Disease severity dictates SARS-CoV-2-specific neutralizing antibody responses in COVID-19

  1. Xiangyu Chen
  2. Zhiwei Pan
  3. Shuai Yue
  4. Fei Yu
  5. Junsong Zhang
  6. Yang Yang
  7. Ren Li
  8. Bingfeng Liu
  9. Xiaofan Yang
  10. Leiqiong Gao
  11. Zhirong Li
  12. Yao Lin
  13. Qizhao Huang
  14. Lifan Xu
  15. Jianfang Tang
  16. Li Hu
  17. Jing Zhao
  18. Pinghuang Liu
  19. Guozhong Zhang
  20. Yaokai Chen
  21. Kai Deng
  22. Lilin Ye

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Abstract

COVID-19 patients exhibit differential disease severity after SARS-CoV-2 infection. It is currently unknown as to the correlation between the magnitude of neutralizing antibody (NAb) responses and the disease severity in COVID-19 patients. In a cohort of 59 recovered patients with disease severity including severe, moderate, mild, and asymptomatic, we observed the positive correlation between serum neutralizing capacity and disease severity, in particular, the highest NAb capacity in sera from the patients with severe disease, while a lack of ability of asymptomatic patients to mount competent NAbs. Furthermore, the compositions of NAb subtypes were also different between recovered patients with severe symptoms and with mild-to-moderate symptoms. These results reveal the tremendous heterogeneity of SARS-CoV-2-specific NAb responses and their correlations to disease severity, highlighting the needs of future vaccination in COVID-19 patients recovered from asymptomatic or mild illness.

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  1. Version published to 10.1038/s41392-020-00301-9
  2. ScreenIT

    SciScore for 10.1101/2020.07.29.20164285: (What is this?)

    Please note, not all rigor criteria are appropriate for all manuscripts.

    Table 1: Rigor

    Institutional Review Board StatementConsent: Human samples: The 59 COVID-19 recovered patients enrolled in the study were provided written informed consent and from different sources.
    Randomizationnot detected.
    Blindingnot detected.
    Power Analysisnot detected.
    Sex as a biological variablenot detected.
    Cell Line Authenticationnot detected.

    Table 2: Resources

    Antibodies
    SentencesResources
    After washing with PBST buffer (0.1% Tween 20 in PBS), the ELISA plates were incubated with anti-human IgG HRP antibody (Bioss Biotech, 0297D) for 45 min, followed by PBST washing and addition of TMB buffer (Beyotime, P0209).
    anti-human IgG
    suggested: None
    Then, the incubated sera/SARS-CoV-2 RBD-mouse FC protein mixture was added into the ELISA plates and allowed to develop for 30 min, followed by PBST washing and incubation with anti-mouse FC HRP antibody (Thermo Fisher Scientific, A16084) for 30 min.
    anti-mouse FC HRP
    suggested: (Thermo Fisher Scientific Cat# A16084, RRID:AB_2534758)
    Depletion of SARS-CoV-2 S protein-specific antibodies: Firstly, SARS-CoV-2 S1 protein (Sino Biological, 40591-V08H) or SARS-CoV-2 RBD protein (Sino Biological, 40592-V08B) or SARS-CoV-2 S2 protein was conjugated with biotin by following the manufacture’s protocol (Thermo Fisher Scientific, A39257).
    SARS-CoV-2 S protein-specific antibodies: Firstly, SARS-CoV-2 S1 protein (Sino Biological, 40591-V08H)
    suggested: None
    SARS-CoV-2 S1 protein
    suggested: None
    SARS-CoV-2 RBD protein
    suggested: None
    Experimental Models: Cell Lines
    SentencesResources
    Then, the ACE2-expressing HEK-293T (ACE2/293T) cells were incubated with the sera/pseudovirus mixture overnight and then cultured with fresh media.
    HEK-293T
    suggested: None
    At 40 hours after the mixture incubation, the luciferase activity of SARS-CoV-2 typed pseudovirus-infected ACE2/293T cells were measured by a luciferase reporter assay kit (Promega, E1910).
    ACE2/293T
    suggested: None
    Serum-virus mixture were then added to the Vero E6 cell monolayers in 48-well plates and incubated at 37°C in 5% CO2 for 1 h.
    Vero E6
    suggested: None

    Results from OddPub: We did not detect open data. We also did not detect open code. Researchers are encouraged to share open data when possible (see Nature blog).

    Results from LimitationRecognizer: An explicit section about the limitations of the techniques employed in this study was not found. We encourage authors to address study limitations.

    Results from TrialIdentifier: No clinical trial numbers were referenced.

    Results from Barzooka: We did not find any issues relating to the usage of bar graphs.

    Results from JetFighter: We did not find any issues relating to colormaps.

    Results from rtransparent:
    • Thank you for including a conflict of interest statement. Authors are encouraged to include this statement when submitting to a journal.
    • Thank you for including a funding statement. Authors are encouraged to include this statement when submitting to a journal.
    • No protocol registration statement was detected.

    About SciScore

    SciScore is an automated tool that is designed to assist expert reviewers by finding and presenting formulaic information scattered throughout a paper in a standard, easy to digest format. SciScore checks for the presence and correctness of RRIDs (research resource identifiers), and for rigor criteria such as sex and investigator blinding. For details on the theoretical underpinning of rigor criteria and the tools shown here, including references cited, please follow this link.

  3. ScreenIT

    SciScore for 10.1101/2020.07.29.20164285: (What is this?)

    Please note, not all rigor criteria are appropriate for all manuscripts.

    Table 1: Rigor

    NIH rigor criteria are not applicable to paper type.

    Table 2: Resources

    No key resources detected.

    Results from OddPub: We did not detect open data. We also did not detect open code. Researchers are encouraged to share open data when possible (see Nature blog).

    Results from LimitationRecognizer: An explicit section about the limitations of the techniques employed in this study was not found. We encourage authors to address study limitations.

    Results from Barzooka: We did not find any issues relating to the usage of bar graphs.

    Results from JetFighter: We did not find any issues relating to colormaps.

    About SciScore

    SciScore is an automated tool that is designed to assist expert reviewers by finding and presenting formulaic information scattered throughout a paper in a standard, easy to digest format. SciScore is not a substitute for expert review. SciScore checks for the presence and correctness of RRIDs (research resource identifiers) in the manuscript, and detects sentences that appear to be missing RRIDs. SciScore also checks to make sure that rigor criteria are addressed by authors. It does this by detecting sentences that discuss criteria such as blinding or power analysis. SciScore does not guarantee that the rigor criteria that it detects are appropriate for the particular study. Instead it assists authors, editors, and reviewers by drawing attention to sections of the manuscript that contain or should contain various rigor criteria and key resources. For details on the results shown here, including references cited, please follow this link.

  4. ScreenIT

    SciScore for 10.1101/2020.07.29.20164285: (What is this?)

    Please note, not all rigor criteria are appropriate for all manuscripts.

    Table 1: Rigor

    NIH rigor criteria are not applicable to paper type.

    Table 2: Resources

    No key resources detected.

    Results from OddPub: We did not detect open data. We also did not detect open code. Researchers are encouraged to share open data when possible (see Nature blog).

    Results from LimitationRecognizer: An explicit section about the limitations of the techniques employed in this study was not found. We encourage authors to address study limitations.

    Results from Barzooka: We did not find any issues relating to the usage of bar graphs.

    Results from JetFighter: We did not find any issues relating to colormaps.

    About SciScore

    SciScore is an automated tool that is designed to assist expert reviewers by finding and presenting formulaic information scattered throughout a paper in a standard, easy to digest format. SciScore is not a substitute for expert review. SciScore checks for the presence and correctness of RRIDs (research resource identifiers) in the manuscript, and detects sentences that appear to be missing RRIDs. SciScore also checks to make sure that rigor criteria are addressed by authors. It does this by detecting sentences that discuss criteria such as blinding or power analysis. SciScore does not guarantee that the rigor criteria that it detects are appropriate for the particular study. Instead it assists authors, editors, and reviewers by drawing attention to sections of the manuscript that contain or should contain various rigor criteria and key resources. For details on the results shown here, including references cited, please follow this link.

  5. ScreenIT

    SciScore for 10.1101/2020.07.29.20164285: (What is this?)

    Please note, not all rigor criteria are appropriate for all manuscripts.

    Table 1: Rigor

    Institutional Review Board Statementnot detected.Randomizationnot detected.Blindingnot detected.Power Analysisnot detected.Sex as a biological variablenot detected.Cell Line Authentication( Notably,( all( sera( with( S1_specific( neutralization( failed( to( neutralize( pseudovirus( infection( after( RBD_specific( NAb( depletion( (Fig. ( 3d,( e),( demonstrating( the( strict( dependency( of( RBD_specific( NAbs( to( disengage( viral( attachment(to(the(host(receptor. (These(data(provided(the(rationale(for(exclusively(using( RBD(as(S1_immunogen(in(vaccine(design,(in(particular,(given(that(several(reports(have( shown(the(enhanced(disease(after(whole(S1(immunization29,30. ( ( ( & Discussion& The( COVID_19( patients( show( stratified( symptoms,( including( asymptomatic,( mild,( moderate( and( severe2. ( Using( RBD_ACE2( blockade,( pseudovirus( neutralization( and( authentic(virus(neutralization,(we(observed(that(disease(severity(positively(correlates( to( NAb( responses. ( The( patients( recovered( from( severe( illness( mounted( the( most( robust( NAb( responses. ( Strikingly,( asymptomatic( patients( fail( to( generate( competent(

    Table 2: Resources

    Antibodies
    SentencesResources
    (It( is( currently( unknown( as( to( the( correlation( between( the( magnitude( of( neutralizing( antibody((NAb)(responses(and(the(disease(severity(in(COVID_19(patients. (In(a(cohort( of(59(recovered(patients(with(disease(severity(including(severe,(moderate,(mild(and( asymptomatic,( we( observed( the( positive( correlation( between( serum( neutralizing( capacity(and(disease(severity,(in(particular,(the(highest(NAb(capacity(in(sera(from(the( patients(with(severe(disease,(while(a(lack(of(ability(of(asymptomatic(patients(to(mount( competent(NAbs. (Furthermore,(the(compositions(of(NAb(subtypes(were(also(different( between( recovered( patients( with( severe( symptoms( and( with( mild_to_moderate( symptoms. ( These( results( reveal( the( tremendous( heterogeneity( of( SARS_CoV_2_ specific( NAb( responses( and( their( correlations( to( disease( severity,( highlighting( the( needs(of(future(vaccination(in(COVID_19(patients(recovered(from(asymptomatic(or(mild( illness. ( ( ( ( As(of(July(28,(2020,(the(pandemic(of(coronavirus(disease(2019((COVID_19),(caused( by( severe( acute( respiratory( syndrome( coronavirus( 2( (SARS_CoV_2)( infection,( has( claimed( 16,341,920( clinically( confirmed( cases( and( 650,805( deaths( worldwide1. ( The( infected(patients(show(heterogeneous(clinical(manifestations,(which(can(be(generally( classified( into( four( groups,( including( severe,( moderate,( mild( and( asymptomatic,( according(to(the(severity(of(symptoms2. (Despite(daily(increasing(confirmed(cases(and( death,(currently(no(medical(agents(are(approved(to(prevent(SARS_CoV_2(infection(or( treat(COVID_19(patients. ( ( A(growing(body(of(evidence(shows( that(recovered(COVID_19(patients(can(generate( IgG_type(antibodies(specifically(binding(to(various(structure(proteins(of(SARS_CoV_2( particles( shortly( after( the( onset( of( disease,( albeit( at( variable( levels3_6. (Among( these( virus(specific(antibodies,(only(those(capable(of(blocking(SARS_CoV_2(spike((S)(protein( mediated( viral( attachment( and/or( entry( of( host( cells,( called( neutralizing( antibodies( (NAbs),(can(effectively(curtail(infection7. (The(convalescent(plasma(or(sera(containing( NAbs( harvested( from( recovered( patients( have( shown( promising( results( in( treating( COVID_19(patients(of(critical(illness(in(several(small_scale(clinic(trials8_11. (In(addition,(a( variety( of( human( monoclonal( antibodies( (mAbs)( of( potent( SARS_CoV_2( neutralizing( activities(has(been(cloned(from(memory(B(cells(from(recovered(COVID_19(patients12_ 21 ,(holding(great(potentials(for(prophylactic(or(therapeutic(use. (However,(little(is(known( regarding(the(relationship(between(disease(severity(and(the(magnitude(of(SARS_CoV_ 2_specific( NAbs( responses( in( patients( recovered( from( COVID_19. ( Defining( the( association(of(disease(severity(to(NAb(responses(will(facilitate(the(screening(of(COVID_ 19( recovered( patients( as( therapeutic( plasma( donors( as( well( as( memory( B( cell( providers(for(cloning(high_affinity(human(neutralizing(mAbs(to(prevent(or(treat(COVID_ 19.
    according(to(the(severity(of(symptoms2
    suggested: None
    ( vaccines,( including( inactivated,( vector_based,( DNA( and( mRNA( vaccines22_25,( are( undergoing( early(stages(of(clinical(trials. (Additionally,(the(NAb(titers(can(predict(the(possibility(of( re_infection(in(patients(recovered(from(a(primary(viral(infection. (Currently,(there(are(few( clues(regarding(whether(the(patients(recovered(from(COVID_19(can(be(protected(from( re_infection(or(will(still(require(vaccination(in(the(future(when(effective(vaccines(become( available. ( ( Results& Antibody& responses& to& SARS0CoV02& in& COVID019& recovered& patients& with& different&symptom&severity& To(explore(the(potential(association(between(SARS_CoV_2(S(protein_specific(antibody( responses(and(the(disease(severity(in(recovered(COVID_19(patients,(we(included(a( cohort( of( 59( adult( patients,( 48( of( mild( (n=4),( moderate( (n=34)( and( severe( (n=10)( symptoms( admitted( to( Guangzhou( Eighth( People’s( Hospital( and( 11( asymptomatic( adult(patients(admitted(to(Chongqing(Public(Health(Center(Hospital. (The(median(age( of( these( patients( was( 47( (33_62,( interquartile( range( (IQR))( years( oldm( 50.8%( of( the( patients( were( femalem( Serum( samples( were( collected( at( the( day( of( discharge( after( symptom(resolution(and(SARS_CoV_2(nucleotide(testing(negative(twice(by(RT_PCR.
    clues(regarding(whether(the(patients(recovered(from(COVID_19
    suggested: None
    (We(first(compared(the(antibodies(that( specifically(binding(to(S1,(RBD(and(S2(of(SARS_CoV_2(in(sera(of(COVID_19(recovered( patients( with( different( illness( severity( by( IgG( ELISA. ( Notably,( severe( and( moderate( symptomatic( patients( mounted( the( most( and( second( robust( S1,( S1_RBD( and( S2( specific( antibodies,( respectively,( while( mild( and( asymptomatic( patients( exhibited( significantly(lower(abundances(of(S1_,(S1_RBD_(and(S2_specific(antibodies((Fig.1a_c),( highlighting(the(disease(severity(as(a(key(determinant(factor(of(the(levels(of(antibodies( specific(to(SARS_CoV_2(S(proteins. ( ( ( Next,(we(assessed(the(abilities(of(antibodies(in(these(COVID_19(recovered(patients(to( block(the(interaction(between(RBD(and(ACE2. (Similar(to(SARS_CoV_2(RBD(binding( antibodies,( the( sera( from( recovered( patients( with( severe( symptoms( displayed( the( highest( scores( of( blocking( RBD_ACE2( engagement,( followed( by( patients( with( moderate(symptoms,(while(antibodies(from(mild(and(asymptomatic(patients(showed( much(inferior(capacity(to(inhibit(RBD_ACE2(interaction((Fig.(2a,(b).
    S2
    suggested: None
          <div style="margin-bottom:8px">
        <div><b>and(S2_specific(antibodies(</b></div>
        <div>suggested: None</div>
      </div>
    
      <div style="margin-bottom:8px">
        <div><b>RBD(binding(</b></div>
        <div>suggested: None</div>
      </div>
    </td></tr><tr><td style="min-width:100px;vertical-align:top;border-bottom:1px solid lightgray">(These(data(together(suggested(that( the( disease( severity( determines( both( the( magnitude( and( neutralizing( capacity( of( SARS_CoV_2_specific(antibodies(in(recovered(COVID_19(patients. ( ( Subtypes& of& neutralizing& antibodies& to& SARS0CoV02& S& proteins& in& COVID019& recovered&patients& Given(that(NAbs(can(potentially(target(both(S1(and(S2(to(block(viral(infection7,(we(set( out(to(distinguish(S1(and(S2_specific(NAbs(in(COVID_19(patients(with(aforementioned( pseudovirus( neutralization( assay. ( To( this( end,( we( used( biotin_labeled( S1( or( S2( recombinant( protein( to( deplete( corresponding( antibodies( in( sera( from( 25( COVID_19( patients( that( were( confirmed( to( be( highly( neutralizing( in( Fig. ( 2c( and( Fig. ( 2e( (Supplementary(Fig.(2a,(b).</td><td style="min-width:100px;border-bottom:1px solid lightgray">
      <div style="margin-bottom:8px">
        <div><b>and(S2</b></div>
        <div>suggested: None</div>
      </div>
    
      <div style="margin-bottom:8px">
        <div><b>and(S2_specific(NAbs(in(COVID_19</b></div>
        <div>suggested: None</div>
      </div>
    </td></tr><tr><td style="min-width:100px;vertical-align:top;border-bottom:1px solid lightgray">(After(depletion,(we(found(that(across(all(neutralizing(sera,( 40%(of(patients(generated(both(competent(S1_(and(S2_NAbs((i.e.,(post(either(S1_(or( S2_specific( antibody( depletion,( sera( can( still( completely( neutralize( pseudovirusesm( labeled(as(“S1/S2_NAbs”)m(while(40%(of(patients(only(generated(S1_competent(NAbs( (“S1_NAbs( only”),( and( 4%( of( patients( only( generated( S2_specific( NAbs( (“S2_NAbs( only”)m(interestingly,(16%(of(serum(samples(strictly(depended(on(the(collaboration(of( S1_(and(S2_specific(NAbs(to(effectively(neutralize(pseudovirus(infection((i.e.,(either(S1_( or(S2_specific(antibody(depletion(in(the(serum(can(result(in(the(failure(of(neutralizationm( labeled(as(“(S1+S2)_NAbs”)((Fig.(3a,(b).</td><td style="min-width:100px;border-bottom:1px solid lightgray">
      <div style="margin-bottom:8px">
        <div><b>and(S2_NAbs(</b></div>
        <div>suggested: None</div>
      </div>
    
      <div style="margin-bottom:8px">
        <div><b>and(S2_specific(NAbs(to(effectively(neutralize(pseudovirus(infection( ( i.e. ,</b></div>
        <div>suggested: None</div>
      </div>
    </td></tr><tr><td style="min-width:100px;vertical-align:top;border-bottom:1px solid lightgray">(Antibodies(post( RBD_depletion(were(shown(to(lose(RBD_binding(ability,(but(still(keep(their(binding(to( both(S1(and(S2(</td><td style="min-width:100px;border-bottom:1px solid lightgray">
      <div style="margin-bottom:8px">
        <div><b>Antibodies(post(</b></div>
        <div>suggested: None</div>
      </div>
    </td></tr><tr><td style="min-width:100px;vertical-align:top;border-bottom:1px solid lightgray">( After( washing( with( PBST( buffer( (0.1%( Tween( 20( in( PBS),( the( ELISA( plates( were( incubated( with( anti_human( IgG( HRP( antibody( (Bioss( Biotech,( 0297D)( for( 45( min,( followed(by(PBST(washing(and(addition(of(TMB(buffer((Beyotime,(P0209).</td><td style="min-width:100px;border-bottom:1px solid lightgray">
      <div style="margin-bottom:8px">
        <div><b>anti_human( IgG( HRP(</b></div>
        <div>suggested: None</div>
      </div>
    </td></tr><tr><td style="min-width:100px;vertical-align:top;border-bottom:1px solid lightgray">(The(ELISA(plates(were(blocked(for(1(hour(with(100( μl( blocking( buffer( (5%( FBS( and( 0.1%( Tween( 20( in( PBS)m( meanwhile,( 50( μl( 10_fold( diluted(patient(or(healthy(control(sera(were(incubated(with(7.5(ng(SARS_CoV_2(RBD_ mouse(FC(protein((Sino(Biological,(40592_V05H)(in(50(μl(blocking(buffer(for(1(hour. ( Then,(the(incubated(sera/SARS_CoV_2(RBD_mouse(FC(protein(mixture(was(added(into( the(ELISA(plates(and(allowed(to(develop(for(30(min,(followed(by(PBST(washing(and( incubation(with(anti_mouse(FC(HRP(antibody((Thermo(Fisher(Scientific,(A16084)(for( 30(min. (Next,(the(ELISA(plates(were(washed(with(PBST(and(treated(with(TMB(buffer( (Beyotime,(P0209).</td><td style="min-width:100px;border-bottom:1px solid lightgray">
      <div style="margin-bottom:8px">
        <div><b>RBD_</b></div>
        <div>suggested: None</div>
      </div>
    
      <div style="margin-bottom:8px">
        <div><b>A16084</b></div>
        <div>suggested: (Thermo Fisher Scientific Cat# A16084, <a href="https://scicrunch.org/resources/Any/search?q=AB_2534758">AB_2534758</a>)</div>
      </div>
    
      <div style="margin-bottom:8px">
        <div><b>P0209</b></div>
        <div>suggested: None</div>
      </div>
    </td></tr><tr><td style="min-width:100px;vertical-align:top;border-bottom:1px solid lightgray">(All(experiments(related( to( authentic( viruses( were( performed( in( the( certified( BSL_3( facility( of( Sun( Yat_sen( University. (The(SARS_CoV_2(viral(RNA(fold(reduction(=(2(CT(value(of(sample(_(CT(value(of(mock).& & Depletion& of& SARS0CoV02& S& protein0specific& antibodies. ( Firstly,( SARS_CoV_2( S1( protein((Sino(Biological,(40591_V08H)(or(SARS_CoV_2(RBD(protein((Sino(Biological,( 40592_V08B)(or(SARS_CoV_2(S2(protein(was(conjugated(with(biotin(by(following(the( manufacture’s( protocol( (Thermo( Fisher( Scientific,( A39257). ( Then,( biotin_conjugated( proteins(were(incubated(with(BeaverBeads(Mag(Streptavidin(Matrix((Beaver,(22305)( at(4oC(for(1.5(hours.</td><td style="min-width:100px;border-bottom:1px solid lightgray">
      <div style="margin-bottom:8px">
        <div><b>SARS0CoV02&</b></div>
        <div>suggested: None</div>
      </div>
    
      <div style="margin-bottom:8px">
        <div><b>S&</b></div>
        <div>suggested: (Acris Antibodies GmbH Cat# AP22305SU-S, <a href="https://scicrunch.org/resources/Any/search?q=AB_10757407">AB_10757407</a>)</div>
      </div>
    
      <div style="margin-bottom:8px">
        <div><b>protein0specific&</b></div>
        <div>suggested: None</div>
      </div>
    
      <div style="margin-bottom:8px">
        <div><b>S1</b></div>
        <div>suggested: None</div>
      </div>
    </td></tr><tr><td style="min-width:100px;vertical-align:top;border-bottom:1px solid lightgray">(After(washing(with(PBS,(the(SARS_CoV_2(S(protein(coupled(beads( were( next( incubated( with( diluted( patient( sera( at( 4oC( for( 1.5( hours. ( Then,( the( supernatants(were(harvested(and(quality(controlled(by(ELISA(assays(for(SARS_CoV_ 2(S(proteins. ( & & Statistics. (The(SARS_CoV_2(antibody(titers(or(virus(neutralizing(function(of(the(sera( belonging(to(patients(with(different(severity(were(compared(with(the(one_way(ANOVA( test( (Tukey’s( multiple( comparisons( test).</td><td style="min-width:100px;border-bottom:1px solid lightgray">
      <div style="margin-bottom:8px">
        <div><b>antibody(titers(or(virus(neutralizing(function(of(the(sera(</b></div>
        <div>suggested: None</div>
      </div>
    </td></tr><tr><td style="min-width:100px;vertical-align:top;border-bottom:1px solid lightgray">( The( cutoff( value( in( each( pseudovirus( neutralizing(function(assay(was(determined(by(the(ROC(curve(analysis(and(was(of(the( highest(likelihood(ratio. (Correlations(between(different(SARS_CoV_2(antibody(titers(or( between(SARS_CoV_2(antibody(titers(and(pseudovirus(titers(or(between(SARS_CoV_2( antibody(titers(and(SARS_CoV_2(virus(titers(were(analyzed(using(Pearson’s(correlation( coefficient.</td><td style="min-width:100px;border-bottom:1px solid lightgray">
      <div style="margin-bottom:8px">
        <div><b>antibody(titers(or(</b></div>
        <div>suggested: None</div>
      </div>
    
      <div style="margin-bottom:8px">
        <div><b>antibody(titers(and(pseudovirus(titers(or(between(SARS_CoV_2</b></div>
        <div>suggested: None</div>
      </div>
    
      <div style="margin-bottom:8px">
        <div><b>antibody(titers(and(SARS_CoV_2</b></div>
        <div>suggested: None</div>
      </div>
    </td></tr><tr><td style="min-width:100px;text-align:center; padding-top:4px;" colspan="2"><b>Software and Algorithms</b></td></tr><tr><td style="min-width:100px;text=align:center"><i>Sentences</i></td><td style="min-width:100px;text-align:center"><i>Resources</i></td></tr><tr><td style="min-width:100px;vertical-align:top;border-bottom:1px solid lightgray">(It( is( currently( unknown( as( to( the( correlation( between( the( magnitude( of( neutralizing( antibody((NAb)(responses(and(the(disease(severity(in(COVID_19(patients. (In(a(cohort( of(59(recovered(patients(with(disease(severity(including(severe,(moderate,(mild(and( asymptomatic,( we( observed( the( positive( correlation( between( serum( neutralizing( capacity(and(disease(severity,(in(particular,(the(highest(NAb(capacity(in(sera(from(the( patients(with(severe(disease,(while(a(lack(of(ability(of(asymptomatic(patients(to(mount( competent(NAbs. (Furthermore,(the(compositions(of(NAb(subtypes(were(also(different( between( recovered( patients( with( severe( symptoms( and( with( mild_to_moderate( symptoms. ( These( results( reveal( the( tremendous( heterogeneity( of( SARS_CoV_2_ specific( NAb( responses( and( their( correlations( to( disease( severity,( highlighting( the( needs(of(future(vaccination(in(COVID_19(patients(recovered(from(asymptomatic(or(mild( illness. ( ( ( ( As(of(July(28,(2020,(the(pandemic(of(coronavirus(disease(2019((COVID_19),(caused( by( severe( acute( respiratory( syndrome( coronavirus( 2( (SARS_CoV_2)( infection,( has( claimed( 16,341,920( clinically( confirmed( cases( and( 650,805( deaths( worldwide1. ( The( infected(patients(show(heterogeneous(clinical(manifestations,(which(can(be(generally( classified( into( four( groups,( including( severe,( moderate,( mild( and( asymptomatic,( according(to(the(severity(of(symptoms2. (Despite(daily(increasing(confirmed(cases(and( death,(currently(no(medical(agents(are(approved(to(prevent(SARS_CoV_2(infection(or( treat(COVID_19(patients. ( ( A(growing(body(of(evidence(shows( that(recovered(COVID_19(patients(can(generate( IgG_type(antibodies(specifically(binding(to(various(structure(proteins(of(SARS_CoV_2( particles( shortly( after( the( onset( of( disease,( albeit( at( variable( levels3_6. (Among( these( virus(specific(antibodies,(only(those(capable(of(blocking(SARS_CoV_2(spike((S)(protein( mediated( viral( attachment( and/or( entry( of( host( cells,( called( neutralizing( antibodies( (NAbs),(can(effectively(curtail(infection7. (The(convalescent(plasma(or(sera(containing( NAbs( harvested( from( recovered( patients( have( shown( promising( results( in( treating( COVID_19(patients(of(critical(illness(in(several(small_scale(clinic(trials8_11. (In(addition,(a( variety( of( human( monoclonal( antibodies( (mAbs)( of( potent( SARS_CoV_2( neutralizing( activities(has(been(cloned(from(memory(B(cells(from(recovered(COVID_19(patients12_ 21 ,(holding(great(potentials(for(prophylactic(or(therapeutic(use. (However,(little(is(known( regarding(the(relationship(between(disease(severity(and(the(magnitude(of(SARS_CoV_ 2_specific( NAbs( responses( in( patients( recovered( from( COVID_19. ( Defining( the( association(of(disease(severity(to(NAb(responses(will(facilitate(the(screening(of(COVID_ 19( recovered( patients( as( therapeutic( plasma( donors( as( well( as( memory( B( cell( providers(for(cloning(high_affinity(human(neutralizing(mAbs(to(prevent(or(treat(COVID_ 19.</td><td style="min-width:100px;border-bottom:1px solid lightgray">
      <div style="margin-bottom:8px">
        <div><b>SARS_CoV_2_</b></div>
        <div>suggested: None</div>
      </div>
    </td></tr><tr><td style="min-width:100px;vertical-align:top;border-bottom:1px solid lightgray">(Notably,(23.5%(of(these(sera(required(the(combination(of(S1_(and( S2_specific(NAbs(to(effectively(neutralize(pseudovirus(infection((Fig.(3c). (Collectively,( our(data(revealed(the(highly(heterogeneous(nature(of(NAb(responses(against(SARS_ CoV_2( S( protein( and( such( diversity( seemed( to( be( closely( associated( with( disease( severity. ( The( immune( mechanisms( underlying( the( diversity( of( NAbs( responses( in( COVID_19(patients(with(different(degree(of(symptoms(warrant(further(investigations. ( ( ( ( Finally,(we(investigated(whether(NAbs(depleted(by(S1_recombinant(protein(are(actually( targeting( RBD( for( their( neutralizing( capacity. ( For( this( purpose,( we( depleted( RBD_ specific(antibodies(in(10(serum(samples(showing(S1_specific(neutralization(by(biotin_ conjugated(RBD(protein(mediated(pull_down((Supplementary(Fig.(2c).</td><td style="min-width:100px;border-bottom:1px solid lightgray">
      <div style="margin-bottom:8px">
        <div><b>RBD_</b></div>
        <div>suggested: None</div>
      </div>
    </td></tr><tr><td style="min-width:100px;vertical-align:top;border-bottom:1px solid lightgray">( P( values( less( than( 0.05( were( defied( as( statistically( significant. ( Prism( 6( software(was(used(for(statistical(analysis.& & Data&availability&statements& The( data( sets( in( the( study( are( available( from( the( corresponding( authors( upon( reasonable(request. ( & Acknowledgements& This(work(was(supported(by(grants(from(the(National(Science(and(Technology(Major( Project((No. 2017ZX10202102_006_002(to(L.</td><td style="min-width:100px;border-bottom:1px solid lightgray">
      <div style="margin-bottom:8px">
        <div><b>The(</b></div>
        <div>suggested: None</div>
      </div>
    </td></tr></table>

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  6. Version published to 10.1101/2020.07.29.20164285 on medRxiv