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In the current SARS-CoV-2 pandemic a key unsolved question is the quality and duration of acquired immunity in recovered individuals. This is crucial to solve, however SARS-CoV-2 has circulated for under five months, precluding a direct study. We therefore monitored 10 subjects over a time span of 35 years (1985-2020), providing a total of 2473 follow up person-months, and determined a) their antibody levels following infection by any of the four seasonal human coronaviruses, and b) the time period after which reinfections by the same virus can occur. An alarmingly short duration of protective immunity to coronaviruses was found by both analyses. We saw frequent reinfections at 12 months post-infection and a substantial reduction in antibody levels as soon as 6 months post-infection.
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1
Humancoronavirusreinfectiondynamics:lessonsforSARS‐CoV‐2
Authors
ArthurW. D.Edridge1,JoannaKaczorowska1, AlexisC.R.Hoste2,Margreet Bakker1,Michelle Klein1,
Maarten F. Jebbink1, Amy Matser3, Cormac M. Kinsella1, Paloma Rueda2, Maria Prins3,4, Patricia
Sastre2,MartinDeijs1,LiavanderHoek1,*
Affiliations
1. Laboratory of Experimental Virology, Department of Medical Microbiology and Infection
Prevention,AmsterdamInfection&ImmunityInstitute,AmsterdamUMC,UniversityofAmsterdam,
Meibergdreef15,1105AZAmsterdam,TheNetherlands.
2.INGENASA,InmunoloayGenéticaAplicadaS.A.,Av.delaInstitución Libre de Enseñanza,39, 
28037Madrid,Spain
3.DepartmentofInfectiousDiseases,PublicHealthServiceofAmsterdam,NieuweAchtergracht100,
1018WTAmsterdamTheNetherlands.
4. Amsterdam UMC, University of Amsterdam, Department of Infectious Diseases, Amsterdam
Infection& ImmunityInstitute,AmsterdamUMC,University ofAmsterdam,Meibergdreef15,1105
AZAmsterdam,TheNetherlands.
*Correspondingauthor
ABSTRACT
InthecurrentSARS‐CoV‐2pandemicakeyunsolvedquestionisthequalityanddurationofacquired
immunity in recovered individuals. This is crucial to solve, however SARS‐CoV‐2 has circulated for
underfivemonths,precludingadirectstudy.Wethereforemonitored10subjectsoveratimespanof
35years(1985‐2020), providinga total of2473follow upperson‐months,and determineda)their
antibodylevelsfollowinginfectionbyanyofthefourseasonalhumancoronaviruses,andb)thetime
periodafterwhichreinfectionsbythesameviruscanoccur.Analarminglyshortdurationofprotective
immunitytocoronaviruseswasfoundbybothanalyses.Wesawfrequentreinfectionsat12months
post‐infectionandsubstantialreductioninantibodylevelsassoonas6monthspost‐infection.
ONESENTENCESUMMARY:Coronavirusprotectiveimmunityisshort‐lasting

. CC-BY 4.0 International licenseIt is made available under a
is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. (which was not certified by peer review) The copyright holder for this preprint this version posted May 18, 2020. .https://doi.org/10.1101/2020.05.11.20086439doi: medRxiv preprint
2
MAINTEXT
SARS‐CoV‐2isanovelcoronavirusresponsibleforanongoingpandemic.Itsrapidtransmissionismost
probably caused bythefactthatthe virus entered a grossly naive, thus highly susceptible, human
population, combinedwiththecapacity ofthevirusto transmit duringtheasymptomaticphaseof
infection.Sincenopharmaceuticalinterventionsareuniversallyavailableorapplied,currentpolicies
tolimitthespreadofSARS‐CoV‐2revolvearoundcontainment,socialdistancing,andtheassumption
thatrecovered patientsdevelopprotectiveimmunity.Itisstillunclearwhetherprotectiveimmunity
isindeed inducedafterinfection, andforhowlong.Thedurationofprotectionwillimpactnotonly
theoverallcourseofthecurrentpandemic,butalsothepost‐pandemicperiod.Todate,noconcrete
evidenceofreinfectionbySARS‐CoV‐2isavailable,norisanyexampleofreinfectionbySARS‐CoV‐1or
MERS‐CoV,yetthisislikelyinfluencedbytherecentemergenceofSARS‐CoV‐2andthelimitedscale
of the SARS‐CoV‐1 and MERS‐CoV epidemics. The limited available data on potential protective
immunityagainstcoronavirusreinfectionisderivedfromoneexperimentalinfectionstudyin
volunteers(1),fromwhichitisgenerallyassumedthatreinfectionbycoronavirusescanoccur.Natural
coronavirusinfectionsandsusceptibilitytoreinfectionhavenotbeen investigatedthusfar. If they
occur,reinfectionswillprobablybedictatedbytwovariables:exposuretothevirus,andthequality
ofsustainedimmunity(2).
Even though it is not possible to investigate SARS‐CoV‐2 reinfections yet, the seasonal
coronavirusesmayserveasareliablemodel.Therearefourspeciesofseasonalcoronaviruses,HCoV‐
NL63,HCoV‐229E,HCoV‐OC43,andHCoV‐HKU1.Allareassociatedwithmostlymildrespiratorytract
infections. However, aside from being etiological agents of common cold, the four viruses are
biologically dissimilar. Two belong to the genus Alphacoronavirus, and two to the genus
Betacoronavirus.The virusesuse characteristicreceptormoleculestoentera targetcell,andbased
onreceptordistributiontheydonotallenterthesameepithelialcelltypeinthelungs(3).Giventhis
variability,theseasonalcoronavirusesarethemostrepresentativeviru sgroupfr omwhichtoco nclude
generalcoronaviruscharacteristics,particularlycommondenominatorslikehostprotectiveimmunity
and susceptibility to reinfection. Since most people experience their first seasonal coronavirus
infectionduringearlychildhood(46),reinfectionslaterinlifecanbeinvestigated.
Theaimofthisstudywastoinvestigatethetimeperiodbetweencoronavirusreinfectionsand
thedynamicsofantibodydeclinefollowinginfection.Theseparameterswereassessedbymeasuring
theimmuneresponsetoeachindividualseasonalcoronavirus,overanextendedperiod.Wefollowed
healthysubjectsformultipledecadesatregularintervals.AsIgGlevelsonlyincreaseaftersuccessful
infection and—importantly—remain constant after unsuccessful viral challenge (1), increased
antibodylevelsidentifyaninfection.Weusedthecarboxylterminalofthenucleocapsidprotein(NCt)
as the target antigen in ELISA, as this protein is immunogenic, relatively low in interspecies
conservation,yethighinintraspeciesconservationwhencomparedtotheSpikeprotein(4,710).
Frequencyofinfectionsandreinfections.
Fromaprospectivecohortstudyfollowingadultmales(seeM&Mand (11)), ten subjects were
randoml yselected.Foll ow‐upof subject sstartedin1985 and,besidesagapinfollowupbetween1997
and2003,continueduntil2020atregularintervals(every3monthspriorto1989,andevery6months
afterwards,Table1).Thecumulativeperiodatwhichsubjectswerecontinuouslyfollowedtotaled
morethan200person‐years(2473months).Atstartofthestudy,subjectagerangedfrom27to40
years; by the end of follow‐up , subjects were 49 to 66 years old.Thestudywasapprovedbythe
MedicalEthicsCommitteeoftheAmsterdamUniversityMedicalCenter of the University of
Amsterdam,theNetherlands(MEC07/182).
. CC-BY 4.0 International licenseIt is made available under a
is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. (which was not certified by peer review) The copyright holder for this preprint this version posted May 18, 2020. .https://doi.org/10.1101/2020.05.11.20086439doi: medRxiv preprint
3
Infections by seasonal coronaviruses were defined as 1.4‐fold increase in antibody levels
occurringbetweentwovisits(1),andadditionallythestandard deviationsofthemeanatbothvisits
notoverlapping.Atotalof132events,rangingfrom3to22persubject,metthesecriteriaandwere
thusconsideredinfections(Table1).Theincidenceratesofseasonalcoronavirusreinfectionsper100
person‐yearsof follow‐upwas15.3 (95%CI10.0‐23.4);20.1(95% CI14.2‐28.7);16.4(95%CI 10.4‐
26.1);6.3(95%CI2.4‐16.8),forHCoV‐NL63,HCoV‐229E,HCoV‐OC43andHCoV‐HKU1respectively.To
test whether serological infection criteria represented symptomatic infections , we compared self‐
reported influenza like illnesses in the interval directly preceding the antibody peaks. Indeed,
reportingoffeverandcoughweresignificantlyassociated(Fisher’sexacttestp=0.031,supplementary
tableS1).
Table1.Studysubjectsandseasonalcoronavirusinfectionsduringfollowup.
Subject Year Age
Continuous
follow‐up
period
CoronavirusInfections
Start End Start End Months Years Total* NL63 229E HKU1 OC43
1 1985 2017 32 64 265 22.1 14 4 3 1 6
2 1985 2019 30 64 310 25.9 15 5 6 3 1
3 1985 2020 29 64 340 28.3 6 2 3 0 1
4 1985 2010 33 59 230 19.2 22 3 12 2 5
5 1985 2010 27 53 232 19.3 9 5 3 1 0
6 1985 1997 37 49 144 12.0 3 1 1 0 1
7 1985 2003 32 49 138 11.5 13 3 5 1 4
8 1986 2014 34 62 256 21.3 10 3 5 0 2
9 1985 2010 40 75 342 28.6 22 7 5 3 7
10 1985 2011 35 60 233 19.4 18 4 6 2 6
Total  2473 205.6 132 37 49 13 33
Medianreinfectiontimesof33(IQR18–60),31(IQR15–42),27(IQR21–49),and46(IQR
36–68)monthswerefoundforHCoV‐NL63,HCoV‐229E,HCoV‐OC43andHCoV‐HKU1,respectively,
and30(IQR18–54)monthsforallvirusescombined(Fig.1A).Therewasnostatisticallysignificant
differencebetweentheinfectionintervallengthsoftheindividualviruses(Kruskal‐Wallistest,P=0.74).
Inafewcases,re‐infectionsoccurredasearlyas6months(twotimesforHCoV‐229Eandonetimefor
HCoV‐OC43)and9months(twotimesforHCoV‐NL63).Themostfrequentobservedreinfectiontime
was 12 months. For reinfections occurring as early as 6 months, we observed no reduction in
antibodies between infections (Fig. 1A, white circles). At longer infection intervals, intermediate
reductionsinantibodylevelswereobserved.
Theability todetect short‐termreinfectionsislimitedbythesamplinginterval.Importantly
though,noreinfectionwasobservedatthefirstsubsequentfollow‐upvisitaftera 3monthinterval
(Fig.1A).Wedidobserveseveralreinfectionsatsubsequentvisitswitha6‐monthinterval,suggesting
that reinfections within 6 month s do not occur. To further support this point, weexamined ratios
betweenantibodylevelsbetweentwovisits,bothfor3and6monthfollow‐ups.AsshowninFig.1B,
only ratios below 1 were found in the observations with every 3monthsampling,andwecan
thereforesafelyconcludethatreinfectionsoccurfrom6monthson,yetmostprobablynotearlier.
. CC-BY 4.0 International licenseIt is made available under a
is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. (which was not certified by peer review) The copyright holder for this preprint this version posted May 18, 2020. .https://doi.org/10.1101/2020.05.11.20086439doi: medRxiv preprint
4
Figure1Infectionandreinfectioncharacteristics,andwaningimmunity for seasonal coronaviruses.(A) The
intervaldurationsbetweenreinfections.Onlyreinfectionswhich were observed within a continuous follow‐u p
periodareshown.Whitedotsindicatereinfectionsforwhichnointermediatedecreaseinantibodylevelscouldbe
observed. Black vertical lines describe median reinfection times. (B) Changes in antib ody levels post‐infection
relativetothefollow‐upintervalduration.Eachcirclerepresentsaninfection. Thex‐axisdescribesthetimeuntil
thenext follow‐upvisit post‐infection.The y‐axisdescribesthechange inantibody levelatthesubsequentvisit.
Largercircles representsahigherratio‐riseinantibodylevelsattheinitialinfection.Thehorizontallineindicates
theborderbetweenincreases(>1.0)ordecreases(<1.0)inantibodylevelsatthenextstudyvisit(C)Kaplan‐Meier
curve showing decline of antibodies post infe ction (100%, 75% and 50%). The visit at which the infection wa s
establishedwas countedas timepoint0,caseswere subsequentlyfollowed. Anevent isdefinedwhen antibody
levels drop below the indicated level. When the antibody level did not decrease to the indicated levels, an
observationwascensoredatthelasttimepointofactivefollow‐up.
Antibodydynamicsafterinfection.
Onsomeoccasions,antibodyrisesreachedhighlevels(uptoratio11),representedinFig.1Baslarger
circles,yetthesehighvalueswereneversustainedatthenextstudyvisit(Fig.1B).Toinvestigatethese
dynamicsfurther,wecalculatedthetimeuntila50%,75%,orfullreturnofantibodylevelstobaseline
(pre‐infectionantibodylevels).AscanbeseeninFig.1C,within6monthspost‐infectionthemajority
ofpeoplelost50%oftheirantibodies,whereasafterayearthemajoritylost75%.Acompletereturn
tobaselinelevelsoccurredwithin4yearsforhalfofinfections(Fig.1C).
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5
Simultaneousinfectionsbyalpha‐andbetacoronaviruses.
AlthoughourELISAtestsusingtheCterminalpartoftheNproteinwerecautiouslydesignedtobe
specificforeachindividualvirus,wecannotruleoutthatacertaindegreeofantibodycross‐reactivity
occurred.Wethereforeinvestigatedhowofteninfectionscoincided,sincecross‐reactivitymayhave
ledtofalselabelingofinfections. We observed no significant simultaneous infections for
Alphacoronavirus(HCoV‐NL63orHCoV‐229E)alongsideBetacoronavirus(HCoV‐HKU1orHCoV‐OC43),
however, we did see that infections by the betacoronaviruses HCoV‐OC43 and HCoV‐HKU1 often
coincided (38.5%, Table 2).Likewise,foralphacoronaviruses,HCoV‐229Einfectionscoincided with
HCoV‐NL63infectionsin59.5%ofthecases,andviceversain44.9%ofthecases.Hence,thereisarisk
thatweoverestimated the numberinfectionsandthus reinfections. We thereforere‐analyzedthe
datawithamorestringentdefinitionofinfection,includingonlythestrongestantibodyriseinduced
bya BetacoronavirusorAlphacoronavirusatagiventimepoint.Underthisdefinitionwestillfound
infectionintervalscomparabletotheoriginaldata(supplementaryFig.S2),withminimuminfection
intervals as short as 6 months and frequent reinfections at 12 months, although the number of
reinfectionswasobviouslyreduced.
Table2.Coincidingcoronavirusinfections
Simultaneousinfections(%)
Infection HCoV‐NL63 HCoV‐229E HCoV‐OC43 HCoV‐HKU1
HCoV‐NL63 NA 44.9 3.0 7.7
HCoV‐229E 59.5 NA 18.2 23.1
HCoV‐OC43 2.7 12.2 NA 38.5
HCoV‐HKU1 2.7 6.1 15.2 NA
Broadly acting antibodies recognizing SARS‐CoV‐2. In theory, antibodies induced by (repeated)
coronavirus infections may have broad coronavirus‐recognizing characteristics. We therefore
performedanadditionalELISAonall10subjects,thistimeusingthecompleteNproteinofSARS‐CoV‐
2, to allow detection of broadly reacting antibodies. Visual inspection suggested that broadly
recognizing antibodies wer e produced, and were most likely induced by combined infections with
HCoV‐NL63andHCoV‐HKU1(subjects2,9and10,supplementaryFig.S1).
Coronavirusinfectionsinchangingseasons.
To date it is uncertain whether SARS‐CoV‐2 will share the same winter prevalence peak that is
observedforseasonalcoronavirusesinnon‐equatorialcountries.However,itisimportanttoconsider
thatwinterpreferenceof seasonal coronaviruses has only beendetermined by testingrespiratory
samplesofpeoplethatexperienceddisease(12).Samplingandstorageisthereforedictatedbyhaving
symptomsandnotbystudyprotocol.Ifco ronavirusspreadcontinuesunabatedinsummer,yetpeople
rarely display symptoms (e.g. because of higher vita min D levels) and are therefore not sampl ed,
infectionswillremainundetected.Ourserologicalstudyisuniquebecauseitavoidsthissamplingbias.
TheNetherlandshas a typicaltemperateclimate,andour study samples werecollectedatregular
intervals.Thesamplingofeachsubjectstartedatdifferenttimesoftheyear,and,becauseofthe3or
6monthsregimeofvisits,sampleswerecollectedthroughoutallseasons.Consequently,wecanfor
thefirsttimevisualizeinanunbiasedmannertheseasonalityofcoronavirusinfections.Asshownin
Fig.2,May,June,July,AugustandSeptemberindeedshowthelowestprobabilityofinfectionsforall
fourseasonalcoronaviruses(Wilcoxonsigned‐ranktest,p=0.005).
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6
Fig.2Seasonalityofinfections.Theprevalenceof thefour seasonal coronavirusesshown as theprobability of infection
onsetforaspecificmonth.Themonthsbetweenandincludingthemonthsofthefollow‐upvisitsatwhichtheinfectionwas
establishedandthepriorfollow‐upvisitwerecounted.Thevaluepermonthwasdividedbythenumberofmonthsbetween
follow‐upvisits.

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is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. (which was not certified by peer review) The copyright holder for this preprint this version posted May 18, 2020. .https://doi.org/10.1101/2020.05.11.20086439doi: medRxiv preprint
7
DISCUSSION
Weshow,forthefirsttime,thatreinfectionswithallseasonal coronaviruses occur in nature.The
majorityofreinfectionsoccurredwithin3years.IfSARS‐CoV‐2willbehavelikeaseasonalcoronavirus
inthefuture,asimilarpatternmaybeexpected.However,thistimespanbetweeninfectionsdoesno t
indicatethatan individual’sprotectiveimmunitylastsforthesameperiodoftime,asreinfectionis
alsodependentonre‐exposure.Infact,basedontheminimuminfectionintervalsandthedynamics
ofantibodywaningthatweobserved,theprotectiveimmunity maylast aslittle as6 to12 months.
Recently Kissler et al.modeledthe protective immunity andreinfectiondynamicsHCoV‐OC43 and
HCoV‐HKU1 and estimated a 45 week period of protective immunity(13).Ourserologicalstudy
confirmsthisprediction.
WhenweviewourfindingsinlightofthecurrentcontrolactionstakenforSARS‐CoV2,itis
clearthatcoronavirusreinfectionriskiskeytopublichealthpolicy.Herewerevealariskthatinthe
nearfuture,serologybasedteststhatmeasurepreviousinfectionsforSARS‐CoV‐2mayhavelimited
use if that infection has occurred >1 year prior to sampling. Additionally, vaccine studies should
anticipate that sustained protective immunity may be uncertain for coronaviruses, and repeated
yearlyorhalf‐yearlyvaccinationsmaybeneededtocircumventongoingtransmission.
ThereisongoingdiscussionregardingherdimmunityforSARS‐CoV‐2control.Herdimmunity
occurswhenathresholdproportion ofapopulation isimmunetoacertainpathogen,andprotects
evennon‐immune individuals against theinfectionbylimitingoverall spread. This effect has been
observedforavarietyofviruses,mainlythosethatarepartiallycontrolledviavaccinationprograms,
suchashepatitisAvirus(14),influenzaAvirus(15), andhuman papillomavirus(16).Inthecaseof
SARS‐CoV‐2,achievingherdimmunitymaybechallengingduetorapidlossofprotectiveimmunity.It
wasrecentlysuggestedthatrecoveredindividualsshouldreceiveaso‐called“immunitypassport”(17)
whichwouldallowthemtorelaxsocialdistancingmeasuresandprovide governmentswith dataon
herdimmunitylevels inthepopulation. However,asprotective immunitymaybelostby6 months
post infection, the prospe ct of reaching functional herd immunity by natural infection seems very
unlikely.
It is generally assumed that exposure to each seasonal coronavirus is not equal. The
BetacoronavirusHCoV‐HKU1is consideredtohave thelowestprevalence (4,13)andwefoundthe
same. We also observed that antibody levels to HCoV‐HKU1 were low over the whole range (all
samplestested).WhetherthisindicatesHCoV‐HKU1infectionelicitsapoorinductionofantibodiesis
intriguing,yetnot answerableinourstudy. Weuseda relativelysmallpartoftheNproteinasthe
antigeninourtests,tomostspecificallyidentifyinfectionsbyeachvirusindividually.Thissmallpart
oftheproteinmaynotcontainthemostimmunodominantepitopesofHCoV‐HKU1.Aneutralization
testwouldideallybedonetosolvetheissueofprotectiveimmunityraisedbyHCoV‐HKU1;however,
unfortunatelynoculturingsystemsuitableforneutralizationtestingisavailableforHCoV‐HKU1(18).
WenoticedthreesubjectstocarryantibodiesrecognizingSARSCoV‐2N protein atcertain
timepoints.ItisunlikelythattheyhadbeeninfectedwithaSARS‐CoV‐2‐likevirusin1985(subject10),
1992(subject2),or 2006(subject 9),and wethereforesuggestthatbroadly actingantibodiesmay
havebee ninduce dbycoin cidin ginfect ionsofanAlpha‐andaBetacoronavirus(inoursub ject(s) HCoV
HKU1andHCoV‐NL63).Toexplorethisfindingwelookedat thegenetic distanceandconsequently
aminoacid differencesinthestructuralproteinofthevariouscoronaviruses(supplementaryTable
S2).Notably,SARS‐CoV‐2Nproteinhasonly32%and34%identityontheaminoacidlevelwiththeN
proteinofHCoV‐OC43andHCoV‐HKU1respectively,andonly26%and24%identitywithHCoV‐NL63
andHCoV‐229Erespectively. Similarly,thedistancebetweenAlphacoronavirusandBetacoronavirus
Nproteinislarge (only 24% to26%aminoacid identity). Still, we cannot exclude the presenceof
conserved(conformational) epitopesin HCoV‐HKU1andHCoV‐NL63 Nproteinthat mayresultin a
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8
more broadly acting antibody response, due to simultaneous exposure in concurrent infections.
Additionalscreening,includingmoresubjects,isrequiredforconfirmation.
Ourstudywassubjecttolimitations.Oneistheinabilitytosequencethevirusgenomeduring
infection.Intheory,strainvariationcouldplayaroleinsusceptibilitytoreinfection.HCoV‐NL63,HCoV‐
OC43,andHCoV‐HKU1allshowdifferentco‐circulatinggeneticclusters(1921).ForHCoV‐229E,there
arenomajorgeneticsubtypesknown,likethecurrentSARS‐CoV‐2situation(22,23).Itcouldbethat
ourobservationofshort‐termimmunityisinfluencedbygenotypevariation,andastudyonprotective
immunitywouldthereforeideallyallowsequencingofre‐infectingstrainsfromrespiratorymaterial;
however,thisisintractableinanaturalinfectionstudybecausevirussheddinginreinfectionscanbe
asshortasoneday(1).Anotherlimitationisthatthestudiessubjectswereallmales.ForCOVID‐19,
andalsoHCoV‐NL63,menhaveahigherincidenceofdisease(25,26),anditisthereforeofinterestto
determinethedynamicsofprotectiveimmunityalsoinacohortofhealthywomen.
In conclusion, seasonal human coronaviruses have little in common, apart from causing
commoncold.Still,theyallseemtoinduceashort‐lastingimmunitywithrapidlossofantibodies.This
maywellbeageneraldenominatorforhumancoronaviruses.
REFERENCES
1.K.A.Callow,Effectofspecifichumoralimmunityandsomenon‐specificfactorsonresistance
ofvolunteerstorespiratorycoronavirusinfection.Epidemiology&Infection.95,173–189
(1985).
2.L.vanderHoek,G.Ihorst,K.Sure,A.Vabret,R.Dijkman,M.deVries,J.Forster,B.Berkhout,
K.Uberla,BurdenofdiseaseduetohumancoronavirusNL63infectionsandperiodicityof
infection.JournalofClinicalVirology.48,104–108(2010).
3.L.vanderHoek,Humancoronaviruses:whatdotheycause?Antiviraltherapy.12,651(2007).
4.R.Dijkman,M.F.Jebbink,E.Gaunt,J.W.A.Rossen,K.E.Templeton,T.W.Kuijpers,L.vander
Hoek,ThedominanceofhumancoronavirusOC43andNL63infectionsininfants.Journalof
ClinicalVirology.53,135–139(2012).
5.W.Zhou,W.Wang,H.Wang,R.Lu,W.Tan,Firstinfectionbyallfournon‐severeacute
respiratorysyndromehumancoronavirusestakesplaceduringchildhood.BMCInfectious
Diseases.13,1–8(2013).
6.H.Hofmann,K.Pyrc,L.vanderHoek,M.Geier,B.Berkhout,S.Pöhlmann,Humancoronavirus
NL63employsthesevereacuterespiratorysyndromecoronavirusreceptorforcellularentry.
ProceedingsoftheNationalAcademyofSciencesoftheUnitedStatesofAmerica.102,7988–
7993(2005).
7.E.G.Severance,I.Bossis,F.B.Dickerson,C.R.Stallings,A.E.Origoni,A.Sullens,R.H.Yolken,
R.P.Viscidi,Developmentofanucleocapsid‐basedhumancoronavirusimmunoassayand
estimatesofindividualsexposedtocoronavirusinaU.S.metropolitanpopulation.Clinical
andVaccineImmunology.15,1805–1810(2008).
8.P.Sastre,R.Dijkman,A.Camuñas,T.Ruiz,M.F.Jebbink,L.vanderHoek,C.Vela,P.Rueda,
DifferentiationbetweenhumancoronavirusesNL63and229Eusinganoveldouble‐antibody
sandwichenzyme‐linkedimmunosorbentassaybasedonspecificmonoclonalantibodies.
ClinicalandVaccineImmunology.18,113–118(2011).
. CC-BY 4.0 International licenseIt is made available under a
is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. (which was not certified by peer review) The copyright holder for this preprint this version posted May 18, 2020. .https://doi.org/10.1101/2020.05.11.20086439doi: medRxiv preprint
9
9.R.Dijkman,M.F.Jebbink,N.B.elIdrissi,K.Pyrc,M.A.Müller,T.W.Kuijpers,H.L.Zaaijer,L.
vanderHoek,HumancoronavirusNL63and229Eseroconversioninchildren.Journalof
ClinicalMicrobiology.46,2368–2373(2008).
10.C.Lehmann,H.Wolf,J.Xu,Q.Zhao,Y.Shao,M.Motz,P.Lindner,Alineimmunoassayutilizing
recombinantnucleocapsidproteinsfordetectionofantibodiestohumancoronaviruses.
DiagnosticMicrobiologyandInfectiousDisease.61,40–48(2008).
11.W.P.H.vanBilsen,A.Boyd,M.F.S.vanderLoeff,U.Davidovich,A.Hogewoning,L.vander
Hoek,M.Prins,A.Matser,DivergingtrendsinincidenceofHIVversusothersexually
transmittedinfectionsinHIV‐negativeMSMinAmsterdam.AIDS.34(2020)(availableat
https://journals.lww.com/aidsonline/Fulltext/2020/02010/Diverging_trends_in_incidence_of
_HIV_versus_other.16.aspx).
12.E.R.Gaunt,A.Hardie,E.C.J.Claas,P.Simmonds,K.E.Templeton,Epidemiologyandclinical
presentationsofthefourhumancoronaviruses229E,HKU1,NL63,andOC43detectedover3
yearsusinganovelmultiplexreal‐timePCRmethod.Journalofclinicalmicrobiology.48,
2940–2947(2010).
13.S.M.Kissler,C.Tedijanto,E.Goldstein,Y.H.Grad,M.Lipsitch,Projectingthetransmission
dynamicsofSARS‐CoV‐2throughthepostpandemicperiod.Science(2020),
doi:10.1126/science.abb5793.
14.D.Smith,C.Huynh,A.J.Moore,A.Frick,C.Anderson,M.Porrachia,B.Scott,S.Stous,R.
Schooley,S.Little,HerdImmunityLikelyProtectedtheMenWhoHaveSexWithMeninthe
RecentHepatitisAOutbreakinSanDiego,California.ClinicalInfectiousDiseases.68,1228–
1230(2019).
15.E.Q.Mooring,S.Bansal,Increasingherdimmunitywithinfluenzarevaccination.
Epidemiology&Infection.144,1267–1277(2016).
16.R.L.Cameron,K.Kavanagh,J.Pan,J.Love,K.Cuschieri,C.Robertson,S.Ahmed,T.Palmer,K.
G.J.Pollock,Humanpapillomavirusprevalenceandherdimmunityafterintroductionof
vaccinationprogram,Scotland,2009–2013.Emerginginfectiousdiseases.22,56(2016).
17.A.Bendavid,etal.,https://www.medrxiv.org/content/10.1101/2020.04.14.20062463v1
(2020).
18.K.Pyrc,A.C.Sims,R.Dijkman,M.Jebbink,C.Long,D.Deming,E.Donaldson,A.Vabret,R.
Baric,L.vanderHoek,R.Pickles,CulturingtheUnculturable:HumanCoronavirusHKU1
Infects,Replicates,andProducesProgenyVirionsinHumanCiliatedAirwayEpithelialCell
Cultures.JournalofVirology.84,11255–11263(2010).
19.P.C.Y.Woo,S.K.P.Lau,C.C.Y.Yip,Y.Huang,H.‐W.Tsoi,K.‐H.Chan,K.‐Y.Yuen,
Comparativeanalysisof22coronavirusHKU1genomesrevealsanovelgenotypeand
evidenceofnaturalrecombinationincoronavirusHKU1.Journalofvirology.80,7136–7145
(2006).
20.K.Pyrc,R.Dijkman,L.Deng,M.F.Jebbink,H.A.Ross,B.Berkhout,L.vanderHoek,Mosaic
structureofhumancoronavirusNL63,onethousandyearsofevolution.Journalofmolecular
biology.364,964–973(2006).
. CC-BY 4.0 International licenseIt is made available under a
is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. (which was not certified by peer review) The copyright holder for this preprint this version posted May 18, 2020. .https://doi.org/10.1101/2020.05.11.20086439doi: medRxiv preprint
10
21.S.K.P.Lau,P.Lee,A.K.L.Tsang,C.C.Y.Yip,H.Tse,R.A.Lee,L.‐Y.So,Y.‐L.Lau,K.‐H.Chan,P.
C.Y.Woo,MolecularepidemiologyofhumancoronavirusOC43revealsevolutionofdifferent
genotypesovertimeandrecentemergenceofanovelgenotypeduetonatural
recombination.Journalofvirology.85,11325–11337(2011).
22.D.Chibo,C.Birch,Analysisofhumancoronavirus229Espikeandnucleoproteingenes
demonstratesgeneticdriftbetweenchronologicallydistinctstrains.Journalofgeneral
virology.87,1203–1208(2006).
23.S.M.J.Farsani,R.Dijkman,M.F.Jebbink,H.Goossens,M.Ieven,M.Deijs,R.Molenkamp,L.
vanderHoek,Thefirstcompletegenomesequencesofclinicalisolatesofhumancoronavirus
229E.VirusGenes.45,433–439(2012).
25. P.Mo,XingY,XiaoY,DengL,ZhaoQ,WangH,XiongY,ChengZ,GaoS,LiangK,LuoM,Chen
T,SongS,MaZ,ChenX,ZhengR,CaoQ,WangF,ZhangY.Clinicalcharacteristicsofrefractory
COVID‐19pneumoniainWuhan,China.ClinInfectDis.2020Mar16.pii:ciaa270.doi:
10.1093/cid/ciaa270.
26. L.vanderHoek,SureK,IhorstG,StangA,PyrcK,JebbinkMF,PetersenG,ForsterJ,Berkhout
B,UberlaK.CroupisassociatedwiththenovelcoronavirusNL63.PLoSMed.2005
Aug;2(8):e240.

Acknowledgments
TheauthorsgratefullyacknowledgetheAmsterdamCohortStudies(ACS)onHIVinfectionandAIDS,acollaborationbetween
the Public Health Service of Amsterdam, the Amsterdam UMC of the University of Amsterdam, Sanquin B lood Supply
Foundation,MedicalCenter JanvanGoyen, andthe HIVFocusCenteroftheDC‐Clinics.ItispartoftheNetherlandsHIV
MonitoringFoundation andfinanciallysupportedbytheCenterforInfectiousDiseaseControlof theNetherlandsNational
InstituteforPublicHealthandtheEnvironment.TheauthorsthankallACSparticipantsfortheircontribution,aswellasthe
ACS study nurses, data‐managers, and lab technicians. This work was supported by a grant from the European Union's
Horizon2020researchandinnovationprogramme,undertheMarieSkłodowska‐CurieActionsgrantagreementno.721367
(HONOURs),AmsterdamUMCfundingconnectedtoHONOURs,andtheAmsterdamUMCPhDscholarshipofA.W.D.Edridge.
Authorcontributions:A.W.D.E:Conceptualization,Writing– originaldraft,review andediting,Investigation,Visualization,
Formal Analysis, Validation;  J.K.: Investigation, Writing  – original draft, review and editing, A.C.R.H.: Resources; M.B.:
Investigation,Resources;M.K.: Investigation;M.F.J.: Investigation,Methodology;A.M.: FormalAnalysis;C.M.K.:Writing–
originaldraft,reviewandediting,FormalAnalysis; P.R.:Resources; M.P.:Resources;P.S.: Resources;M.D.:Investigation,
Methodology;L.v.d.H.:Conceptualization,Writing–originaldraft,Writing‐reviewandediting,Supervision.Competing
interests:Authorsdeclarenocompetinginterests.
. CC-BY 4.0 International licenseIt is made available under a
is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. (which was not certified by peer review) The copyright holder for this preprint this version posted May 18, 2020. .https://doi.org/10.1101/2020.05.11.20086439doi: medRxiv preprint
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... However, more knowledge on the contribution of neutralizing antibodies to protection against future infections is needed. A study that investigated antibody response and immunity to the well-known seasonal coronaviruses HCoV-NL63, HCoV-229E, HCoV-OC43, and HCoV-HKU1 has shown substantial reduction of antibodies as soon as 6 months post-infection and frequent reinfections 12 months post-infection [22]. Moreover, there is much debate on the possibility of waning immunity, with a growing amount of evidence of a decline in neutralizing antibodies [20,23,24]. ...
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It is unknown to what extent the human coronaviruses (HCoVs) OC43, HKU1, 229E and NL63 infect healthy children. Frequencies of infections are only known for hospitalized children. Comparing infection frequencies in children who have mild infections with frequencies in children needing hospital uptake will determine whether infection by one of the four HCoVs leads to more severe disease. In addition, the sequence of seroconversions can reveal whether infection by one HCoV protects from infection by other HCoVs. Two distinct study groups were monitored: healthy children and children hospitalized due to respiratory infection. HCoV natural infection rates in healthy children were obtained by serology in 25 newborns (followed 0-20months). The frequencies of severe HCoVs infection was determined by real time RT-PCR among 1471 hospitalized infants (<2-years old) with acute respiratory tract disease. The majority of healthy children seroconverted for HCoV-OC43 (n=19) and HCoV-NL63 (n=17), less for HCoV-HKU1 (n=9) and HCoV-229E (n=5). Notably, HCoV-HKU1 seroconversion was absent after HCoV-OC43 infection. Also HCoV-229E infection was rarely observed after HCoV-NL63 infection (1 out of 5). In the hospital 207 (14%) out of 1471 children were HCoV positive. Again we observed most infection by HCoV-OC43 (n=85) and HCoV-NL63 (n=60), followed by HCoV-HKU1 (n=47) and HCoV-229E (n=15). HCoV-NL63 and HCoV-OC43 infections occur frequently in early childhood, more often than HCoV-HKU1 or HCoV-229E infections. HCoV-OC43 and HCoV-NL63 may elicit immunity that protects from subsequent HCoV-HKU1 and HCoV-229E infection, respectively, which would explain why HCoV-OC43 and HCoV-NL63 are the most frequently infecting HCoVs. There are no indications that infection by one of the HCoVs is more pathogenic than others.