Mucosal Vaccines, Sterilizing Immunity, And The Future Of SARS-CoV-2 Virulence

Abstract:

Kev tiv thaiv kom tsis muaj menyuam tom qab txhaj tshuaj tiv thaiv yog tsim nyog los tiv thaiv kev kis tus kab mob los ntawm cov tshuaj tiv thaiv, uas tuaj yeem ua rau muaj kev phom sij tshwj xeeb hauv tsev kho mob thaum tswj cov neeg mob qaug zog. Kev tiv thaiv kom tsis muaj menyuam yuav tsum muaj cov tshuaj tiv thaiv kab mob nruab nrab ntawm qhov chaw kis kab mob, uas rau cov kab mob ua pa xws li SARS-CoV-2 txhais tau tias qhov tshwm sim ntawm neutralizing IgA hauv mucosal secretions. Kev txhaj tshuaj tiv thaiv kab mob los ntawm kev xa tawm intramuscular induces tsis muaj lossis qis-titer neutralizing IgA tiv thaiv cov tshuaj tiv thaiv antigens. Mucosal priming lossis boosting yog xav tau los muab kev tiv thaiv kom tsis muaj menyuam.

Nyob rau sab nraud ntawm cov nyiaj npib, ua kom tsis muaj kab mob, los ntawm zeroing interhuman kis tau tus mob, tuaj yeem kaw SARS-CoV-2 hauv cov tsiaj reservoirs, tiv thaiv kev ua rau muaj kev phom sij ntawm tib neeg raws li qhov tshwm sim nrog cov kab mob coronaviruses. Peb tshuaj xyuas qhov zoo thiab qhov tsis zoo ntawm txhua lub tswv yim txhaj tshuaj, cov tshuaj tiv thaiv mucosal SARS-CoV-2 tam sim no tab tom txhim kho, thiab lawv qhov cuam tshuam rau kev noj qab haus huv pej xeem.

Ntxiv nrog rau kev txhawb nqa peb txoj kev tiv thaiv kab mob nrog kev pab ntawm cov tshuaj tiv thaiv, yog tias peb noj zaub mov tsis zoo, tsis muaj kev tawm dag zog, peb nquag ntxhov siab thiab tsis so, thiab peb yuav mob yooj yim. Qee lub sij hawm vim qee yam tsis paub, nws yuav yog vim tsis muaj kev saib xyuas kev noj qab haus huv, lub cev tiv thaiv kab mob kuj tuaj yeem ua rau tsis muaj zog. Lub cev tiv thaiv kab mob yog peb thawj kab ntawm kev tiv thaiv kab mob. Yog li ntawd, peb yuav tsum txhim kho peb txoj kev tiv thaiv. Tsis tas li ntawd, cov kev tshawb fawb tau pom tias polysaccharides nplua nuj nyob rau hauv Cistanche tuaj yeem tiv thaiv cov nyhuv inhibitory ntawm isoprenaline (ISO) thiab dexamethasone (DEX) ntawm lymphocyte proliferation ntawm ntau dua concentrations, thiab tiv thaiv cov nyhuv inhibitory ntawm siab concentrations ntawm qog suppressor- ntawm lymphocyte proliferation, koom tes. nrog ib tug tsawg concentration ntawm qog suppressor- los txhawb kev loj hlob ntawm lymphocytes, txhim khu kev tiv thaiv.

Nyem cistanche tubulosa extract hmoov khoom

Ntsiab lus:

COVID-19; SARS-CoV-2}}; neutralizing antibody; BNT162b2; mRNA-1273; IgA; IgG; sterilizing tiv thaiv kab mob; tshuaj tiv thaiv mucosal; tshuaj tiv thaiv intranasal; tshuaj tiv thaiv qhov ncauj.

1. Taw qhia

Tam sim no tau pom zoo, txhaj tshuaj tiv thaiv COVID-19 intramuscularly txhaj tshuaj tiv thaiv (cov ntsiab lus hauv daim duab 1) txo cov mob hnyav thiab cov tsos mob, tab sis tseem tso cai rau tus kab mob asymptomatic. Feem ntau muaj feem cuam tshuam los ntawm kev kis kabmob kis tau zoo yog tias cov tshuaj tiv thaiv no tso cai rau kev sib kis ntawm SARS-CoV-2 thiab lub peev xwm ntawm tus kab mob tuaj yeem rov ua dua nyob rau hauv ib lub chaw txhaj tshuaj muaj peev xwm xaiv cov tshuaj tiv thaiv kab mob. Cov tshuaj tiv thaiv COVID-19 tam sim no feem ntau ua rau cov tshuaj tiv thaiv kab mob hauv chav kawm IgG (feem ntau ntawm IgG1 thiab IgG3 subclasses [1]), thiab me me lossis tsis ua pa IgA.

Txawm hais tias cov qib IgG feem ntau raug saib xyuas hauv cov ntshav los ntsuas kev tiv thaiv kab mob, qhov isotype, tsis zoo li IgA, tsis zais rau hauv cov mucosal lumen ntawm polymeric Ig receptor (pIgR) thiab yuav tsum cia siab rau kev thauj mus los tsis zoo los ntawm cov chaw no. Tom qab kev tswj hwm ntawm IgG, tsuas yog ib qho ntawm 1000 molecules hauv cov ntshav mus txog bronchoalveolar lavage (BAL) kua [2–4]. Raws li, IgG artificially fused rau pIgR-binding peptides muaj ntau dua sawv cev hauv cov pa ua pa thiab tiv thaiv ntau dua hauv cov qauv kev sib tw tsiaj [5].

Txij li cov ntshav qab zib IgG tsis zoo nkag mus rau hauv qhov chaw mucosal thiab cov ntshav ntsuas ntawm cov tshuaj tiv thaiv-elicited IgG tsis cuam tshuam txog kev tiv thaiv kab mob ua pa. Txawm li cas los xij, tom qab priming nrog ib qho tshuaj tiv thaiv intramuscular, tom qab mob ua rau lub cim xeeb-B-cell tsiv teb tsaws thiab tso tawm ntawm IgA ntawm qhov chaw mucosal [6]. Tsis tas li ntawd, ib qho kev mob hauv cov hlab ntsws ua kom cov tshuaj tiv thaiv kab mob nkag mus rau hauv qhov chaw xws li cov tshuaj tiv thaiv kab mob tuaj yeem muab kev tiv thaiv ntxov hauv qhov teeb meem ntawm kev kis kab mob. Yog li ntawd, kev txhaj tshuaj intramuscular muab qee qhov kev ntsuas ntawm kev tiv thaiv hauv lub qhov ntswg qhov ntswg tiv thaiv SARS-CoV-2, raws li pom los ntawm kev txo cov tsos mob tom qab kis kab mob.

Tus kab mob asymptomatic suav rau ib feem peb ntawm SARS-CoV-2-positive nasopharyngeal swabs (NPS), thiab ze li 75 feem pua ​​​​ntawm cov neeg mob yog asymptomatic thaum lub sij hawm ntawm qhov zoo NPS yuav nyob asymptomatic [7]. Cov kev kwv yees no yuav muaj ntau dua nyob rau hauv cov tshuaj tiv thaiv, qhov twg cov kab mob sib kis tau tshwm sim hauv cov neeg mob asymptomatic [8]. Ib tug neeg yuav hnov ​​​​zoo, tab sis chaw nres nkoj replicating SARS-CoV-2 nyob rau hauv lub nasopharyngeal mucosa thiab muaj peev xwm kis tau mus rau lwm tus. Muab hais tias kev kuaj PCR txhua hnub yuav raug cuam tshuam dhau thiab kim nyob rau hauv randomized tswj kev sim (RCT), ntau tus kws tshawb nrhiav tau tawm tswv yim siv NPS PCR los txhim kho kev kwv yees ntawm cov tshuaj tiv thaiv zoo (VE) tiv thaiv SARS-CoV-2 kab mob. Cov kev ntsuas kab mob kis no kuj tseem siv tau los kwv yees kev ua tau zoo tiv thaiv kev sib kis, piv txwv tias muaj kev sib raug zoo ntawm tus kab mob kis thiab kis tau tus mob [9].

Ntxiv kev txhawb nqa qhov kev pom no yog cov ntaub ntawv los ntawm chaw kho mob pom zoo monoclonal antibodies (mAb) rau Spike protein-intravenous lossis subcutaneous txhaj tshuaj tiv thaiv SARS-CoV-2 mAbs ua rau muaj kev noj qab haus huv zoo tshaj plaws hauv txoj hlab pa, tiv thaiv SARS-CoV-2 replication thiab lub ntsws raug mob, tab sis cia cov kab mob muaj zog hauv qhov ntswg turbinates hauv cov qauv tsiaj [10]. Vim li no, kev xa cov tshuaj tiv thaiv-SARS-CoV-2 mAbs raug tshawb xyuas [11].

Peb tham txog ntawm no cov tswv yim los tiv thaiv tus kab mob asymptomatic hauv cov tshuaj tiv thaiv (piv txwv li, yuav ua li cas thiaj li hu ua "sterilizing immunity"), thiab theoretical txaus ntshai ntawm txoj hauv kev no.

2. Qhov txawv ntawm Kab Mob thiab Kab Mob

Cov lus nug yooj yooj yim no yog qhov nyuaj los teb kom meej. Cov tshuaj tiv thaiv tiv thaiv kab mob hauv qhov chaw thaum tus tswv tsev ntsib cov kab mob tshwj xeeb. Txhawm rau tshuaj xyuas seb cov tshuaj tiv thaiv ua haujlwm li cas nws yog ib qho tseem ceeb kom paub qhov txawv ntawm kev kis kab mob thiab kab mob. Kev kis kab mob yog qhov tau txais ntawm microbe los ntawm tus tswv tsev thaum tus kab mob yog lub xeev ntawm tus tswv tsev-microbe kev sib cuam tshuam thaum tus tswv tsev tau ua rau muaj kev puas tsuaj txaus los cuam tshuam rau homeostasis [12]. Rau feem ntau cov tshuaj tiv thaiv ua tau zoo, qhov kev ntsuas ntawm kev ua tau zoo tau txo qis ntawm cov kab mob vim qhov zaus ntawm kev kis tus kab mob tsis tau ntsuas. Feem ntau cov tshuaj tiv thaiv tam sim no elicit T-lymphocyte cov lus teb thiab feem ntau IgG, uas tiv thaiv kab mob hauv lub cev. Robbins et al. npaj siab tias cov tshuaj tiv thaiv ua haujlwm los ntawm kev ua kom tsis muaj kab mob inoculum thiab cov txheej txheem no yuav tsum muaj qee yam tshuaj tiv thaiv kab mob [13].

Yog tias cov chaw, qhov chaw pib kis tus kab mob, yog qhov chaw nkag mus rau cov ntshav IgG ces cov tshuaj tiv thaiv tuaj yeem tiv thaiv kev kis kab mob, tab sis feem ntau, cov tshuaj tiv thaiv tiv thaiv kab mob los ntawm kev txo cov inoculum, uas ua rau txo tus tswv tsev puas tsuaj thiab yuav muaj kab mob. Nyob rau hauv cov ntaub ntawv ntawm SARS-CoV-2, muaj pov thawj hais tias thawj kab mob thiab replication tshwm sim nyob rau hauv lub qhov ntswg ciliated hlwb [14], ib qhov chaw uas tsis muaj peev xwm nkag tau mus rau cov ntshav IgG tshwj tsis yog tias muaj kev puas tsuaj rau cov mucosal cov ntaub so ntswg uas. tso cai rau transudation ntawm cov proteins hauv cov ntshav mus rau qhov chaw. Yog li ntawd, cov tshuaj tiv thaiv tam sim no rau COVID-19 tiv thaiv kab mob tab sis tsis kis kab mob.

3. Kev tiv thaiv kab mob ua kom tsis muaj menyuam ua haujlwm li cas

Sterilizing tiv thaiv yuav tsum tau raws sij hawm neutralization ntawm nyuaj invader los ntawm lub humoral tiv thaiv kab mob. Qhov no txhais tau hais tias cov tshuaj tiv thaiv feem ntau cuam tshuam ntau dua li kev tiv thaiv kab mob ntawm tes, yam tsawg kawg rau cov kab mob thiab cov kab mob microbes uas kis tau ncaj qha cuam tshuam los ntawm cov tshuaj tiv thaiv tshwj xeeb. Ntawm kev ua pa mucosae, IgA yog cov tshuaj tiv thaiv zoo tshaj plaws. Secretory IgA (sIgA), uas muaj dimeric IgA, J saw, thiab secretory tivthaiv, yog secreted los ntawm cov qog (xws li, salivary los yog mammary) thiab mucosa-koom nrog lymphoid cov ntaub so ntswg (MALT) mus rau mucosae, qhov twg nws neutralizes pathogens.

Ntawm qhov txaus siab, sIgA nyob rau hauv cov neeg mob ua ntej kis tau tus mob mis [15,16] thiab qaub ncaug [17] cross-react nrog SARS-CoV-2, tab sis seb puas muaj kev tiv thaiv heterologous tiv thaiv tseem tsis paub. sIgA, nrog lawv lub neej luv luv ntawm 6.3 hnub, kuj sawv cev rau biomarker muaj txiaj ntsig rau kev txiav txim siab tsis ntev los no SARS-CoV-2 kab mob. Mucosal tiv thaiv kab mob kuj tseem raug siv rau kev tiv thaiv kab mob passive. Piv txwv li, ntau tus neeg tshawb nrhiav tau npaj cov khoom noj tau [18] lossis intranasal [19] qe-derived IgY rau passive immunotherapy, thiab qhia cov kab mob antigens nyob rau hauv nplooj ntawm cov nroj tsuag noj tau (piv txwv li, lettuce) kuj raug tshawb xyuas los txhawb kev tiv thaiv kab mob [20] Ib yam li ntawd, inhalable bispecific single-domain antibodies neutralize Omicron hauv tus qauv nas [21].

4. Clinically Successful History Precedents with Mucosal Vaccines

Ntau qhov chaw mucosal yog qhov chaw muaj peev xwm rau kev xa tshuaj tiv thaiv (piv txwv li, conjunctival, qhov ntswg, qhov ncauj, pulmonary, qhov chaw mos, thiab qhov quav mucosae); Txawm li cas los xij, cov laj thawj logistical thiab kab lis kev cai tau ua rau cov kws tshawb fawb tsom mus rau feem ntau ntawm qhov ncauj, qhov ntswg, thiab cov hlab ntsws [22]. Cov tshuaj tiv thaiv kab mob ua pa muaj ntau qhov ua tau zoo ntawm cov tshuaj tiv thaiv ib txwm muaj, ua kom yooj yim rau kev txhaj tshuaj tiv thaiv kab mob loj [23] -cov tshuaj tiv thaiv kom ruaj khov thiab txee lub neej rau cov tshuaj tiv thaiv hmoov qhuav, tsis mob xa khoom siv cov tshuaj nqus tau pov tseg hauv tsev [24] (uas txo qis qhov yuav tsum tau ua rau siab heev. cov neeg ua haujlwm kho mob tau txais kev cob qhia), thiab cog lus tias yuav tshem tawm lub cev tiv thaiv kab mob suav nrog sIgA [23].

Piv txwv ntawm cov tshuaj tiv thaiv mucosal ua tau zoo raws li cov kab mob kis tau zoo suav nrog cov tshuaj tiv thaiv qhov ncauj rau cov kab mob hauv plab (poliovirus thiab rotavirus) thiab tshuaj tiv thaiv kab mob hauv lub ntsws rau cov kab mob ua pa (tus kab mob khaub thuas thiab adenovirus).

Thawj cov tshuaj tiv thaiv kab mob polio tau tsim los ntawm Jonas Salk hauv xyoo 1955 tau ua haujlwm tsis muaj zog thiab siv tshuaj intramuscularly. Zoo li cov tshuaj tiv thaiv COVID-19 tam sim no, nws txo qis kev pheej hmoo ntawm kev mob, tab sis tsis tuaj yeem tiv thaiv kev kis kab mob. Xyoo 1960, Albert Sabin tau tsim ib qho tshuaj tiv thaiv kab mob polio hauv qhov ncauj uas siv peb hom kab mob poliovirus; Txoj hauv kev no tau ua rau yuav luag tag nrho kev tshem tawm tus mob polio thoob ntiaj teb, nrog tsawg li 140 tus neeg mob tau tshaj tawm xyoo 2020 hauv Pakistan thiab Afghanistan. Txawm li cas los xij, kev sib xyaw ua ke ntawm cov kab mob sib kis nrog cov kab mob poliovirus tsiaj qus ua rau muaj kev sib kis hauv zos los ntawm hom 2 poliovirus suav nrog hauv cov tshuaj tiv thaiv qhov ncauj trivalent (hu ua tshuaj tiv thaiv kab mob poliovirus (cVDPDV2)), nrog rau 1089 tus neeg mob hauv 26 lub teb chaws hauv 2020. Qhov no txhawb, Tom qab lub Plaub Hlis 2016, qhov kev tshem tawm ntawm cov kab mob los ntawm cov tshuaj tiv thaiv qhov ncauj trivalent, thiab thaum kawg rov qab mus rau cov tshuaj tiv thaiv inactivated [25,26].

Cov tshuaj tiv thaiv qhov ncauj rau tus kab mob rotavirus tau ua haujlwm rau qee lub sijhawm hauv cov menyuam yaus, ua kom pom kev ua tau zoo thiab kev nyab xeeb [27,28].

Cov tshuaj tiv thaiv kab mob khaub thuas intranasal tau siv thawj zaug hauv xyoo 1960 hauv lub qub Soviet Union. Cov tshuaj tiv thaiv kab mob ua npaws uas muaj ntawv tso cai rau tib neeg siv cov kab mob nasopharynx-associated lymphoid cov ntaub so ntswg (NALT) suav nrog FluMist/Fluenz ™ (MedImmune, Gaithersburg, MD, USA) [29] thiab Nasovac ™ nyob rau hauv cov tshuaj tsuag qhov ntswg uas tsim los ntawm Lub Tsev Kawm Ntawv Qib Siab ntawm Is Nrias teb. Tib lub koom haum kuj tsim ib qho intranasal, nyob attenuated influenza virus A(H1N1), tshuaj tiv thaiv [30]. Tsis muaj ib lub tuam txhab tshuaj tiv thaiv kab mob npaws loj tau koom nrog cov tshuaj tiv thaiv kab mob hauv lub cev tsis tau yog li feem ntau ntawm kev txhaj tshuaj tiv thaiv kab mob khaub thuas niaj hnub no tseem tau txhaj tshuaj intramuscularly.

Oral vaccines against wild-type adenovirus serotype 4 and 7 (Ad4 and Ad7) were developed by the National Institutes of Health (NIH) and the US Department of Defense (DoD) in the 1970s. They were originally co-administered [31,32] and then re-formulated in 2011 [33–37]. Both vaccines have increased safety since they do not disseminate systemically while inducing systemic serum homotypic nAb [34,36,37], and providing >90 feem pua ​​​​kev ua tau zoo tiv thaiv kab mob ntawm 12 lub lis piam [33,34,36,37], uas yog kav ntev li 6 xyoo [38].

Yog li ntawd, cov tshuaj tiv thaiv uas muab los ntawm mucosal txoj kev muaj txiaj ntsig zoo thiab siv tshuaj kho mob. Cov tshuaj tiv thaiv no muab cov txheej txheem tseem ceeb rau kev tswj hwm tus kab mob COVID-19 kev sib kis thiab muab kev txhawb zog zoo uas cov tshuaj tiv thaiv zoo sib xws tuaj yeem siv los tiv thaiv SARS-CoV-2.

5. IgA Antibodies Ua lub luag haujlwm tseem ceeb hauv Neutralizing SARS-CoV-2 tab sis Tsis tshua muaj txiaj ntsig tom qab txhaj tshuaj tiv thaiv kab mob

Natural SARS-CoV-2 kab mob feem ntau daws tau nrog cov tsos mob ntawm cov ntshav liab monomeric IgA. Feem ntau ntawm kev ua haujlwm nruab nrab hauv cov ntshav ntshav convalescent nyob hauv IgM thiab IgA feem [39,40]. Txawm li cas los xij, thaum cov ntshav IgG rau Spike protein tseem nyob hauv 92 feem pua ​​​​ntawm cov neeg koom nrog tom qab 7 lub hlis, cov tshuaj tiv thaiv kab mob IgA (thiab IgM) poob sai sai tom qab thawj lub hlis tom qab pib mob [41–43].

Dimeric IgA nyob rau hauv secretions zoo ib yam li muaj lub luag haujlwm tseem ceeb hauv SARS-CoV-2 neutralization [44] - tom qab kis tau tus mob, cov ntshav siab IgA loj heev tshwm sim hauv cov neeg mob uas muaj mob hnyav COVID-19- txuam nrog mob ua pa nyuaj siab (ARDS) [45], thiab Spike-specific IgA yog qhov tseem ceeb hauv tib neeg cov kua mis [15,16,46].

In general, intramuscularly delivered vaccines induce poor mucosal IgA responses. After the first immunization, BNT162b2 induces anti-Spike IgG1, IgG3, and IgA1 (and sometimes IgG2 and IgA2) in serum, but only IgG in saliva. One to two weeks after the second dose, IgG levels in saliva and the upper respiratory tract are boosted, while IgA appears in some subjects [47]. Serum IgA has kinetics of induction and time to peak levels (21 days after the first dose and 7–10 days after the second dose) that are similar to IgG, but a faster decline (>23 feem pua ​​​​txo los ntawm qhov ncov ntawm hnub ntxiv rau 80 tom qab thawj koob) [48].

Rau tib neeg cov kua mis, cov isotype profile txawv ntawm cov tshuaj tiv thaiv kab mob tom qab-COVID-19 thiab tom qab txhaj tshuaj. Nyob rau hauv sib piv rau tej yam ntuj tso kab mob, kev txhaj tshuaj nrog mRNA tshuaj tiv thaiv thaum lub sij hawm lactation nce anti-receptor-binding domain (RBD) IgA qib hauv cov mis nyuj [49,50], tab sis tsis nyob rau hauv cov ntshav [50]. Hmoov tsis, tsuas yog<10% of milk samples from vaccinees have high IgA endpoint titers, but secretory antibody released in milk is both stable and resistant to enzymatic degradation in neonatal mucosal tissues [3,4].

Lub paucity ntawm IgA tom qab txhaj tshuaj tiv thaiv tsis yog mucosal qhia tias cov neeg mob tau txhaj tshuaj tiv thaiv kab mob, thaum tsis tshua muaj tsos mob lossis asymptomatic, tseem tuaj yeem kis tus kabmob SARS-CoV-2. Tseem tsis tau muaj pov thawj tseeb txog seb cov tshuaj tiv thaiv kab mob asymptomatically kis tau li cas vim qhov kev xav ntawm cov kab mob virions tuaj yeem tiv thaiv kab mob thiab tsis kis kab mob [51–54], tab sis cov kab mob zoo sib xws pom hauv NPS los ntawm cov tshuaj tiv thaiv kab mob tiv thaiv cov neeg muaj kab mob qhia tau tias muaj kab mob sib kis. txaus ntshai kis tau tus mob. Txawm li cas los xij, cov neeg txhaj tshuaj tiv thaiv kab mob uas tsim cov tsos mob (piv txwv li, kev sib kis) kis tau rau SARS-CoV-2 [55]. Cov mob me me COVID-19 nyob rau hauv cov tshuaj tiv thaiv tib neeg seropositive nrog PCR zoo nyob rau hauv cov kab mob sib txawv (xws li, qhov quav swabs) kuj tau tshaj tawm [56], thiab qhia tias kev kis kab mob hauv cov tshuaj tiv thaiv no tsis txwv rau nasopharynx. Cov ntaub ntawv rau cov neeg mob asymptomatic, cov tshuaj tiv thaiv muaj kev txhawj xeeb tshwj xeeb hauv tsev kho mob chaw [8], qhov twg cov neeg mob mus rau hauv tsev kho mob thiab cov txheej txheem phais endonasal feem ntau tsim cov aerosols [57].

Tsis yog txhua qhov tshuaj tiv thaiv kab mob sib npaug tsis zoo ntawm kev ua rau mucosal IgA. Piv txwv li, BNT162b2, tab sis tsis yog CoronaVac, induced nasal anti-S1 IgA cov lus teb thaum ntxov li 14 hnub tom qab thawj koob tshuaj nyob rau hauv 72 feem pua ​​​​ntawm cov kev kawm, uas pheej mus txog 50 hnub tom qab koob thib ob hauv 45 feem pua ​​​​ntawm cov kev kawm [58] thiab tseem ntxias IgA hauv cov kua mis [59]. Txawm li cas los xij, IgA qib hauv mucosae tshwm sim los ntawm BNT162b2 lossis mRNA{12}} qis tom qab thawj koob tshuaj thiab poob qis tom qab koob thib ob.

6. Kev xa cov tshuaj tiv thaiv kab mob ua pa yuav tsum tau ua kom muaj Sterilizing Immunity tiv thaiv SARS-CoV-2

Cov qauv tsiaj uas muaj feem cuam tshuam txog tus kabmob coronaviruses SARS-CoV [60–70] thiab MERSCoV [60,71–74] qhia tias kev txhaj tshuaj tiv thaiv mucosal ua rau muaj kev tiv thaiv kab mob ntev ntev thiab mucosal. Cov pov thawj preclinical los ntawm cov kev tshawb fawb hauv cov nas (cov nas, golden hamsters, thiab ferrets) tau zoo ib yam rau SARS-CoV-2 (saib hauv [23,75–79] thiab xaus rau hauv Table 1), nrog rau qhov caveat tias ntau kev tshawb fawb tseem tsis tau raug tshuaj xyuas. Yam tsawg kawg yog 14 qhov tshuaj tiv thaiv mucosal tau nce mus rau thawj theem ntawm kev sim tshuaj raws li 14 Lub Kaum Ob Hlis 2021 (Table 2), thiab ntau tus tuaj yeem nkag mus rau hauv khw hauv 2022.

Txoj kev uas tsis yog intramuscular kuj tuaj yeem ua rau antigen koob tshuaj sparing, uas tuaj yeem cuam tshuam rau kev txo qis kev tsim khoom hauv lub cev thaum muaj kev sib kis. Thaum qhov no tau raug pov thawj rau txoj kev subcutaneous [80], nws tsis tau raug pov thawj rau txoj kev mucosal.

Txawm hais tias peb tsis muaj kev tshawb fawb txog kev ua tau zoo ntawm qhov ncauj lossis nqus tau cov tshuaj tiv thaiv hauv tib neeg cov ntsiab lus uas tsis muaj qhov chaw ntawm lub cev tiv thaiv kab mob (piv txwv li, cov menyuam yaus tom qab tshem tawm cov adenoids thiab tonsils [81], lossis tom qab phais mob ntxiv), nws zoo li tsim nyog xav tias qhov cov kab mob mucosal uas tseem tshuav yog txaus los txhawb cov lus teb los ntawm qhov tseeb tias tsis muaj cov ntaub ntawv keeb kwm uas cov tib neeg no muaj kev cuam tshuam ntau dua tom qab tau txais lwm hom tshuaj tiv thaiv.

7. Sterilizing Immunity and the Future of SARS-CoV-2 Virulence

Nyob rau hauv cov ntaub ntawv ntawm cov tshuaj tiv thaiv tsis inducing sterilizing tiv thaiv kab mob, kev sib kis tsis tu ncua yuav tsum ua kom yooj yim txo qis rau tib neeg cov tswv, txawm hais tias kev paub txog cov tshuaj tiv thaiv "txo" hauv cov tsiaj ua liaj ua teb tsis tau ua tiav. Piv txwv li, siv cov kab mob Marek (MDV) hauv cov qaib, cov tshuaj tiv thaiv tsis muaj tshuaj tiv thaiv tuaj yeem nce [104] lossis txo qis [105] virulence. Feem ntau, qhov ntau tus kab mob kis mus, qhov zoo dua yuav tsum yog nws hloov mus rau tus tswv tsev. Cov qauv Evolutionary qhia tias kev sib pauv ntawm kev ua phem thiab kev sib kis ua rau muaj qhov ua kom muaj zog tiv thaiv kab mob thaum txo tus kab mob, tab sis nws tsis paub meej tias qhov no yog qhov tshwm sim thoob ntiaj teb rau txhua tus kab mob [106]. Ntau yam nyob ntawm kev sib raug zoo ntawm kev ua phem thiab kev kis tus kabmob thiab tus nqi ntawm kev ua phem rau microbe hauv nqe lus nug [107].

Rau cov kab mob uas xav tau kev ua phem rau kev sib kis mus rau ib tus tswv tsev tshiab lub peev xwm rau cov kab mob yog qhov tseem ceeb rau lawv txoj sia nyob thiab kev txo qis yuav tsum tsis txhob xav tau [107]). Rau SARS-CoV-2 peb twb paub lawm tias kev kis tus kab mob asymptomatic tuaj yeem ua tau, txhais tau hais tias kev ua phem tsis yog qhov tseem ceeb rau kev sib kis. Qhov ceev ntawm attenuation (ntau xyoo mus rau tsheej lab ntawm xyoo) stems los ntawm kev sib txawv xws li lethality thiab kis tau tus mob efficiency, ua rau nws tsis yooj yim sua kom twv twv. Txawm hais tias kev txo qis nrog kev ncig ntawm tib neeg tsis yog ib txoj hauv kev thoob plaws ntiaj teb, yav dhau los ntau tus kab mob ua pa tau ua rau lub sijhawm luv luv, suav nrog tus mob coronaviruses (xws li, OC-43, uas tau hloov zuj zus los ntawm tus kab mob ua rau muaj kev cuam tshuam ntawm 1885-1894 Lavxias teb sab mob khaub thuas kis thoob qhov txhia chaw. [108] rau tus kab mob tam sim no ua rau mob khaub thuas). Cov ntaub ntawv pov thawj ntawm cov kab mob me me ntawm tib neeg kuj los ntawm ntau tus kab mob RNA (piv txwv li, kab mob npaws A(H1N1) [109,110], dengue virus type 2 [111], thiab Ebolavirus, los ntawm HIV [112,113], txawm hais tias cov kab mob no nyob deb. Kev kis tus kab mob SARS-CoV-2 tsis tu ncua yog lub sijhawm tsis tau muaj dua los saib xyuas cov naj npawb ntawm cov menyuam yaus (Rt) hauv lub sijhawm tiag tiag, thiab peb tau pom qhov nce ntawm 1.2 rau thawj hom Wuhan mus rau 4.0 rau tam sim no Delta-ntxiv. variant ntawm kev txhawj xeeb (VOC) [114]: nyob rau hauv lwm yam lus, ntau virulent thiab tsawg transmissive variants tau sai hloov los ntawm ntau transmissive thiab tsawg virulent variants.

Tam sim no, cov txheej txheem hloov pauv tau txuas ntxiv nrog ntau dua 170 Delta sublineages sib tw nrog ib leeg [115] thiab lwm VOC, dubbed Omicron, tsis ntev los no tau tshaj tawm [116,117]. Muab qhov kev sib kis ntau zuj zus ntawm cov kab mob SARS-CoV-2 strains los ntawm asymptomatic carriers thaum lub sij hawm kaw cia, kev sib tw ntawm attenuated SARS-CoV-2 strains nrog cov tsis-attenuated sawv daws yuav tau xav tias yuav pab txo tau tag nrho virulence [ 118] ib. Cov kab mob kis kab mob kis tau yog ib qho tseem ceeb ntawm kev txhaj tshuaj tiv thaiv kab mob rau ntau xyoo lawm, thiab lawv cov phiaj xwm yuav tsum tsis txhob kwv yees.

Ntawm qhov tod tes, cov tshuaj tiv thaiv ua rau muaj kev tiv thaiv kab mob tsis zoo hauv tib neeg tuaj nrog qhov kev pheej hmoo ntxiv ntawm kev tiv thaiv kev ua kom tsis muaj zog los ntawm kev tshem tawm cov kab mob sib kis thiab kev hloov pauv yog li thawb tus kab mob mus rau hauv cov tsiaj reservoirs, qhov uas nws tseem yog ib qho zoonosis nrog rau qhov muaj peev xwm ntawm kev rov ua dua rau tib neeg cov neeg nrog ntau yam. nce morbidity thiab lethality (rov qab-adaptation). SARS-CoV-2 yog tus kab mob panzootic, thiab, ntawm qhov txaus siab, tag nrho plaub VOCs tam sim no tuaj yeem kov yeej qhov kev txwv tsis pub dhau rau tus nas ACE2, thiab VOCs tus kheej qhia txog kev sib raug zoo dua rau nas, ferret, thiab civet ACE2 receptors ua tsaug rau N501Y thiab E484K hloov pauv hauv RBD ntawm Spike.

Uas tau hais tias, nce kev ncig tuaj nrog qhov kev pheej hmoo loj ntawm cov kab mob qis dua rov qab mus rau qhov muaj kev phom sij ntau dua, ntawm ib qho kev hloov pauv nucleotide, tshem tawm, lossis rov ua dua. Ntau tus kab mob coronavirus subgenera muaj lub siab nyiam rau kev sib koom ua ke hauv thaj chaw GC genome tsawg, thaj chaw tsis-coding, ntug ntawm cov noob, thiab qhov chaw tsis sib haum xeeb [119]. Rau SARS-CoV-2, ob txoj kab sib txuas ua ke twb nyob rau hauv kev xa tawm (XA thiab XB).

Tsis tas li ntawd, cov kab mob RNA yog qhov ua rau muaj kev hloov pauv, nthuav tawm lawv mus rau qhov hu ua "leej mutagenesis" [120], uas tau xav tias yuav ua rau muaj kev ploj tuag sai sai ntawm SARS-CoV-1 [121]. Nrog SARS-CoV-2, qhov kev xav no tau siv tsis ntev los no los piav qhia txog qhov txo qis ntawm qhov tshwm sim ntawm Delta VOC hauv Nyij Pooj [114], tab sis kev sib tw los ntawm ntau cov sublineages tseem yog lwm txoj kev piav qhia. Yog li ntawd, ob qho tshuaj tiv thaiv kab mob thiab tsis ua kom tsis muaj menyuam yuav muaj feem cuam tshuam loj rau txoj haujlwm ntawm SARS-CoV-2 virulence evolution rau tib neeg, uas tuaj yeem tsim teeb meem tshiab rau yav tom ntej vim tib neeg tseem ntsib kev hem thawj los ntawm tus kab mob no.

8. Qhov Kev Sib Tw Ntawm Cov Tshuaj Tiv Thaiv Tsis Tiv Thaiv

Ib yam li txhua qhov kev xav tau hauv zej zog, feem ntau yuav tsum muaj kev sib haum xeeb ntawm cov kev xav tau ntawm cov neeg tsis muaj zog thiab kev nyab xeeb ntawm cov neeg tiv thaiv kab mob. Cov lus teb tshuaj tiv thaiv tsis zoo, txuas ntxiv tom qab peb koob tshuaj, tseem yog teeb meem loj rau cov neeg mob tiv thaiv kab mob [122]. Cov tib neeg no tseem muaj kev pheej hmoo kis mob thiab kab mob thiab sawv cev rau cov pej xeem tseem ceeb tau txais txiaj ntsig zoo ntawm cov tshuaj niaj hnub los kho ntau yam mob oncologic thiab rheumatologic nrog cov kev kho mob uas cuam tshuam kev tiv thaiv kab mob. Yog li, qhov teeb meem ntawm cov neeg tsis muaj tshuaj tiv thaiv kab mob tiv thaiv kab mob yuav ua rau muaj kev cuam tshuam rau kev siv zog los tiv thaiv lossis xaus kev kis tus kab mob kis thoob qhov txhia chaw vim cov tswv tsev no tseem muaj kev phom sij rau SARS-CoV-2 thiab, los ntawm kev rov ua dua tus kab mob ntev ntev, sawv cev. ib qho zoo tagnrho toj roob hauv pes rau qhov tshwm sim ntawm tus kab mob variants. Kev tiv thaiv nrog kev tiv thaiv kab mob tiv thaiv kab mob yog tam sim no ua tau nrog sc mAbs cocktails (xws li cov tshuaj tiv thaiv kab mob ntev), im hyperimmune sera, lossis iv convalescent plasma. Thaum RCTs tseem tab tom ua, muaj qhov laj thawj loj heev rau kev cia siab tias yuav ua tau zoo los ntawm kev tiv thaiv kev tiv thaiv ua ntej.

9. Puas yog Tus Kab Mob Khaus Viv (Systemic COVID-19) Cov tshuaj tiv thaiv tsuas yog txhaj tshuaj tiv thaiv tus kheej xwb?

Cov tshuaj tiv thaiv kab mob tsis tuaj yeem muab kev tiv thaiv tsiaj txhu raug lees paub tias yog "kev qia dub" los ntawm cov xovxwm dav dav, piv txwv li, lawv suav hais tias muaj txiaj ntsig tshwj xeeb rau cov tshuaj tiv thaiv lawv tus kheej, uas tau dim ntawm cov kab mob hnyav. Qhov no yog qhov kev nkag siab tsis zoo uas tau muab cov txiaj ntsig zoo hauv zej zog ntawm kev txo qis COVID-19 kev tuag thiab kev tuag thiab kev mob hauv tsev kho mob, cov txiaj ntsig ntawm cov tshuaj tiv thaiv kab mob mus deb dhau qhov kev txo qis ntawm COVID-19 chav kawm.

Piv txwv li, lub sijhawm luv luv ntawm kev kis kab mob hauv NPS (txawm hais tias qhov siab tshaj plaws feem ntau zoo ib yam li cov neeg tsis tau txhaj tshuaj) ua rau txo qis kev sib kis hauv zej zog thiab txo qis qhov tshwm sim ntawm kev hloov pauv hauv-tus tswv tsev. Ntawm qhov kev xav dav dav, qhov sib txawv ntawm SARS-CoV-2 kab mob yog qhov sib cuam tshuam nrog tus nqi ntawm kev txhaj tshuaj (tshwj xeeb qhia rau Delta VOC ntawm tus kheej qhov kev xav, cov kab mob sib kis tau zoo los ntawm cov neeg mob tshuaj tiv thaiv kab mob qhia 2.{{ 4}}fold qis dua qhov sib txawv hauv cov paub SARS-CoV-2 B cell epitopes hauv kev sib piv rau cov neeg mob uas tsis tau txhaj tshuaj tiv thaiv COVID-19 [123]. Yog li, cov tshuaj tiv thaiv twb muaj peev xwm ua rau muaj kab mob lom ntawm cov kab mob zoo los ntawm kev txo qis nws txoj kev sib txawv ntawm caj ces.

10. Cov lus xaus

Cov tshuaj tiv thaiv tseem yog qhov kev cia siab zoo tshaj plaws rau kev xaus COVID-19 kev sib kis thiab txo cov neeg tuag. Kev txhim kho ntau yam tshuaj tiv thaiv zoo nyob rau thawj xyoo ntawm kev kis tus kabmob kis tau zoo yog qhov ua tiav zoo kawg. Cov tshuaj tiv thaiv mucosal tsis yog lub hauv paus / thawj txoj hauv kev uas tau ua nrog SARS-CoV-2 vim tias, thaum pib kis tus kabmob kis, peb tsis muaj kev paub txog kev ua kom tsis muaj menyuam ua haujlwm tiv thaiv tus kabmob coronaviruses.

Txawm li cas los xij, cov tshuaj tiv thaiv uas ua rau muaj kev tiv thaiv kab mob tsis muaj kev tiv thaiv mucosal tsis zoo yuav xaus kev kis tus kab mob vim tias cov no tiv thaiv kab mob thiab tsis kis kab mob thiab txhua kis ntawm tus kab mob cuam tshuam nrog cov kab mob sib kis nrog lub sijhawm rau qhov tshwm sim ntawm cov tshuaj tiv thaiv kab mob sib txawv. Txhua qhov kev tiv thaiv los yog kev kho tib neeg kev cuam tshuam tawm tsam tus kab mob ua rau muaj kev xaiv siab uas tuaj yeem ua rau muaj qhov tshwm sim ntawm kev khiav tawm [124] thiab cov tshuaj tiv thaiv tsis muaj qhov zam. Qhov no tuaj yeem siv rau kev sib tw ntawm cov kab ke nrog rau kev hloov pauv hauv cov tshuaj tiv thaiv kom nrawm. Qhov xwm txheej nrog COVID-19 hu rau kev tshawb fawb txuas ntxiv hauv kev tsim tshuaj tiv thaiv thiab muab qhov kev puas tsuaj thoob ntiaj teb coj los ntawm SARS-CoV-2 peb cia siab tias yuav xav tau, thiab kev txhim kho, tiam tshiab ntawm cov tshuaj tiv thaiv uas elicit mucosal tiv thaiv tiv thaiv ntau yam kab mob antigens. Cov kev tshawb fawb ntxiv ua ke nrog kev saib xyuas tom qab txhaj tshuaj tiv thaiv thiab kev tshuaj ntsuam genetic sequencing ntawm SARS-CoV-2- cov ntaub ntawv zoo tau lees paub los qhia meej txog qhov cuam tshuam ntawm kev hloov pauv tus kab mob ntuj tsim nrog kev txhaj tshuaj tiv thaiv.

Nyiaj txiag:

Qhov kev tshawb fawb no tsis tau txais nyiaj txiag sab nraud.

Institutional Review Board Statement:

Tsis siv tau.

Cov Lus Qhia Txog Kev Pom Zoo:

Tsis siv tau.

Cov ntaub ntawv muaj nyob:

Cov ntaub ntawv muaj nyob rau hauv lub chaw khaws ntaub ntawv pej xeem siv tau.

Kev tsis sib haum xeeb ntawm kev txaus siab:

DF tau txais cov nqi them rau pawg thawj coj saib xyuas los ntawm Novavax. Lwm tus neeg sau ntawv tshaj tawm tsis muaj teeb meem ntawm kev txaus siab cuam tshuam nrog cov ntawv sau no.

Cov ntaub ntawv

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