Safety And Seroconversion Of Immunotherapies Against SARS-CoV-2 Infection: A Systematic Review And Meta-Analysis Of Clinical Trials Part 3

Hais txog kev cob qhia kev tiv thaiv kab mob tshiab SARS-CoV-2, cov kev tshawb fawb yav dhau los tau qhia lawv lub peev xwm los cob qhia kev tiv thaiv kab mob, uas yog kev tiv thaiv kab mob tiv thaiv kab mob tshwj xeeb [46].

Nrog rau kev txhim kho txuas ntxiv ntawm kev tshawb fawb thiab thev naus laus zis thiab kev nce qib ntawm tib neeg lub neej, tib neeg lub neej tau nce ntxiv ntawm kev siv tshuab, thiab tib neeg tau maj mam paub txog qhov tseem ceeb ntawm kev noj qab haus huv. Txawm li cas los xij, tib neeg kev tawm tsam tiv thaiv kab mob txuas ntxiv mus.

Tam sim no, lub ntiaj teb tab tom ntsib teeb meem kev noj qab haus huv los ntawm cov kab mob tshiab. Cov kab mob no yog qhov tshiab thiab muaj zog, ua rau muaj kev raug mob hnyav thiab kev poob nyiaj txiag. Tib neeg yuav tsum xav txog yuav ua li cas nrog tus kab mob tshiab no.

Kev tiv thaiv kab mob tseem ceeb tshwj xeeb hauv cov ntsiab lus no. Kev tiv thaiv kab mob yog lub cev tiv thaiv tus kheej thiab nws lub peev xwm los tawm tsam cov kab mob sab nraud. Kev tiv thaiv muaj zog tuaj yeem ua rau lub cev noj qab haus huv thiab tiv thaiv kev cuam tshuam ntawm ntau yam kab mob. Kev tiv thaiv tsis txaus ua rau tib neeg muaj ntau yam kab mob. Yog li ntawd, kev tswj hwm thiab txhim kho kev tiv thaiv kab mob yog qhov tseem ceeb heev.

Yog li, yuav ua li cas txhim khu kev tiv thaiv? Ua ntej tshaj plaws, peb yuav tsum ua kom muaj lub neej zoo. Noj cov zaub mov noj qab nyob zoo thiab noj ntau yam khoom noj uas tsim nyog; pw tsaug zog zoo thiab ua kom lub sijhawm pw tsaug zog txaus; qoj ib ce kom tsim nyog rau kev tawm dag zog koj lub cev thiab txhim kho koj qhov kev tawm tsam. Tsis tas li ntawd, koj tuaj yeem ntxiv dag zog rau kev tiv thaiv thiab txhim kho lub cev tiv thaiv los ntawm kev txhaj tshuaj tiv thaiv thiab lwm txoj hauv kev.

Txhawm rau tiv thaiv cov kab mob tshiab, peb yuav tsum muaj kev tiv thaiv peb tus kheej. Kev tuav lub cev tiv thaiv tsis tau tsuas yog tus cwj pwm ntawm tus kheej nkaus xwb tab sis kuj yog lub luag haujlwm hauv zej zog uas txhua tus yuav tsum ua kom tiav. Peb yuav tsum siv txoj kev tshawb fawb thiab kev ntseeg ruaj khov kom dhau los ntawm lub sijhawm nyuaj no ua ke. Nws tuaj yeem pom tau tias peb yuav tsum txhim kho kev nco, thiab Cistanche deserticola tuaj yeem txhim kho kev nco, vim Cistanche deserticola tseem tuaj yeem tswj hwm qhov sib npaug ntawm cov neurotransmitters, xws li nce qib ntawm acetylcholine thiab kev loj hlob. Cov khoom no tseem ceeb heev rau kev nco thiab kev kawm. Tsis tas li ntawd, Cistanche deserticola tseem tuaj yeem txhim kho cov ntshav khiav thiab txhawb nqa cov pa oxygen, uas tuaj yeem ua kom lub hlwb tau txais cov as-ham txaus thiab lub zog, yog li txhim kho lub hlwb tseem ceeb thiab kev ua siab ntev.

Nyem paub ntxiv los txhim kho kev nco

Uas tau hais tias, lub tswv yim hais tias kev tiv thaiv kab mob, yog tias muaj thiab tsuas yog muaj, hauv kev tiv thaiv kev tiv thaiv tau raug cuam tshuam tas li vim muaj cov qauv lees paub receptors (PRRs), uas tau hloov pauv hloov pauv hauv cov kab mob ntau yam kab mob thiab tuaj yeem paub tshwj xeeb txog kab mob microbes viainnate immune. cev [47].

Raws li qhov piv txwv rau lub tswv yim dogmatic, innate immunememory cuam tshuam nrog PRR-mediated txoj hauv kev tau tshaj tawm los hla-tiv thaiv tib neeg lub cev los ntawm cov kab mob tsis cuam tshuam los ntawm epigenetic reprogramming hauv innate immune cells [48].

Vim li ntawd, kev tiv thaiv kab mob heterologous plays lub luag haujlwm tiv thaiv cov kab mob tshiab uas cuam tshuam rau tib neeg yam tsis muaj tshuaj lossis tshuaj tiv thaiv; lub luag hauj lwm no tseem hu ua kev cob qhia innate tiv thaiv [49]. Kev txhaj tshuaj BCG, keeb kwm tsim los rau menyuam yaus tuberculosis, kab mob sib kis nrog cov neeg mob siab thiab cov neeg tuag, yog ib qho tshuaj tiv thaiv ntau tshaj plaws [9].

Induction ntawm nonspecific tiv thaiv los ntawm kev txhaj tshuaj tiv thaiv BCG tau pom nyob rau hauv ob qho tib si tsiaj thiab tib neeg kev tshawb fawb [50,51], suav nrog ntau yam kev tswj hwm kev sim (RCTs) [52,53].

Piv txwv li, kev txhaj tshuaj BCG tau pom tias muaj kev tiv thaiv kab mob sib kis hnyav (SCID) nas los ntawm kev tshaj tawm candidiasis ntawm kev cawm dim los ntawm 30% mus rau 100%, nrog T thiab B lymphocyte-kev ywj pheej txoj hauv kev koom nrog [50].

Kev tiv thaiv kab mob sib kis hauv BCG-cov tshuaj tiv thaiv SCID nas tau coj los ntawm kev ua kom muaj zog ntawm innate receptor nucleotide-binding oligomerization domain-containingprotein 2 (NOD2) thiab kev hloov pauv ntawm epigenetic ntawm histone 3 lysine 4 trimethylation (H3K4me3}{1} thaj tsam 1} , nrog rau lwm cov cytokines inflammatory nyob rau hauv monocytes. Tsis tas li ntawd, kev txhaj tshuaj BCG kuj tau qhia tias yuav ua rau cov genome-wide epigeneticreprogramming ntawm tib neeg monocytes thiab tsim IL-1 tawm tsam viremia tshwm sim los ntawm yellowfever kab mob hauv tib neeg kev tshawb fawb [51].

Nyob rau hauv cov xwm txheej zoo li no, epigenetic reprogrammingis suav tias yog ib qho tseem ceeb ntawm kev cob qhia kev tiv thaiv kab mob hauv lub cev los tsim kev tiv thaiv kab mob los ntawm kev tswj cov noob ua kom muaj kev hloov kho histone, xws li H3K4 methylationor H3K27 acetylation. Ib yam li ntawd, ob peb RCTs tau txhawb nqa BCG txhaj tshuaj tiv thaiv-inducedheterologous immunological nyhuv ntawm kev txo qis kev mob thiab kev tuag ntawm cov menyuam mos, nrog rau cov menyuam yaus uas muaj kev kis kab mob uas tsis yog TB [52,53].

Yog li ntawd, heterologous tiv thaiv paub nrog BCG cov tshuaj tiv thaiv tau raug suav hais tias yog ob qho tib si tiv thaiv thiab kho kev ntsuas rau SARS-CoV-2 kab mob [54].

Cov tshuaj tiv thaiv kab mob tua los yog inactivated yog hais txog kev txhaj tshuaj ntawm cov kab mob uas tau poob lawv cov kab mob uas tsim muaj peev xwm tab sis khaws tag nrho lossis ib feem ntawm cov qauv uas muaj ntau yam tshuaj uas tuaj yeem phagocytosed thiab zom los ntawm cov tshuaj tiv thaiv kab mob (APCs), mainlydendritic cells (DCs), Paub txog kev tiv thaiv kab mob tom qab kev tswj hwm subcutaneous lossis intramuscular.

Tom qab ntawd, antigen-loaded APCs ntawm loj histocompatibility complextype II (MHC II) molecules yuav tsiv mus nyob rau theem nrab lymphoid organ mus rau prime naivehelper T (Th) hlwb, uas pab antigen-cov kabmob B hlwb sib txawv rau lub cim xeeb Bcells los yog luv luv plasma hlwb uas. thawj zaug zais IgM, tom qab ntawd nkag mus rau hauv chav kawm antibody hloov mus tsim IgG. Txij li ib nrab-lub neej ntawm IgM yog kwv yees li 2 hnub, isotype hloov mus rau IgGw yuav lav qhov ntev ib nrab-lub neej ntawm ib ncig ntawm 20 hnub, ua kom muaj kev tiv thaiv kev tiv thaiv kab mob [55]. Ntxiv rau kev muab ntau yam antigens, tua lossis inactivatedvaccines ruaj khov thiab muaj kev nyab xeeb tab sis yuav tsum tau ntau koob tshuaj kom tshem tawm qhov kev tiv thaiv zoo thiab kev tiv thaiv dav dav nrog cov tshuaj adjuvant [56].

Uas tau hais tias, qhov tsis zoo ntawm cov tshuaj tiv thaiv kab mob los yog tsis muaj zog muaj xws li lub caij nyoog cov kab mob uas tsis muaj zog uas muaj cov tshuaj tiv thaiv kab mob kom dim ntawm kev tiv thaiv kab mob uas tseem yuav txo qis kev tiv thaiv kab mob thaum txhaj tshuaj [57]. Zuag qhia tag nrho, cov tshuaj tiv thaiv tua lossis tsis ua haujlwm tau raug suav hais tias muaj peev xwm sib tw rau kev txhaj tshuaj tiv thaiv kab mob tshwm sim, piv txwv li, SARS-CoV-2.

Cov tshuaj tiv thaiv subunit ua ib hom kab mob ntawm cov tshuaj tiv thaiv inactivated koom nrog immunogenic peptides ntawm cov kab mob uas tsim los ua rau APC-mediated T thiab B cell nco tiv thaiv kab mob tom qab subcutaneous lossis intramuscular tswj hwm ntawm ntau yam dosesplus adjuvants.

Cov txheej txheem sib txuas ntawm inducing active tiv thaiv yog zoo ib yam li cov tshuaj tua kab mob los yog activated. Candidate antigens nyob rau hauv cov tshuaj tiv thaiv subunit feem ntau yog xa los ntawm cov kab mob genetic engineered vectors, xws li cov kab mob kab mob los yog cov kab mob muaj sia nyob rau cov tshuaj tiv thaiv DNA recombinant.

Nyob rau hauv rooj plaub ntawm tus mob coronavirus, S protein raws li tus neeg sib tw antigen rau ob qho tshuaj tiv thaiv subunit thiab neutralizing antibodies yuav kho qhov kev sib khi ntawm hostcell receptor ACE2 rau cov kab mob kis, nrog rau cov kab mob sib kis (RBD) ntawm S proteins zoo sib xws hauv SARS-CoV{{ 3}} and SARS-CoV.

Tshwj xeeb, S protein muaj ob subunits, S1 thiab S2. Lub S1 subunit muaj cov amino-terminal domain thiab anRBD.

RBD khi rau ACE2 raws li nws lub hom phiaj ntawm tus tswv tsev receptor, uas pib cov txheej txheem kis. Yog li, cov tshuaj tiv thaiv subunit muaj peev xwm ua rau muaj cov tshuaj tiv thaiv kab mob tshwj xeeb-neutralizingantibodies uas yuav tsom rau cov protein S, yog li tiv thaiv kev kis tus kab mob.

Cov tshuaj tiv thaiv kab mob no tau nthuav tawm hauv FDA pom zoo kev sim tshuaj feem ntau yog siv ncaj qha lossis siv cov kab mob kis nrog rau adenovirus, lossis kab mob kab mob xws li probiotics. Tsis tas li ntawd, cov tshuaj tiv thaiv nanoparticle-raws li cov tshuaj tiv thaiv kab mob ua pa [58] kuj raug soj ntsuam hauv cov chaw kuaj mob uas tau teev tseg, qhov twg S antigen-encoded mRNAs muaj nyob rau hauv lipid-composednanoparticles tuaj yeem ncaj qha mus rau kev ua haujlwm S antigens tom qab inoculation.

Muaj qhov zoo thiab qhov tsis zoo ntawm txhua qhov kev tsim tshuaj tiv thaiv. Piv txwv li, cov tshuaj tiv thaiv DNA tsis zoo li cov tshuaj tiv thaiv kab mob xws li mRNA lossis cov khoom lag luam protein [59], thaum cov tshuaj tiv thaiv mRNA tsis ruaj khov li cov tshuaj tiv thaiv DNA.

Cov tshuaj tiv thaiv kab mob viral feem ntau yog cov tshuaj tiv thaiv kab mob ntau dua li cov neeg siv lwm cov vectors, tab sis cov kab mob kab mob yuav ua rau txo qis kev ua tau zoo vim muaj kev tiv thaiv kab mob ua ntej rau vector [60]. Cov tshuaj tiv thaiv subunit, tsom rau S protein, cov kab mob tseem ceeb tshaj plaws uas khi rau ACE2 ntawm cov tswv tsev cell, suav hais tias muaj kev nyab xeeb dua li cov tshuaj tiv thaiv kab mob thiab ntau dua li cov tshuaj tiv thaiv tsis muaj zog.

Raws li serologicalevidence los ntawm cov kev tshawb fawb tso tawm, feem ntau cov tshuaj tiv thaiv protein, tshuaj tiv thaiv RNA, thiab inactivatedvaccines xav tau ob koob tshuaj los muab cov qib seroconversion muaj zog nrog ORs tshaj 100, thaum cov tshuaj tiv thaiv kab mob viral tuaj yeem xav tau ib koob nkaus xwb kom ncav cuag qib sib piv ntawm seroconversion (Table 3 thiab Daim duab 3). Kev khaws cia rau cov tshuaj tiv thaiv kab mob protein, DNAvaccines, thiab cov tshuaj tiv thaiv kab mob tsis muaj zog suav nrog qhov kub ntawm 2 txog 8 ◦C (36 txog 46 ◦F), thaum cov tshuaj tiv thaiv RNA yuav txawv ntawm cov khoom, suav nrog (1) 2 txog 8 ◦C (36 txog 46 ◦F) rau kev siv tam sim lossis −20 ◦C (−4◦F) rau lub sijhawm ntev ntawm mRNA-1723, thiab (2) −80 ◦C(−112 ◦F) rau BNT162b1.

Cov tshuaj tiv thaiv kab mob viral vector raug pom zoo khaws cia ntawm 2 txog 8 ◦C (36 to46 ◦F) rau kev siv tam sim lossis −20 ◦C (−4◦F) rau kev khaws cia ntev (Table 3) [61].

Passive tiv thaiv kab mob yog hais txog kev hloov pauv ntawm kev tiv thaiv kab mob humoral, uas cuam tshuam txog kev tiv thaiv immunoglobulins, IgG, tshwj xeeb, yog muab los ntawm cov neeg tiv thaiv kab mob toneutralize cov kab mob hauv cov neeg tsis muaj kab mob [62].

Cov tshuaj tiv thaiv raws li kev tiv thaiv kab mob sib kis tau raug pom zoo rau kev tiv thaiv kab mob sib kis thiab kev kho mob, tshwj xeeb tshaj yog thaum cov tshuaj tiv thaiv tiv thaiv kab mob ntev ntev tsis nyiam vim cov kab mob no yog "kev sib tw tiv thaiv lub sijhawm" [63]; Piv txwv li, cov tshuaj tiv thaiv uas tau pom tias yuav txo qis kev tuag ntawm cov neeg mob uas muaj kab mob hnyav xws li kab mob khaub thuas A thiab Ebolaviruses yuav koom nrog kev txhaj tshuaj tiv thaiv kab mob hauv cov hlab ntsha uas muab faib los ntawm cov ntshav plasma ntawm cov neeg mob rov qab los lossis cov neeg tau txais cov tshuaj tiv thaiv kab mob [64,65].

Ib yam li ntawd, kev hloov ntshav plasma tau raug suav tias yog tus neeg sib tw rau kev kho mob tam sim rau cov neeg mob hnyav COVID-19 los ntawm kev ntsuas suav nrog kev ncaj qha nruab nrab thiab kev tiv thaiv kab mob, nrog rau yav tas los koom nrog (1) kev thaiv ntawm cytokines lossis ua tiav, (2) kev tiv thaiv DC kev loj hlob, lossis (3) ua rau kev tswj hwm T celldevelopment [66–68].

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