Kev soj ntsuam ntawm Antibody Neutralization Activity Tawm tsam SARS-CoV-2 Variants Thiab Seasonal Human Coronaviruses NL63, HKU1, Thiab 229E Induced Los ntawm Peb Qhov Sib Txawv ntawm COVID-19 Cov Platforms Tshuaj Tiv Thaiv
Oct 26, 2023
Abstract: Kev kis tus kabmob Coronavirus, ua rau muaj kev cuam tshuam tsis ntev los no ntawm tus mob ua pa nyuaj ua pa mob coronavirus 2 (SARS-CoV-2) kis thoob qhov txhia chaw pib xyoo 2019, tau hais txog qhov tseem ceeb ntawm cov tshuaj tiv thaiv zoo los txhawb cov tshuaj tiv thaiv kab mob nrog kev ua haujlwm sib luag. Cov tshuaj tiv thaiv COVID-19 tau tsim sai heev los txo lub nra ntawm SARS-CoV-2 kab mob thiab kab mob hnyav. Kev tiv thaiv hla los ntawm kev kis tus kab mob raws caij nyoog tib neeg tus mob coronavirus (hCoV) tau raug kwv yees tab sis tseem muaj teeb meem. Ntawm no, peb tau tshawb xyuas qhov kev ua haujlwm tsis zoo tawm tsam poj koob yawm txwv SARS-CoV-2 thiab qhov sib txawv ntawm kev txhawj xeeb (VOCs) hauv cov tib neeg tau txhaj tshuaj tiv thaiv ob koob ntawm BNT162b2, mRNA-1273, lossis AZD1222, nrog lossis tsis muaj keeb kwm of SARS-CoV-2 infection. Antibody neutralizing kev ua haujlwm rau SARS-CoV-2 thiab VOCs tau siab dua hauv BNT162b2- cov neeg tau txhaj tshuaj tiv thaiv uas yav dhau los kis tus kab mob SARS-CoV-2 thiab tau muab kev tiv thaiv dav dav. Omicron BA.1 variant yog qhov tiv taus tshaj plaws ntawm VOCs. Kev txhaj tshuaj tiv thaiv COVID-19 tsis muaj kev tiv thaiv tiv thaiv hCoV-HKU1. Hloov pauv, cov tshuaj tiv thaiv kab mob tshwm sim los ntawm mRNA-1273 txhaj tshuaj tiv thaiv tau nthuav tawm kev txhawb nqa hauv lawv qhov kev ua haujlwm nruab nrab tiv thaiv hCoV-NL63, thaum AZD1222 txhaj tshuaj tiv thaiv kab mob ua rau muaj kev tiv thaiv tsis zoo tiv thaiv hCoV-229E, qhia txog qhov sib txawv ntawm cov tshuaj tiv thaiv kab mob thiab kev tiv thaiv kab mob sib txawv. tsim siv los ntawm ntau qhov chaw txhaj tshuaj tiv thaiv. Cov ntaub ntawv no yuav qhia tias tej zaum yuav muaj kev sib koom epitopes ntawm HCoVs thiab SARS-CoV-2 spike proteins.
Keywords: SARS-CoV-2; raws caij nyoog; HKU1; 229E; NL63; neutralization
cistanche tubulosa- txhim kho lub cev tiv thaiv kab mob
1. Taw qhia
Thaum Lub Kaum Ob Hlis 2019, qhov tshwm sim ntawm tus kabmob tshiab muaj npe hu ua mob hnyav ua pa nyuaj ua pa mob coronavirus 2 (SARS-CoV-2) tau kis thoob plaws ntiaj teb, ua rau muaj kev sib kis thoob ntiaj teb [1]. Txij thaum ntawd los, kev siv zog thoob ntiaj teb los tsim kom muaj kev kho mob tsim nyog tau ua rau muaj kev txhim kho ntau lub chaw txhaj tshuaj thiab lwm yam tshuaj tiv thaiv kab mob. Qhov kev hloov pauv zuj zus zuj zus tau muaj qhov txo qis ntawm qhov ua tau zoo ntawm cov tshuaj tiv thaiv kab mob nruab nrab uas tau tsa los ntawm yav dhau los tus kab mob SARS-CoV-2 lossis los ntawm kev txhaj tshuaj [2,3]. Lub Koom Haum Saib Xyuas Kev Noj Qab Haus Huv Ntiaj Teb (WHO) tau txheeb xyuas qhov teeb meem sib txawv raws li qhov sib txawv ntawm kev txhawj xeeb (VOC), thaum lwm cov kev hloov pauv uas tsis ua raws li cov qauv zoo ib yam poob rau hauv kev sib txawv ntawm kev txaus siab (VOI) lossis qhov sib txawv hauv kev tshawb xyuas (VUI). Muaj ntau qhov kev tsom mus rau qhov sib txawv thiab lawv cov yam ntxwv, xws li tshuaj tiv thaiv kab mob evasion thiab rov ua dua tus nqi, nrog ntau cov kev tshawb fawb sib piv cov sib txawv thiab lawv lub peev xwm los nruab nrab [4–8], raws li kev sib kis mus ntxiv mus.
cistanche tubulosa- txhim kho lub cev tiv thaiv kab mob
SARS-CoV-2 belongs to Coronaviridae family that include SARS-CoV-1 [9], Middle Eastern respiratory virus (MERS) [10], and four human coronaviruses 229E, HKU-1 , NL63, and OC43 [11] (Figure 1A). Txawm hais tias SARS-CoV-1 thiab MERS tau muaj kev sib kis uas ua rau mob hnyav rau tib neeg [12], plaub lwm tus kabmob coronaviruses, feem ntau hu ua raws caij nyoog lossis tib neeg tus kabmob coronaviruses (HCoVs), feem ntau ua rau mob me me zoo ib yam li tus mob khaub thuas. [11,13]. Txawm li cas los xij, qee zaus, HCoVs tuaj yeem ua rau mob hnyav [14–16]. SARS-CoV-2, ua ke nrog NL63, siv angiotensin-converting enzyme 2 (ACE2) raws li nws cov cell nkag mus rau lub cev loj [17,18]. Txawm hais tias HKU1 thiab OC43 muaj kev cuam tshuam ntau dua rau SARS-CoV-2, lawv khi rau sialic acids raws li hom kev nkag [19], qhov cuam tshuam ntau dua 229E siv human aminopeptidase (hAPN) [20]. (Daim duab 1B).
Daim duab 1. Phylogenetic tsob ntoo ntawm cov tswv cuab hauv tsev neeg Coronaviridae. * qhia txog cov protein ntau uas tau siv hauv txoj kev tshawb no (A). Structures of spike proteins of SARS-CoV-2, and three of the seasonal HCoVs; HKU1, NL63, thiab 229E, uas tau siv hauv txoj kev tshawb no (B). (PDB codes: 6VXX, 60HW, 6U7H, 5I08, thiab 5SZS). Grey qhia txog S2 lub npe, thaum lub teeb xiav yog N-terminal sau ntawm S1 subunit, thiab xiav tsaus sawv cev rau S1 subunit ntxiv. NL63 muaj ib qho ntxiv teal-coloured seem sawv cev rau ib cheeb tsam tshwj xeeb hauv S1 domain tsis tau pom nyob rau hauv lwm cov kab mob coronaviruses [21].
Thaum pib muaj kev sib kis, muaj kev sib cav txog qhov ua tau tias cov tshuaj tiv thaiv tau tsa tawm tsam HCOVs muaj lub luag haujlwm hauv kev tiv thaiv SARS-CoV-2 [22–25]. Txij thaum ntawd los, kev nce siab hauv HCoVs tau ua rau muaj kev nkag siab txog kev tiv thaiv kab mob uas lawv tsim. Ntau cov ntawv tshaj tawm uas tshawb xyuas qhov cuam tshuam ntawm HCoVs vam khom rau kev siv cov ntawv txheeb xyuas xws li enzyme-linked immunosorbent assays (ELISA) uas ntsuas cov tshuaj tiv thaiv kab mob sib txuas tab sis tsis tau qhia lawv cov peev xwm ua kom tsis muaj zog. Tsis tas li ntawd, kev vam meej ntawm ntau yam tshuaj tiv thaiv platform tau siv los tiv thaiv tib neeg los ntawm kev kis kab mob thiab kab mob hnyav [26], txawm hais tias lawv cov txiaj ntsig tau poob qis dua li qhov tshiab thiab ntau dua kev tiv thaiv kab mob tshwm sim [27]. Ntawm no, peb siv cov kab mob lentiviral-based pseudotyped viruses ntawm SARS-CoV-2, VOCs/VOI, thiab HCoVs, los ntsuas lub zog ntawm cov tshuaj tiv thaiv kab mob hauv nruab nrab uas tshwm sim los ntawm ob koob ntawm BNT162b2 (Pfizer), AZD1222 (Astrazeneca), or mRNA-1273 (Moderna) tiv SARS-CoV-2 and variants B.1.1.7 (Alpha), B.1.351 (Beta), P.1 (Gamma), B.1.617.2 ( Delta), B.1.525 (Eta), thiab B.1.1.529 (Omicron BA.1) (Daim duab 2), thiab seb ib qho ntawm cov tshuaj tiv thaiv no puas tuaj yeem ua rau muaj kev tiv thaiv tsis zoo tiv thaiv HCoVs 229E, HKU1, lossis NL63.
Figure 2. SARS-CoV-2 variants spike mutations siv nyob rau hauv txoj kev tshawb no.
2. Cov ntaub ntawv thiab cov txheej txheem
2.1. Cov ntaub ntawv sau serum neeg mob / Ethics
Sera cov qauv raug sau los ntawm 36 cov neeg mob noj qab haus huv uas tau txhaj tshuaj tiv thaiv. Txoj kev tshawb no tau pom zoo los ntawm San Raffaele Scientific Hospital Ethical Committee (txoj cai tus lej 68/INT/2020). Txhua tus neeg mob rau npe tau sau ntawv tso cai.
2.2. Phylogenetic Tsob Ntoo thiab Similarity Plot
Qhov siab tshaj plaws phylogenetic reconstruction raws li cov noob caj noob ces codon kev sib raug zoo, tau tsim siv ntoo (version 1.6.12) [28] nrog 10, 000 ultra-ceev bootstrap replicates [29] thiab TVM + F + I + G4 hloov qauv, xaiv siv ModelFinder [30]. The sequence similarity plot was builded by aligning spike protein sequences of SARS CoV-2 (QHD43416.1), HKU1 (YP_173238.1) 229E (NP_073551.1) and NL63 ( YP_003767.1), siv lev (version 7.453) [31] (gene pair option) thiab visualized siv D3 JavaScript pob siv nyob rau hauv observable (https://observablehq.com/@spyros-lytras/seasonal cov -spike nkag rau 3 Kaum Ib Hlis 2022).
2.3. Kab lis kev cai
Tib neeg lub raum embryonic 293T/17 (HEK293T/17) hlwb thiab tib neeg hepatocytes Huh- 7 hlwb tau khaws cia hauv DMEM ntxiv nrog 10% fetal bovine serum thiab 1% penicillin / streptomycin. Suav zes qe menyuam hamster (CHO) hlwb tau khaws cia hauv Ham's F12 ntxiv nrog 10% fetal bovine serum thiab 1% penicillin / streptomycin. Cells tau dhau los ua ntu zus los tiv thaiv qhov tsis sib xws los ntawm kev ntxuav nrog phosphate-buffered saline tov thiab tshem tawm nrog trypsin-EDTA. Tag nrho cov hlwb raug incubated ntawm 37 ◦C thiab 5% CO2.
cistanche tsob nroj-nce kev tiv thaiv kab mob
2.4. Pseudotype Virus Production
Tag nrho cov pseudotypes (PVs) tau tsim tawm raws li tau piav qhia yav dhau los [32]. Luv luv, 1000 ng of pc-DNA 3.1+ plasmid bearing the spike of ancestral SARS-CoV-2, variants Alpha, Beta, Delta, Gamma, Eta, Omicron Ba. 1, los yog HCoVs 229E, HKU1, thiab NL63 tau sib xyaw nrog 1000 ng ntawm p8.91 plasmid encoding HIV Gag-pol thiab 1500 ng ntawm pCSFLW plasmid uas muaj Renilla firefly luciferase reporter gene thiab co-transfected mus rau T hlwb ntawm 203% hauv T-75 cov dej haus siv FuGENE-HD. HKU-1 xav tau ib kauj ruam ntxiv ntawm kev ntxiv 1.5 U ntawm exogenous neuraminidase (Sigma) hauv 10 mL ntawm DMEM ntxiv 24 teev tom qab hloov pauv. Txhawm rau sau cov kab mob pseudotyped, cov xov xwm tau tawm mus rau 48 teev tom qab ib hnub ntawm kev hloov pauv thiab lim siv 0.45 µm cellulose acetate lim. Tag nrho cov PVs tau aliquoted thiab khaws cia ntawm −80 ◦C rau cia. Tom qab rov ua dua, peb tsis tuaj yeem ua tus pseudotype HCoV OC43.
2.5. Pseudotype Virus Titration
Tag nrho cov PVs tau titrated raws li tau piav ua ntej [32]. Target cells for SARS-CoV-2, variants, and HCoV NL63 tau npaj ib hnub ua ntej titration los ntawm transfecting ACE-2 thiab TRSSMP2. CHO hlwb tau siv los ua lub hom phiaj rau HKU-1, thiab Huh-7 hlwb tau siv los ua lub hom phiaj rau 229E. Luv luv, 50 µL ntawm PV tau sau tau ntxiv rau hauv kab saum toj kawg nkaus ntawm F-hauv qab 96-zoo phaj (Nunc), thiab serially diluted siv DMEM lossis Ham's F-12 rau HKU-1 PVs nyob rau hauv ib nrab kauj ruam mus rau kab hauv qab ntawm lub phaj ua ntej ntxiv ntawm 10, 000 phiaj hlwb hauv txhua qhov dej. Cov phaj raug xa rov qab mus rau qhov chaw tsim khoom rau 48 teev ua ntej lysis nrog Bright-Glo reagent thiab soj ntsuam cov kab mob luciferase cov neeg ua haujlwm hauv cov kab txheeb ze (RLU) siv Glo-Max luminometer. PV titers raug tshaj tawm hauv RLU/mL.
cistanche tubulosa- txhim kho lub cev tiv thaiv kab mob
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2.6. Pseudotype Microneutralisation (pMN) Kev soj ntsuam
Qhov kev ntsuam xyuas pMN tau ua raws li tau piav qhia dhau los. Luv luv, convalescent sera tau tov nrog DMEM los yog Ham's F-12 ntawm qhov pib 1:40 dilution thiab ces serially diluted 2-fold hauv ib lub tiaj tiaj dawb hauv qab 96-zoo phaj mus rau qhov kawg ua 1:5120. Tag nrho cov qauv tau rov ua dua. PVs tau ntxiv rau txhua qhov dej ntawm qhov kev nkag ntawm 1 × 106 RLU / mL. Cov phaj tau xa rov qab mus rau lub tshuab nqus tsev kab lis kev cai rau 1 h, ua ntej qhov sib ntxiv ntawm pre-transfected ACE-2/TRSSMP2 HEK293T phiaj hlwb lossis CHO hlwb rau HKU-1 thiab Huh{16}} hlwb rau 229E, ntawm qhov ceev ntawm 1 × 104 cell ib qhov dej. Cov phaj raug xa rov qab mus rau qhov chaw tsim khoom rau 48 teev ua ntej lysis nrog Bright-Glo reagent thiab soj ntsuam cov kab mob luciferase cov neeg ua haujlwm hauv cov kab txheeb ze (RLU) siv Glo-Max luminometer. IC50s tau suav nrog GraphPad Prism 8 software siv qhov tsis-linear regression nkhaus raws li tau piav qhia hauv [33].
2.7. Kev txheeb cais
Wilcoxon matched-pair ranked tests tau siv los ntsuas qhov tseem ceeb ntawm kev sib tw. Kruskal-Wallis ANOVA xeem tau siv los ntsuas qhov tseem ceeb thaum muab piv IC50 titers ntawm peb lub platform tshuaj tiv thaiv. Txhua qhov kev xeem tau siv rau ntawm GraphPad Prism 8 software.
3. Cov txiaj ntsig
3.1. Cohort yam ntxwv
Txhawm rau txheeb xyuas qhov muaj peev xwm ua tsis tau zoo ntawm SARS-CoV-2 cov tshuaj tiv thaiv tshwj xeeb tiv thaiv SARS CoV-2 VOCs thiab hCoVs, sera tau los ntawm ob-dosed BNT162b2- txhaj tshuaj tiv thaiv (n=13), AZD1222- txhaj tshuaj tiv thaiv (n=16) thiab mRNA-1273- txhaj tshuaj tiv thaiv (n=7) cov neeg uas muaj thiab tsis muaj keeb kwm ntawm SARS-CoV-2 kab mob tau raug tshuaj xyuas ( Table 1).
Table 1. Cov pej xeem thiab cov yam ntxwv kho mob ntawm pawg neeg.
3.2. Neutralization of SARS-CoV-2 Variants
Peb thawj zaug ua pMN kev soj ntsuam los soj ntsuam qhov loj ntawm qhov tsis zoo ntawm cov tshuaj tiv thaiv kab mob tiv thaiv cov poj koob yawm txwv SARS-CoV-2 thiab ntau yam, tsis hais txog hom tshuaj tiv thaiv (Daim duab 3A). Peb cov txiaj ntsig tau pom tias Omicron BA.1 yog qhov nruab nrab VOC tsawg tshaj plaws (24-fold txo, p =< 0.0001). As expected, we observed the samples from individuals with prior infection had higher neutralisation titers compared with immunologically naïve subjects. The serum from previously infected individuals (Figure 3B), neutralized the Alpha variant more effectively compared with the ancestral strain, as it showed a 1.3-fold decrease in median IC50 titre, followed by Eta and Delta variants, (3.4- and 4.5-fold decrease, respectively). Beta and Gamma variants were more resistant to neutralization (10.9- and 9.7-fold decrease, respectively), and Omicron BA.1 reached a 16.1-fold decrease compared with ancestral SARS-CoV-2. Notably, the majority of these subjects had received the BNT162b2 vaccine. Taken together, these results suggested that in vaccinated subjects the pre-existing immunity raised by natural infection with SARS-CoV-2, or a VOC is more effective in protecting against the spectrum of variants that emerged later over time, compared with immunity triggered by vaccination only. However, the recently emerged variants evolved mechanisms to evade the neutralizing antibody response.
Daim duab 3. Lub peev xwm ntawm cov tshuaj tiv thaiv kab mob hauv cov ntshav los tiv thaiv SARS-CoV-2 thiab VOCs los ntawm cov tib neeg tau txhaj tshuaj tiv thaiv ob koob ntawm BNT162b2, AZD1222, lossis mRNA-1273. Neutralizing antibody teb tawm tsam poj koob yawm txwv SARS-CoV-2 thiab variants, nyob rau hauv yav dhau los cov neeg muaj kab mob (xiav) thiab cov neeg tsis muaj kab mob (liab) tau txais ob koob tshuaj BNT162b2, AZD1222, lossis mRNA-1273 tshuaj tiv thaiv (A) . Wilcoxon matched-pairs tau kos npe rau qib kev ntsuam xyuas kev txheeb xyuas tau siv los sib piv cov poj koob yawm txwv SARS-CoV-2 tawm tsam txhua qhov sib txawv (A). Neutralization profiles ntawm sera los ntawm BNT162b2-cov neeg mob tau txhaj tshuaj nrog keeb kwm ntawm kev kis kab mob ua ntej. Tsis muaj kev ntsuas ntsuas tau siv rau BNT162b2 hauv vaj huam sib luag C vim yog cov qauv me me nrog qhov sib txawv loj. (B). Neutralization profiles ntawm peb hom tshuaj tiv thaiv kab mob sib txawv (C) thiab sib piv ntawm cov tshuaj tiv thaiv platform. (D) Wilcoxon matched-pairs signed rank tests statistical analysis tau siv los sib piv cov poj koob yawm txwv SARS-CoV-2 tawm tsam txhua qhov sib txawv hauv vaj huam sib luag C. Kruskal–Wallis ANOVA tau siv rau kev txheeb xyuas txheeb cais hauv vaj huam sib luag D. ns {{23} } tsis tseem ceeb, * p < 0.05, ** p < 0 01, *** p < 0.001, **** p Less tshaj los yog sib npaug 0.0001.
Tom qab ntawd peb txheeb xyuas cov neeg uas tsis tau ntsib tus kab mob SARS-CoV-2 ua ntej txhaj tshuaj tiv thaiv (Daim duab 3C). Qhov kev ua tau zoo ntawm txhua qhov kev txhaj tshuaj tiv thaiv tau raug tshuaj xyuas nrog rau kev muaj peev xwm ua kom tsis zoo rau ob qho tib si poj koob yawm txwv thiab nws qhov sib txawv. Peb tau pom tias cov sera los ntawm BNT162b2- cov neeg tau txhaj tshuaj muaj qhov nruab nrab ntawm IC50 titers piv nrog cov tau txais los ntawm mRNA-1273- thiab AZD1222- cov neeg tau txhaj tshuaj. Txawm hais tias Alpha variant tsis pom kev tiv thaiv kev tiv thaiv nyob rau hauv ib qho ntawm cov tshuaj tiv thaiv, tag nrho cov VOCs tau tiv taus cov tshuaj tiv thaiv kab mob rau ntau qib (Daim duab 3C). Peb tsis tuaj yeem rho tawm cov ntsiab lus tseem ceeb los ntawm BNT162b2 cov qauv vim muaj qee qhov qauv (n=5) nrog kev sib kis loj heev hauv IC50 titres. Peb tsis tau soj ntsuam qhov sib txawv ntawm qhov sib txawv ntawm peb lub platform tshuaj tiv thaiv nrog rau lawv lub peev xwm los cuam tshuam cov Alpha, Eta, Beta, Gamma, thiab BA.1 variants. Hloov pauv, qhov sib txawv loj tshaj plaws ntawm peb hom tshuaj tiv thaiv tau pom nrog cov poj koob yawm txwv thiab Delta variants, raws li mRNA-1273 pom 1.6- thiab 1.4-fold txo qis hauv nruab nrab IC50 titers, feem. , piv nrog BNT162b2, whereas AZD1222 pom ib 3.8- thiab 4.1-fold txo (Daim duab 3D).
3.3. Neutralization of Seasonal HCoVs
Txhawm rau txiav txim siab seb kev txhaj tshuaj tiv thaiv kab mob SARS-CoV-2 puas tuaj yeem tiv thaiv kab mob HCoVs raws caij nyoog, peb nug seb puas muaj tus kab mob ua ntej nrog SARS-CoV-2 puas muaj kev cuam tshuam rau cov tshuaj tiv thaiv kab mob nruab nrab ntawm HCoVs (Figure 4A ). Peb tau pom tsis muaj qhov nce ntxiv hauv qhov tseem ceeb hauv kev tsis sib haum xeeb tawm tsam 229E lossis HKU-1 ntawm yav dhau los SARS-CoV-2 tus kab mob thiab cov neeg tsis zoo. Conversely, ib qho kev txo qis hauv kev tsis sib haum xeeb tawm tsam NL63 tom qab kev tswj hwm koob thib ob tau pom nyob rau hauv cov tshuaj tiv thaiv uas tau ntsib tus kab mob SARS-CoV-2 (p=0.033) piv nrog cov naïve (p {{ 16.063). Tom qab ntawd peb tau soj ntsuam seb puas yog ib lossis ntau qhov ntawm cov tshuaj tiv thaiv kab mob yuav txhawb nqa titers tiv thaiv HCoVs hauv txhua yam kev kawm, tsis hais txog lawv qhov xwm txheej dhau los (Daim duab 4B). Zuag qhia tag nrho, hauv kev txhaj tshuaj tiv thaiv, qhov nruab nrab antibody neutralization titers tiv thaiv NL63 tau siab dua piv nrog cov tiv thaiv 229E thiab HKU1, tsis hais txog lub platform tshuaj tiv thaiv (Daim duab 4B). Qhov tseem ceeb, NL63 siv ACE2 ua qhov nkag mus rau hauv lub hom phiaj hlwb, zoo li SARS-CoV-2. Hom tshuaj tiv thaiv tsis muaj kev cuam tshuam rau kev txhawb nqa kev ua haujlwm nruab nrab tiv thaiv peb lub caij mob coronaviruses peb tau kawm tom qab kev tswj hwm koob thib ob, tshwj tsis yog NL63 thiab HKU1. IC50 titers tiv thaiv NL63 tau nce ntxiv tom qab koob thib ob siv mRNA-1273 (p=0.03), thaum 229E pom qhov nce ntxiv hauv IC50 titer hauv AZD nkaus xwb1222- cov neeg tau txhaj tshuaj (p { {37}}< 0.001). Conversely, after the second boost of the BNT162b2 vaccine, neutralization titers against HCoV HKU-1 decreased, probably due to the selection of antigen-specific plasma cells with lower affinity for the HKU1 spike. To better understand the impact of COVID-19 vaccination on the protection from seasonal HCoVs in subjects with or without a history of SARS-CoV-2 infection, we analysed the spike protein similarity of HCoVs HKU1, NL63, 229E, and SARS-CoV-2 to investigate whether a particular region could explain the neutralization differences (Figure 4C). The similarity plot generated by comparing pairwise similarity showed HKU1 had higher similarity in all spike regions to the SARS-CoV-2 spike compared with 229E and NL63, consistent with the viruses' taxonomy. However, HKU1 seems to have extra insertions at the C-terminal end of the RBD compared with the other two seasonals and SARS-CoV-2. Furthermore, the S2 region shows much higher similarity to SARS-CoV-2 in all three HCoVs compared with the S1 region (Figure 4C).
Figure 4. Comparing neutralizing responses in HCoVs NL63, 229E, and HKU1 between first- and second-dose vaccination against SARS-CoV-2. Neutralization profile tiv thaiv HCoVs NL63, 229E, and HKU1 in double-dosed BNT162b2, mRNA-1273, or AZD1222 –vacinated subjects with or without a history of SARS-CoV-2 infection. (A). Neutralizing antibody titres tawm tsam HCoVs uas tau hais tseg tom qab thawj koob tshuaj thib ob thiab thib ob ntawm BNT162b2, mRNA{{20}}, lossis AZD1222 cov tshuaj tiv thaiv. (B). Wilcoxon matched-pairs signed rank tests statistical analysis was used in A thiab B. Similarity plots (C) show the HKU-1 spike as have a more similar amino acid sequence to SARS-CoV-2 piv nrog rau ob qho tib si NL63 thiab 229E nyob rau hauv tag nrho cov cheeb tsam ntawm spike protein. Dashed kab nyob rau sab saum toj qhia cov amino acid pairwise zoo sib xws ntawm SARS-CoV-2 thiab 3 HCoV Spike proteins, plotted siv ib tug 400 amino acid qhov rais qhov loj thiab ib kauj ruam ntawm 1. Txoj hauj lwm nrog qhov khoob yog cais tawm ntawm qhov rais. Kab kab rov tav nyob rau hauv qab qhia cov seem seem rau txhua tus ntawm 4 cov kab mob sib kis kab mob sib kis thoob plaws qhov kev sib tw ntev (xim muaj=amino acid muaj; xim tsis muaj=qhov sib txawv). ns=tsis tseem ceeb, * p < 0.05, *** p < 0.001.
4. Kev sib tham
Hauv txoj kev tshawb no, peb tuaj yeem sib piv ncaj qha rau cov tshuaj tiv thaiv kab mob nruab nrab ntawm cov tshuaj tiv thaiv kab mob los ntawm ob hom tshuaj tiv thaiv m-RNA, BNT162b2 thiab mRNA-1273, thiab tshuaj tiv thaiv kab mob adenoviral, AZD1222, tiv thaiv SARS-CoV{{8} }, nws qhov txawv txav, thiab peb lub caij HCoVs. Peb cov ntaub ntawv ntawm cov tshuaj tiv thaiv kab mob tsis zoo tiv thaiv SARS-CoV-2 thiab nws qhov txawv ntawm cov tshuaj txhaj tshuaj, nrog lossis tsis muaj keeb kwm ntawm kev kis tus kabmob yav dhau los, pom zoo nrog cov lus tshaj tawm hauv cov ntaub ntawv [2,4,5,7,34–38 ]. Peb tau lees paub tias kev txhaj tshuaj nrog ob koob tshuaj tiv thaiv cov tshuaj tiv thaiv kab mob tuaj yeem tiv thaiv SARS-CoV-2 thiab VOCs, nrog BNT162b2 eliciting lub siab tshaj plaws neutralization titres, ua raws li mRNA-1273 thiab AZD1222. Txawm hais tias lawv qhov sib txawv ntawm kev tsis sib haum xeeb, tag nrho peb cov tshuaj tiv thaiv tau raug tshaj tawm tias muaj txiaj ntsig zoo hauv kev tiv thaiv COVID hnyav-19 [39–41]. Omicron BA.1 variant yog qhov evasive tshaj plaws ntawm tag nrho cov VOCs soj ntsuam hauv txoj kev tshawb no (Daim duab 3). Tseeb tiag, qhov hloov pauv hnyav hnyav ntawm BA.1 qhov sib txawv ua rau muaj teeb meem rau kev ua tau zoo ntawm cov tshuaj tiv thaiv tam sim no los tiv thaiv COVID-19 thiab tau taw qhia qhov yuav tsum tau saib xyuas kev tiv thaiv tau pom zoo rau qhov no thiab cov tshiab SARS-CoV{ {31}} variants, uas yog Omicron BA.4 thiab BA.5. Bivalent formulations of mRNA-based vaccines, uas muaj ob qho tib si mRNA ntawm qhov sib npaug ntawm cov poj koob yawm txwv SARS-CoV-2 thiab ib qho sib xws ntawm cov kab mob BA.4 thiab BA.5 tau tsim thiab tso cai los tawm tsam kev evasion ntawm lub cev tiv thaiv kab mob elicited los ntawm thawj cov tshuaj tiv thaiv tsim.
HCoVs tau muab faib thoob ntiaj teb thiab ntseeg tias yuav ua rau muaj cov tshuaj tiv thaiv luv luv [42]. Yog li ntawd, muaj kev pheej hmoo siab ntawm kev rov ua dua tshiab ntxiv, tshwj xeeb tshaj yog thaum lub caij ntuj no [13,43-45] txawm tias muaj seroprevalence siab [43,45,46]. Tam sim no tab tom sib cav seb puas muaj tus kab mob ua ntej nrog HCoVs raws caij nyoog elicits cross-reactive antibodies tawm tsam SARS-CoV-2, thiab tseem ceeb tshaj, yog qhov no txhais ua kev tiv thaiv SARS-CoV-2. Hla-reactive antibodies [47–54] thiab T-cell teb [55–61] tau kuaj pom nyob rau hauv pre-pandemic sera thiab noj qab haus huv pub dawb; Txawm li cas los xij, cov kev sim zoo sib xws tau pom qhov txawv ntawm qhov tseeb los ntawm lwm tus neeg tshawb nrhiav [62]. Tsis tas li ntawd, nyob rau hauv ntau yam ntawm cov lus hais saum toj no uas tau nthuav tawm cov tshuaj tiv thaiv kab mob sib kis hauv cov qauv ua ntej kis thoob qhov txhia chaw, tus naj npawb ntawm cov qauv cross-reactive yog ib feem me me ntawm tag nrho cov sera tsom xam, qhia tias cross-reactivity, thaum nws muaj, yog tsawg. . Tib lo lus nug no tau hais txog cov tshuaj tiv thaiv kab mob uas tau txais los ntawm COVID-19 cov tshuaj tiv thaiv, nrog rau cov kev tshawb fawb qhia pom cov tshuaj tiv thaiv kab mob sib kis rau qee yam tab sis tsis yog txhua lub caij HCoVs [63–65]. SARS-CoV-2 txhaj tshuaj tiv thaiv kab mob sib kis tau pom tias ua rau muaj cov tshuaj tiv thaiv kab mob sib kis rau ob qho tib si Alpha- thiab Betacoronaviruses hauv macaques [66]. Nws yog ib qho tseem ceeb kom txiav txim siab seb cov tshuaj tiv thaiv kab mob sib kis tau txhais ua kev tiv thaiv, ua rau cov tshuaj tiv thaiv kab mob tiv thaiv SARS-CoV-2. Qee cov ntawv tshaj tawm qhia tias thaum muaj kev txhawb nqa me me hauv cov tshuaj tiv thaiv rau HCoVs thaum SARS-CoV-2 kis, lawv tsis cuam tshuam nrog kev tiv thaiv [67]. Ib yam li ntawd, cov kev tshawb fawb pom tau hais tias ua ntej kis tau tus kab mob HCoVs tsis tiv thaiv SARS-CoV-2 kab mob thiab kab mob [68,69].
cistanche tubulosa- txhim kho lub cev tiv thaiv kab mob
Peb tsis pom muaj kev txhawb nqa ntawm cov tshuaj tiv thaiv kab mob tiv thaiv kab mob HKU1 hauv peb pawg ntawm SARS-CoV-2- cov neeg mob uas tau txhaj tshuaj, txawm tias lawv cov kab mob SARS-CoV-2 ua ntej kis tau tus mob, tshwj tsis yog cov kws kho mob. BNT162b2. Qhov no yog qhov sib piv nrog ob daim ntawv tshaj tawm uas pom muaj kev txhawb nqa hauv HKU-1 titers tom qab txhaj tshuaj tiv thaiv SARS-CoV-2 los ntawm BNT162b2 [63,64]. Hicks et al. tau pom tias cov tshuaj tiv thaiv uas ua rau HCoV-OC43 thiab HCoVHKU1 muaj qhov cuam tshuam tsawg kawg nkaus nrog SARS-CoV-2, raws li cov txheej txheem homology ntawm cov proteins no [54]. Ntxiv mus, yav dhau los tus kab mob SARS-CoV-2 tsis tau txhawb nqa kev sib koom ua ke tawm tsam HKU1 lossis ntau dua phylogenetically ntsig txog HCoV-229E (Figure 4A). Ib daim ntawv tshaj tawm qhia tias HKU1 tuaj yeem muaj lwm tus neeg sib tw receptor uas tseem tsis tau txheeb xyuas, vim tias muaj qhov tso tawm RBD, nyob deb ntawm thaj chaw sialic acid khi [70,71]. Nws yuav tsum tau muab sau tseg tias neutralizing muaj peev xwm yuav tsis tsuas yog nyob ntawm lub pairwise zoo sib xws ntawm cov amino acids nyob rau hauv cov protein tab sis kuj nyob rau hauv luv luv insertions thiab deletions uas yuav hloov tau cov protein cov qauv conformation. Piv txwv li, HKU-1- tshwj xeeb ntxig rau ntawm C-qhov kawg ntawm RBD (Daim duab 4C) tuaj yeem piav qhia peb cov txiaj ntsig tsis zoo. Hloov pauv, peb pom tias kev tswj hwm koob thib ob hauv cov neeg mob tsis zoo tau nce cov tshuaj tiv thaiv kab mob tiv thaiv NL63 piv nrog cov uas tau txais hauv cov neeg mob yav dhau los tau txais tib koob tshuaj. Qhov no tej zaum yog vim qhov tseeb tias qhov kis tau ntxiv rau cov tshuaj tiv thaiv kab mob sib kis tsis muaj kev cuam tshuam rau cov tshuaj tiv thaiv kab mob tiv thaiv NL63.
Qhov sib txawv ntawm cov tshuaj tiv thaiv kab mob nruab nrab ntawm HCoVs tuaj yeem yog vim qhov sib txawv ntawm qhov sib txawv uas siv los ntawm cov chaw txhaj tshuaj. BNT162b27 encodes ib tug tag nrho-ntev spike nrog K986P thiab V987P kev hloov chaw kom stabilize lub pre-fusion conformation ntawm cov protein [72]. Cov tshuaj tiv thaiv mRNA-1273 muaj cov txheej txheem coding rau qhov sib npaug glycoprotein ruaj khov los ntawm tib qhov kev hloov pauv proline siv hauv cov tshuaj tiv thaiv BNT162b2, nrog rau cov thauj tog rau nkoj transmembrane thiab qhov chaw tsis zoo S1-S2 cleavage site. Lub pre-fusion conformation yog stabilized los ntawm sib law liag proline hloov, uas nyob rau hauv lub S2 subunit nyob rau sab saum toj ntawm lub hauv paus helix [73]. Conversely, ib tug neeg zoo li tus kab mob yog qhia los ntawm cov tshuaj tiv thaiv AZD1222. Raws li peb cov kev kawm tsis raug cai tau muab tshuaj tiv thaiv AZD1222, peb tuaj yeem xav tias hom kab mob ntawm cov kab mob sib kis tau ua rau muaj kev loj hlob ntawm cov tshuaj tiv thaiv kab mob siab dua piv nrog qhov cuam tshuam los ntawm pre-fusion-stabilized protein. Hloov pauv, qhov kev tiv thaiv kab mob thib ob rau SARS-CoV-2 spike tau txhawb nqa cov lus teb tsis zoo tawm tsam NL63 lossis 229E (Daim duab 4B), raws li tau tshaj tawm yav dhau los [67], nyob ntawm lub platform tshuaj tiv thaiv, tsis hais txog qhov ua ntej. kev kis tus kab mob. Interestingly, lwm daim ntawv tshaj tawm tau pom tib yam kev ua haujlwm tsis sib xws, txawm hais tias qhov no tsis hais txog lub platform tshuaj tiv thaiv [74]. Peb kwv yees tias kev sib cuam tshuam tuaj yeem tshwm sim vim qhov zoo sib xws hauv epitopes hauv receptor-binding motif (RBM) ntawm NL63 rau SARS-CoV-2 txij li ob tus kab mob sib koom ACE-2 raws li lawv nkag mus receptor [75 ]. Ib yam li ntawd, ib qho epitope overlapping S2 fusion peptide nyob rau hauv 229E tau raug tshaj tawm rau elicit cross-reactivity tiv thaiv SARS-CoV-2 [48]. Nkauj et al. piav qhia txog kev tiv thaiv cov tshuaj tiv thaiv tsis zoo uas tsom rau S2 subdomain [53]. Tsis tas li ntawd, tsab ntawv tshaj tawm thaum lub sijhawm thawj SARS-CoV-1 tshwm sim kuj pom muaj cov tshuaj tiv thaiv kab mob sib kis tawm tsam NL63 thiab 229E [76], ntxiv dag zog rau qhov kev xav ntawm kev sib koom epitopes ntawm Alphacoronaviruses thiab Betacoronaviruses. Cov protein S ntawm NL63 tsis muaj qhov chaw paub txog furin thiab tsis cleaved thaum biogenesis [77]. Ib yam li ntawd, cov kab mob sib kis tau nthuav tawm los ntawm cov tshuaj tiv thaiv mRNA1273 tsis muaj qhov chaw cleavage; Yog li ntawd, kev sib haum xeeb ntawm cov protein yuav zoo sib xws thiab tuaj yeem ua rau cov tshuaj tiv thaiv tsis zoo tiv thaiv cov epitopes sib koom thiab uas tau txhawb nqa tom qab qhov thib ob raug rau tib antigen.
Cov tshuaj tiv thaiv kab mob ntawm cov kab mob sib kis tau nthuav tawm los ntawm cov tshuaj tiv thaiv sib txawv, ua ke nrog ntau qhov sib txawv uas lawv tuaj yeem tau txais, yuav cuam tshuam rau kev txhim kho ntawm cov tshuaj tiv thaiv kab mob sib txawv nrog ntau qhov sib txawv ntawm ntau qhov epitopes hauv cov kab mob sib kis. Txij li thaum AZD -1222 spike tsis muaj ob qho kev hloov pauv hauv proline kom ruaj khov rau hauv cov qauv trimeric pre-fusion [78,79], qhov muaj cov kab mob tom qab fusion tuaj yeem ua rau muaj kev tiv thaiv kab mob loj dua rau cov epitopes. hauv S2 sau. Qhov no tuaj yeem piav qhia vim li cas peb tsis tau soj ntsuam ib qho kev txhawb nqa hauv kev tsis sib haum xeeb tiv thaiv 229E hauv mRNA-based, pre-fusion-stabilized immunogen lossis cov tshuaj tiv thaiv kab mob. Thaum kawg, txawm tias saib xyuas kev txhawb nqa hauv titers, nws tsis yooj yim rau peb hais seb qhov no puas tau txhais ua kev tiv thaiv titers txij li kev sib raug zoo ntawm kev tiv thaiv SARS-CoV-2 tseem tsis tau txhais. Muaj ntau qhov kev txwv hauv peb txoj kev tshawb fawb los xav txog. Peb cov ntaub ntawv yuav tau txais txiaj ntsig los ntawm cov qauv loj dua hauv txhua hom tshuaj tiv thaiv platform, thiab tswj cov qauv ntawm cov neeg tsis tau txhaj tshuaj tiv thaiv kab mob uas tau kis tus kab mob SARS-CoV-2 lossis tsis. Tsis tas li ntawd, peb tsis tau txheeb xyuas cov theem hauv qab ntawm cov tshuaj tiv thaiv kab mob sib kis los tiv thaiv tus kabmob coronaviruses raws caij nyoog hauv peb pawg ntawm cov kws txhaj tshuaj. Cov tshuaj tiv thaiv kab mob pan-coronavirus yuav tshem tawm cov tshuaj tiv thaiv kab mob uas lees paub thiab cuam tshuam ntau yam ntawm tus kabmob coronaviruses. Qhov no yog qhov nyuaj vim yog cov caj ces ntawm cov kab mob RNA uas nquag hloov pauv thiab ua rau muaj kev tiv thaiv kab mob uas ploj mus dhau sijhawm, ua rau muaj feem cuam tshuam rov qab. Yog li ntawd, kev txheeb xyuas cov epitopes tseem ceeb nyob rau ntawm thaj chaw tshwj xeeb tshaj plaws ntawm cov protein ntau, tshwj xeeb tshaj yog nyob rau ntawm S2 subunit, muaj feem cuam tshuam rau qhov muaj feem cuam tshuam rau cov tshuaj tiv thaiv kab mob uas muaj kev sib raug zoo rau cov cellular receptors uas kho cov kab mob nkag. Ntau qhov kev sib tw tshuaj tiv thaiv tau raug tsim tawm, thiab qee qhov yog raws li cov tshuaj tiv thaiv dual nrog rau ob qho tib si spike thiab nucleocapsid (N) cov khoom [80]. Cov qauv no yog nyob rau theem ua ntej kho mob vim lawv tuaj yeem muab qhov dav thiab ntev dua kev lom zem thiab lub cev tiv thaiv kab mob tiv thaiv kab mob coronaviruses [80].
Cov ntaub ntawv
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