntxiv rau T-cell cov lus teb rau S cuam tshuam nrog qhov loj ntawm IgG thiab IgA antibody titers [32]. Tib txoj kev tshawb no pom tau tias 40-60 feem pua ​​​​ntawm cov neeg tsis tau txais kev pom zoo muaj cov tshuaj CD4 ntxiv rau T hlwb, feem ntau tawm tsam nsp14, nsp4, nsp6, thiab S. Qhov zoo siab, qhov marginal lossis tsis muaj kev cuam tshuam tawm tsam N lossis M tau kuaj pom [32]. Ib yam li ntawd, Braun et al. pom tias 35 feem pua ​​​​ntawm cov tib neeg uas tsis tau pom muaj CD4 ntxiv rau T cells reactive tawm tsam SARS-CoV-2 S protein [36]. S-reactive T hlwb nyob rau hauv unexposed cov ntsiab lus reacted feem ntau rau C-terminal S epitopes, uas qhia ib tug ntau dua degree ntawm homology rau tib neeg CoVs uas ua rau tus mob khaub thuas. Raws li nrogthe idea that common cold CoVs induce T-cells cross-reactive with SARS-CoV-2, T-cell lines generated from S-reactive T cells response to the C terminal of the common cold CoVs 229E and OC42 S [36 ]. Tsis tas li ntawd, lub cim xeeb ntev ntev T cells reactive tiv thaiv N of SARS-CoV-1 display robust cross-reactivity to N of SARS-CoV-2 [33]. Hauv txoj kev tshawb no, cov tib neeg uas tsis muaj SARS lossis COVID-19 muaj T cells reactive nrog SARS-CoV-2 nsp7 thiab nsp13, tej zaum yog vim tsiaj CoVs [33].

Cov txiaj ntsig zoo sib xws ntawm ntau yam ntawm lub cim xeeb ua ntej CD4 ntxiv rau T hlwb, tshwj xeeb tshaj yog tawm tsam S tau pom los ntawm Mateus, thiab al. [37]. Hauv lwm txoj kev tshawb fawb, qhov ntau dua ntawm cov tib neeg uas tsis tau pom dua (81 feem pua) tau pom tias muaj SARS-CoV-2-reactive T-cell teb reactive rau epitopes uas tau nthuav tawm los ntawm MHC chav kawm I thiab II [38] tom qab {{8 }} hnub stimulation. Reactivity tiv thaivSARS-CoV-2epitopes hauv orf1 thiab orf8 tau tshwj xeeb sau tseg. Ntawm kev sib raug zoo, cov epitopes no muaj qhov zoo sib xws rau cov mob khaub thuas CoVs. Txoj kev tshawb no kuj tau tshaj tawm tias 56 feem pua ​​​​ntawm cov tshuaj tiv thaiv-tsis zoo rau cov neeg mob tau kuaj pom tias muaj COVID-19 Txawm li cas los xij muaj T cov lus teb (dua, tom qab 12 hnub ntawm kev txhawb nqa nrog antigen), thiab zoo ib yam li saum toj no, kev sib raug zoo ntawm HLA DR- txwv. T-cell teb thiab cov tshuaj tiv thaiv kab mob tau sau tseg. Kev sib txawv ntawm T-cell cov lus teb, nyob rau hauv cov nqe lus ntawm kev lees paub tus nqi ntawm epitopes, tau txo qis hauv cov neeg mob uas muaj cov tsos mob hnyav dua. SARS-CoV-2-cov kab mob tshwj xeeb T tau raug sau tseg hauv cov neeg mob zoo thaum tsis muaj cov tshuaj tiv thaiv kab mob. Ntawm 13 tus neeg mob uas tsis muaj IgG los ntawm ELISA tiv thaiv S1 tom qab lub sijhawm nruab nrab ntawm 60 hnub, 78 feem pua ​​​​tau muaj SARS-CoV-2- tshwj xeeb T cell teb [39]. Schulien, thiab al. tau qhia SARS-CoV-2- tshwj xeeb CD8 ntxiv rau T hlwb hauv yim tus neeg mob uas tsis zoo rau S thiab N IgG [40]. Cov txiaj ntsig zoo sib xws ntawm T-cell teb thaum tsis muaj cov tshuaj tiv thaiv kab mob sib kis tau tshaj tawm los ntawm Sekine, thiab al. [12]. SARS-CoV-2-specific peripheral Tfh cells (tshwj xeeb yog tawm tsam S) tau pom tias muaj kev cuam tshuam nrog cov tshuaj tiv thaiv kab mob nruab nrab [41]. Kev txaus siab tshwj xeeb rau kev tsim tshuaj tiv thaiv thiab kev paub txog kab mob yuav ua rau txiav txim siab yog tias muaj cov kab mob sib kis T-hlwb, suav tias yog tsim los ntawm lwm cov kab mob sib kis, ua lub luag haujlwm hauv qhov tshwm sim ntawm tus kab mob SARS-CoV-2.

2. Antibody responses against SARS-CoV-2

Antibody cov lus teb rau cov kab mob tuaj yeem ntsuas tau siv cov kev ntsuas uas txiav txim siab lub peev xwm ntawm cov tshuaj tiv thaiv kab mob los khi rau nws cov cognate antigen lossis los ntawm kev soj ntsuam ua haujlwm, xws li cov ntsuas kev ua haujlwm tsis zoo. IgG, IgM, thiab IgA binding assays tiv thaiv S (los yog var- ntau ntu ntawm S) lossis N tuaj yeem ntsuas tau siv ELISA, chemiluminescence immunoassays, thiab ntau lwm lub platform [42–47]. Neutralizing assays tau siv cov kab mob SARS-CoV-2, uas yuav tsum muaj biosafety level 3 (BSL3) los yog SARS-CoV-2 S protein pseudotyped nrog retroviruses lossis vesicular stomatitis virus (VSV) [48, 49] ib. Kev kuaj kab mob sib kis tsis zoo, pseudotyped-virus neutralizing kev soj ntsuam, thiab kev txheeb xyuas kev sib raug zoo feem ntau cuam tshuam nrog ib leeg [43,50–53]. Lwm hom kev ntsuas kev ua haujlwm, xws li cov uas tso siab rau kev sib cuam tshuam ntawm Fc ntu ntawm cov tshuaj tiv thaiv kab mob thiab Fc receptors ntawm cov tshuaj tua kab mob los yog macrophages, kuj tau siv los kawm SARS-CoV-2 cov lus teb rau lub cev [54, 55] ib.

2. 1. Antibody kinetics

Anti-S thiab anti-N binding IgM, IgA, thiab IgG cov tshuaj tiv thaiv kab mob tuaj yeem kuaj pom ntawm 7 thiab 12 hnub tom qab cov tsos mob tshwm sim hauv kwv yees li 50 feem pua ​​​​ntawm COVID-19 cov neeg mob [47,56–58]. Txawm hais tias feem ntau cov kab mob kis tau los ntsuas IgM ua ntej IgG, hauv qee cov neeg mob nrog COVID-19, IgG ua ntej IgM [47,57]. Qhov zoo siab, qhov kev thim rov qab ntawm qhov kev txiav txim ib txwm ntawm IgM ua ntej IgG kuj tau pom nrog cov kab mob tshwm sim los ntawm SARS-CoV-1 [59,60].IgM thiab IgA cov tshuaj tiv thaiv kab mob siab tshaj plaws ntawm li 2-3 lub lis piam tom qab pib cov tsos mob, thiab lawv muaj nyob rau hauv cov neeg mob feem ntau los ntawm lub sijhawm ntawd [32,57,61]. IgM poob qis los yog tsis paub meej txog li 4-5 lub lis piam hauv cov neeg mob feem ntau [62]. IgG tshuaj tiv thaiv yog ntsuas tau hauv 50 feem pua ​​​​ntawm cov neeg mob los ntawm li 10 hnub thiab nce siab ntawm li 21 hnub tom qab cov tsos mob tshwm sim [58]. Yuav luag txhua tus neeg mob kis tau tus mob IgG teb [32,57,61]. Tom qab qhov siab kawg no, qib qis qis tab sis tseem nyob hauv cov tib neeg feem ntau nyob rau lub sijhawm txuas mus rau 5- 7 lub hlis [63]. Interestingly, anti-N IgG titers poob sai dua li cov tshuaj tiv thaiv kab mob qhia tawm tsam receptor-binding domain (RBD) lossis S2 [63].

Neutralizing antibodies txhim kho raws li lub sijhawm zoo sib xws, nce siab ntawm 14–21 hnub [58], thiab ntsuas tau ze li ntawm txhua tus neeg mob [64]. Neutralizing cov tshuaj tiv thaiv kuj poob qis los ntawm 8- 12 lub lis piam tab sis tseem ntsuas tau rau feem coob ntawm cov neeg mob los ntawm 5-7 lub hlis (saib hauv qab no rau kev sib tham ntxiv) [63,65]. Txawm hais tias cov tshuaj tiv thaiv tsis ntev los no tsis muaj kev ntseeg siab IgG, ntshav, lossis ntshav IgM thiab, tsis muaj zog, IgA1 anti-S cov tshuaj tiv thaiv kuj tuaj yeem tiv thaiv tus kab mob [66]. Nws yuav tsum tau sau tseg tias cov tib neeg uas muaj cov titers qis lossis txawm tias qhov ntsuas tsis tau pom ntawm cov tshuaj tiv thaiv kab mob tseem tuaj yeem tiv thaiv los ntawm kev kis kab mob tom ntej, vim tias nco B hlwb muaj nyob rau hauv cov neeg mob zoo [67,68]. Lub cim xeeb B hlwb txuas ntxiv mus rau somatic hypermutation tshaj rau lub hlis, tejzaum nws yog vim muaj kev pheej hmoo ntawm antigens hauv plab [68]. Qhov tseem ceeb, ntau qhov kev tshawb fawb tau pom tias cov neeg mob hnyav dua tsim cov tshuaj tiv thaiv kab mob siab dua, tshwj xeeb tshaj yog IgG, rau S lossis N dua li cov neeg mob mob me me [56,69–72]. IgG avidity rau RBD, S, thiab N, uas nce ntxiv raws sijhawm, kuj pom tias muaj ntau dua rau cov tib neeg uas cuam tshuam ntau dua [73,74]. Ib qho kev sib raug zoo ntawm cov tshuaj tiv thaiv kab mob thiab qhov hnyav tau raug sau tseg rau kev kis kab mob nrog rau lwm cov kab mob, suav nrog SARS-CoV-1 thiab MERS-CoV [75,76]. Qhov yuav piav qhia rau qhov no yog qhov ntau dua cov tshuaj tiv thaiv kab mob, cuam tshuam nrog ntau dua lossis ntau dua cov kab mob kis mus ntxiv, ua rau cov tshuaj tiv thaiv ntau dua. Txawm li cas los xij, nws kuj tseem muaj peev xwm hais tias cov tshuaj tiv thaiv kab mob muaj feem cuam tshuam rau cov kab mob ntawm COVID-19 (saib hauv qab). Cov tshuaj tiv thaiv kab mob hauv cov me nyuam zoo li txawv ntawm cov neeg laus. Hauv kev tshawb fawb piv rau cov neeg laus uas muaj tus kab mob me me, cov neeg laus uas muaj tus kab mob hnyav, cov menyuam nyob hauv tsev kho mob nrog ntau lub cev ua mob rau lub cev (MIS-C), thiab cov menyuam yaus uas muaj tus kab mob COVID-19 tab sis tsis yog MIS-C (kwv yees li ib nrab ntawm cov uas tsis muaj tsos mob. ), siab dua los tiv thaiv S IgG, IgM thiab IgA cov lus teb tau raug sau tseg hauv cov neeg laus uas muaj tus kab mob hnyav dua li lwm pawg [77]. Anti-S antibody titers tsis txawv ntawm ob pawg menyuam yaus thiab cov neeg laus uas muaj tus kab mob me. Hauv qhov sib piv, cov lus teb los tiv thaiv N IgG yog qhov tsis tshua muaj qis hauv ob pawg menyuam yaus piv rau ob pawg neeg laus. Cov txiaj ntsig no tau qhia tias cov lus teb los tiv thaiv N yog nyob ntawm lub hnub nyoog tab sis tsis yog ntawm tus kab mob hnyav Cov kws sau ntawv kuj tau pom qhov tsis zoo sib xws ntawm hnub nyoog thiab kev tiv thaiv S IgG hauv cov neeg mob uas tsis yog-MISC-C thiab kev sib raug zoo ntawm hnub nyoog thiab kev tiv thaiv. -N IgG titers hauv cov neeg laus uas muaj mob me me [77]. Neutralizing antibody teb tau qis dua ntawm ob pawg menyuam yaus piv rau ob pawg neeg laus. Txawm hais tias muaj qhov poob qis hauv kev ua haujlwm nruab nrab nrog cov neeg mob hnub nyoog hauv pawg menyuam yaus uas tsis yog MIS-C, tsis muaj kev sib raug zoo ntawm kev ua haujlwm ntawm neu-realizing thiab cov neeg mob hnub nyoog hauv pawg neeg laus [77]. Zuag qhia tag nrho, cov txiaj ntsig no qhia txog kev tiv thaiv kab mob sib txawv, nrog rau cov kev kawm kis kab mob, hauv cov menyuam yaus thiab cov neeg laus.

2.2. Tiv thaiv cov tshuaj tiv thaiv kab mob

Nws yog qhov txaus siab rau kev tsim tshuaj tiv thaiv, nrog rau kev tiv thaiv kab mob thiab kev tiv thaiv kab mob, kom nkag siab txog ob qho tib si epitope qhov tshwj xeeb thiab kev ua haujlwm ntawm kev tiv thaiv cov lus teb. Raws li cov qauv tsiaj, tshwj xeeb tshaj yog nas, hamsters, thiab tsis yog tib neeg primates, nws yog qhov tseeb tias neutralizing monoclonal.antibodies (mAbs) qhia tawm tsam S lossis RBD ntawm S tuaj yeem hloov kho SARS-CoV-2 kab mob. Piv txwv li, Hassan et al. Ua qauv qhia nyob rau hauv nas transduced nrog adenovirus encoding tib neeg ACE2 (hACE2) tias qhov dej ntawm chimeric neutralizing mAb ib hnub ua ntej kev sib tw intranasal nrog SARS-CoV-2 tuaj yeem txo cov kab mob hauv lub ntsws thiab txo qis kev mob thiab poob phaus [78] . Lwm txoj kev tshawb fawb pom tau tias muaj kev tiv thaiv zoo sib xws ntawm tib neeg mAbs hauv hACE2-cov nas hloov pauv tau sib tw nrog SARS-CoV-2 thiab hauv cov tsiaj qus BALB/C cov nas sib tw nrog nas-adapted strain ntawm SARS-CoV{{ 13] [79] ib. Tib mAbs muab peb hnub ua ntej qhov kev sib tw hauv rhesus macaques ua rau tsis muaj tus kab mob kuaj pom hauv qhov ntswg qhov ntswg lossis bronchoalveolar lavage kua [79]. Kev siv tshuaj tiv thaiv ntawm tib neeg mAb kuj tseem ua tau zoo hauv kev txo cov kab mob ntsws ntsws thiab poob phaus hauv hamsters [80]. Cov txiaj ntsig tsawg dua tau pom thaum mAb tau muab ob teev tom qab tus kab mob sib tw. Lwm txoj kev tshawb fawb hauv hamsters nrog mAb sib txawv kuj tau pom nyob rau hauv vivo tiv thaiv nrog txo tus kab mob ntsws thiab txo qhov hnyav [81]. Qee qhov nruab nrab mAbs kuj muaj nyob rau hauv vitro Fc-receptor-mediated kev ua haujlwm [55,82]. Txawm li cas los xij, rau peb txoj kev paub, tsis muaj pov thawj ncaj qha tias cov tshuaj tiv thaiv tsis muaj nruab nrab uas tuaj yeem ua rau cov tshuaj tiv thaiv kab mob ntawm cov cellular cytotoxicity (ADCC) lossis lwm yam Fc- receptor-mediated antibody kev ua ub no tuaj yeem tiv thaiv lossis hloov kho kab mob. Hauv tib neeg, cov plasma convalescent tau txais los ntawm cov tib neeg uas tau zoo los ntawm COVID-19 tau raug tshuaj xyuas rau ob qho tib si ua ntej kev tiv thaiv thiab kev kho tus kab mob tsim. Txog kev kho mob, muaj cov cim qhia los ntawm cov ntaub ntawv tau txais sab nraud ntawm kev sim randomized tias thaum muab ntxov, convalescent plasma muaj qee yam cuam tshuam rau kev kis kab mob. Cov plasma zoo li no yuav ua haujlwm zoo dua thaum muab ua ntej, thiab tej zaum yuav muaj kev sib raug zoo ntawm kev ua tau zoo thiab kev ua haujlwm nruab nrab ntawm plasma [83]. Txawm li cas los xij, qhov loj, qhib-label randomized soj ntsuam kev sim ua nyob rau hauv Is Nrias teb tsis txhawb qhov kev ua tau zoo ntawm cov ntshav plasma ntawm cov neeg mob hauv tsev kho mob uas muaj tus kab mob sib kis loj heev -19 [84]. Lwm qhov kev sim loj tsis tu ncua yog ntsuas kev siv cov ntshav plasma hauv kev tiv thaiv thiab kho. mAbs nrog rau kev ua haujlwm nruab nrab kuj tseem raug tshuaj xyuas rau kev kho mob me thiab mob hnyav COVID-19 hauv kev tshawb fawb soj ntsuam randomized. Cov txiaj ntsig tau los ntawm ib qho ntawm cov kev sim tsis tu ncua tau luam tawm thiab pom tias muaj kev txo qis hauv kev kis kab mob thiab mus pw hauv tsev kho mob hauv cov neeg tau txais mAb [85].

Thaum tseem tos cov ntaub ntawv tseem ceeb ntxiv ntawm lub luag haujlwm ntawm neutralizing cov tshuaj tiv thaiv kab mob hauv kev tiv thaiv tib neeg los ntawm COVID-19, nws tau lees paub tias cov neeg uas muaj cov tshuaj tiv thaiv yav dhau los uas tau raug rau ntawm lub nkoj nuv ntses rau SARS-CoV-2 tsis tau rov qab. - mob [86]. Tsis tas li ntawd, ib tus neeg mob rov kis tus kab mob no tau pom tias tsis muaj qhov cuam tshuam rau kev kis tus kab mob thawj zaug, qhia txog qhov muaj peev xwm ua rau qhov tsis zoo li no tau tso cai rau rov kis tus kab mob [87]. Thaum kawg, hauv tsev neeg ntawm ob niam txiv nrog PCR-confirmed symptomatic SARS-CoV{11}} tus kab mob, tag nrho peb ntawm lawv cov asymptomatic, pheej rov PCR-tsis zoo cov me nyuam muaj salivary anti-CoV-2 antibodies (feem ntau yog IgA) [ 88] ib. Qhov no qhia tau hais tias cov menyuam yaus tuaj yeem txhim kho lub cev tiv thaiv kab mob uas tiv thaiv kev tsim ntawm SARS-CoV-2 [88]. Muab cov ntaub ntawv cog lus tsiaj, zoo li, cov tshuaj tiv thaiv uas tuaj yeem cuam tshuam cov qib txaus ntawm cov tshuaj tiv thaiv kab mob tsawg kawg yuav txhim kho cov txiaj ntsig tom qab tus kab mob SARS-CoV-2.

2.3. Neutralizing antibody epitopes

Muab qhov txiaj ntsig ntawm kev ua kom tsis muaj zog ntawm kev tsis sib haum xeeb ntawm mAbs hauv cov qauv tsiaj, nws yog ib qho tseem ceeb uas yuav tsum ua kom pom cov epitopes uas khi rau xws li mAbs. Ntau cov epitopes hauv S tau raug sau tseg los khi rau cov tshuaj tiv thaiv kab mob. Inhibition ntawm binding los ntawm RBD rau hACE2 yog lub mechanism uas feem ntau neutralizing antibodies inhibit SARS-CoV-2 [55,89]. Txawm li cas los xij, neutralizing epitopes uas tsis thaiv ACE2 los yog khi sab nraum RBD tau raug txheeb xyuas [90–94]. Piv txwv li, qee qhov ntawm cov tshuaj tiv thaiv kab mob sterically inhibit RBD-hACE2 kev sib cuam tshuam lossis kev hloov pauv hloov pauv uas txwv kev khi. mAbs kuj tseem tuaj yeem cuam tshuam cov kab mob los ntawm inhibiting fusion, txheej txheem uas kho los ntawm thaj tsam S2 ntawm cov kab mob sib kis. Txawm hais tias kev ua haujlwm nruab nrab tshwm sim nrog kev tiv thaiv lub cev ntawm ntau cov noob caj noob ces, muaj kev nyiam rau peb Ig hnyav hloov pauv cov noob [89].

2.4. Antibody-dependent enhancement of infection (ADE)

ADE hais txog qhov tshwm sim uas cov tshuaj tiv thaiv kab mob nce tus kab mob sib kis, feem ntau los ntawm Fc lossis ntxiv cov receptors, thiab tau piav qhia hauv vitro rau ntau tus kab mob [95]. Hauv vivo, ADE tej zaum yuav yog lub luag haujlwm rau feem ntau ntawm cov kab mob dengue mob hnyav [96,97]. Tsis tas li ntawd, ADE koom nrog cov kab mob ntawm tus mob coronavirus feline infectious peritonitis virus [98,99]. Hauv vitro thiab qee cov ntaub ntawv hauv vivo taw qhia txog lub luag haujlwm ntawm ADE hauv MERS thiab SARS [100–102]. Hais txog COVID-19, ADE tau raug coj los ua kev txhawj xeeb rau cov tshuaj tiv thaiv thiab tau thov kev kho mob ntshav qab zib mAb, thiab yog qhov muaj peev xwm ua rau muaj kab mob. Txawm li cas los xij, txog niaj hnub no, tsis muaj cov lus ceeb toom txog qhov tshwm sim tsis zoo ntawm cov neeg tau txais cov tshuaj tiv thaiv, thiab tsis muaj kev sim tshuaj kho mob lossis kev nthuav dav siv cov ntshav plasma lossis mAbs tau nthuav tawm cov xwm txheej tsis zoo cuam tshuam txog ADE. Sib nrug los ntawm ib txoj kev tshawb fawb hauv hamsters qhov kev kho tshuaj tiv thaiv zoo li tau ua rau qhov tsis muaj qhov tseem ceeb tshaj qhov hnyav dua li cov tsiaj tsis kho, tam sim no tsis muaj pov thawj hauv vivo ntawm ADE tshwm sim hauv qhov teeb meem ntawm SARS-CoV-2 kab mob [81]. Ntxiv rau kev txhawj xeeb txog cov tshuaj tiv thaiv lossis kev siv tshuaj tiv thaiv kab mob, cov lus teb de novo antibody muaj peev xwm los kho ADE lossis pab txhawb rau pathogenesis lwm yam. Qhov no yuav ua tau raws li qhov tseeb tias qhov tshwm sim hnyav ntawm COVID-19 feem ntau tshwm sim tom qab thawj lub lim tiam ntawm kev mob, thaum lub sij hawm thaum cov tshuaj tiv thaiv tsis pom thiab thaum cov kab mob kis tau tsawg [4,103,104]. Raws li tau sau tseg saum toj no, qhov kev sib raug zoo ntawm cov tshuaj tiv thaiv kab mob thiab cov kab mob hnyav kuj zoo ib yam nrog lub luag haujlwm ntawm pathogenesis hauv de novo antibody teb tawm tsam SARS-CoV-2. Hauv qhov no, ib daim ntawv tsis ntev los no, tseem tsis tau txheeb xyuas, pom muaj kev sib koom ua ke ntawm cov tshuaj tiv thaiv rau ib qho epitope hauv N thiab mob hnyav [45]. Thaum kawg, txawm hais tias cov ntaub ntawv tsis muaj, cov tshuaj tiv thaiv ua ntej rau lwm tus CoVs tuaj yeem cuam tshuam qhov tshwm sim ntawm COVID-19 hauv qhov tsis zoo (lossis muaj txiaj ntsig).

3. Cov lus xaus

Nyob rau lub sijhawm luv luv ntawm tsawg dua ib xyoos, ntau tau kawm txog SARS-CoV-2-kev tiv thaiv kab mob tshwj xeeb. Muaj ntau txoj hauv kev, kev tiv thaiv zoo li zoo ib yam li qhov uas tau txais los ntawm lwm yam kab mob. Nyob rau hauv tas li ntawd, nws yog zoo li hais tias cov tshuaj tiv thaiv-mediated tiv thaiv yuav cia siab rau neutralizing antibodies thiab hais tias ib tug txaus thiab ruaj teb cov lus teb yuav xav tau kev pab T-cell. Tsis tas li ntawd, T hlwb yuav muaj feem cuam tshuam los tswj kev kis kab mob. Txawm li cas los xij, cov lus nug tseem ceeb tseem tsis tau teb. Txawm li cas los xij, kev siv tshuaj tiv thaiv lub cev muaj peev xwm txaus rau kev tiv thaiv kab mob los yog, thaum ntxov tom qab kis kab mob, tuaj yeem hloov kho cov kab mob, lawv lub luag haujlwm tseem ceeb hauv pathogenesis tseem tsis meej. Ib yam li ntawd, los yog tsisSARS-CoV-2-T cells tshwj xeeb tuaj yeem tiv thaiv kev kis kab mob lossis ua lub luag haujlwm hauv pathogenesis tsis paub. Txij li cov kab mob hloov zuj zus nyob rau hauv lub cev tsis muaj zog, nws yog ib qho tseem ceeb uas yuav tsum tau ceev faj txog SARS-CoV-2 hom kab mob uas tiv thaiv kab mob los yog tshuaj tiv thaiv kab mob humoral lossis cellular tiv thaiv kab mob. Cov kev tsis txaus ntseeg tseem ceeb tseem hais txog seb puas muaj kev tiv thaiv kab mob rau lwm tus mob coronaviruses ua rau COVID-19 qhov tshwm sim thiab seb puas tau kis tus kab mob SARS-CoV-2 tuaj yeem ua rau muaj kev tiv thaiv kab mob thaum tsis muaj tus kab mob rov ua dua tshiab. Thaum kawg, kev ua haujlwm ntev ntawm ob qho tib si humoral thiab T-cell tiv thaiv tau txais tom qab kis kab mob yog qhov tsis paub tseeb, muab lub sijhawm luv ntawm kev paub nrog cov kab mob.