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AcceleratingDiagnostics inaTimeofCrisis

Accelerating DiagnosticsinaTime ofCrisis

Editedby StevenC.Schachter

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Informationonthistitle: www.cambridge.org/9781009396981

DOI: 10.1017/9781009396998

©CambridgeUniversityPress&Assessment2024

Thispublicationisincopyright.Subjecttostatutoryexceptionandtotheprovisions ofrelevantcollectivelicensingagreements,noreproductionofanypartmaytake placewithoutthewrittenpermissionofCambridgeUniversityPress&Assessment.

Firstpublished2024

AcataloguerecordforthispublicationisavailablefromtheBritishLibrary.

LibraryofCongressCataloging-in-PublicationData

Names:Schachter,StevenC.,editor.|Bolton,WadeE.,1947– editor.

Title:Acceleratingdiagnosticsinatimeofcrisis:theresponsetoCOVID-19andaroadmapforfuturepandemics/ editedbyStevenC.Schachter,WadeE.Bolton.

Description:Cambridge,UnitedKingdom;NewYork,NY:CambridgeUniversityPress,2023.|Includes bibliographicalreferencesandindex.

Identiﬁers:LCCN2023023826(print)|LCCN2023023827(ebook)|ISBN9781009396981(paperback)|ISBN 9781009396998(ebook)

Classiﬁcation:LCCRA644.C67(print)|LCCRA644.C67(ebook)|NLMWC506.1|DDC616.2/4144–dc23/eng/ 20230828

LCrecordavailableat https://lccn.loc.gov/2023023826

LCebookrecordavailableat https://lccn.loc.gov/2023023827

ISBN978-1-009-39698-1Paperback

CambridgeUniversityPress&Assessmenthasnoresponsibilityforthepersistence oraccuracyofURLsforexternalorthird-partyinternetwebsitesreferredtointhis publicationanddoesnotguaranteethatanycontentonsuchwebsitesis,orwill remain,accurateorappropriate.

Everyeﬀ orthasbeenmadeinpreparingthisbooktoprovideaccurateandup-to-dateinformationthatisin accordwithacceptedstandardsandpracticeatthetimeofpublication.Althoughcasehistoriesaredrawn fromactualcases,everyeﬀ orthasbeenmadetodisguisetheidentitiesoftheindividualsinvolved. Nevertheless,theauthors,editors,andpublisherscanmakenowarrantiesthattheinformationcontained hereinistotallyfreefromerror,notleastbecauseclinicalstandardsareconstantlychangingthrough researchandregulation.Theauthors,editors,andpublishersthereforedisclaimallliabilityfordirector consequentialdamagesresultingfromtheuseofmaterialcontainedinthisbook.Readersarestrongly advisedtopaycarefulattentiontoinformationprovidedbythemanufacturerofanydrugsorequipment thattheyplantouse.

DedicatedtoLindleyHallforhismentorship,JohnParrishforhispioneeringworkto acceleratehealth-caresolutionsandtoWallaceandJoeCoulterandtheirspiritofScience ServingHumanity.

ThisworkwassupportedbytheNationalInstituteofBiomedicalImagingand BioengineeringunderGrant5U54EB015408-06.Theviewsexpressedinthismanuscript arethoseoftheauthorsanddonotnecessarilyrepresenttheviewsoftheNationalInstitute ofBiomedicalImagingandBioengineering;theNationalHeart,Lung,andBloodInstitute; theNationalInstitutesofHealth;ortheUSDepartmentofHealthandHumanServices.

TheeditorsandchapterauthorsarethankfulforthevisionaryleadershipofFrancis Collins,BruceTromberg,JillHeemskerk,TiﬀaniLash,andToddMerchakinguidingthe developmentandimplementationoftheRapidAccelerationofDiagnostics(RADx®)Tech programandfacilitatingtheclosecollaborationofcruciallyessentialgovernmentagencies andnongovernmentalorganizationsinthiseﬀort.

ListofContributors ix

Foreword xiii

HarveyV.Fineberg

Preface xv

WadeE.Bolton

Acknowledgments xvii

Introduction 1

TaniaFernandez

1 EarlyDetection,Response, andSurveillanceoftheCOVID-19 PandemicCrisis 6

EnriqueM.Rabellino,Alexandra Smith,andMartaC.Cohen

2 ImmunologyofCOVID-19 andIneﬀectiveImmunity 31

AdolfoFirpo-BetancourtandEnrique M.Rabellino

3 ClinicalManagement:ARoadmap BasedonOneNewYorkCity Hospital’sResponsetotheCOVID-19 Pandemic 50

BarbaraBarnett,YvetteCalderon, BethanyKranitzky,YoungImLee,Erick Eiting,LinaMiyakawa,WaleedJavaid, andSaralynneBrown

4 ContributionofRADx® Tech totheRapidDevelopment ofCOVID-19DiagnosticTests 74

StevenC.Schachter,JohnM.Collins, MichaelK.Dempsey,LauraL. Gibson,MatthewL.Robinson,and PaulTessier

5 CoordinationofResourcesforthe ManufacturingandDeploymentof COVID-19DiagnosticAssays 88

MarenDowning,MiaCirrincione, AdamSamuta,KevinLeite,Sam

Dolphin,EmilyMuth,JoseValdesuso, andBrianWalsh

6 QualityandRiskManagement ProcessesforDiagnosticAssays duringanEmergencyPandemic Response 103

DevonC.CampbellandChristieJohnson

7 DevelopmentofAssaystoDiagnose COVID-19 125

YukariC.ManabeandWilliamClarke

8 LaboratoryVeriﬁcationandClinical ValidationofCOVID-19Diagnostic Assays 143

AnuradhaRao,LedaBassit,Julie Sullivan,WilburLam,andJennifer K.Frediani

9 ImportanceofTimelySequencing, Tracking,andSurveillance ofEmergentVariants 166

JessicaLin,MorganGreenleaf,Yang Lu,LedaBassit,CassandraWesselman, andAnnePiantadosi

10 TheRADx® RegulatoryCore andItsRoleinCOVID-19Emergency UseAuthorizations 194

ErikaTyburskiandCathrynCambria

11 CommercializationandMarket AssessmentofCOVID-19Assays 211 ManuelKingsley,SunshineMoore, HeathNaquin,EliseoVelasquez,Emily Kennedy,andGraceBendinger vii

TestingStrategiestoMitigate COVID-19DiseaseSpread 236

PaulTessierandAnette E.Hosoi 13 APandemicNotJustofInfection butofInequality:TheSocial ImpactofCOVID-19 250 MaraAspinallandLizRuark 14 SummaryandPathForward forFuturePandemics 263 WadeE.BoltonandSteven C.Schachter

Index 274

Contributors

MaraAspinall

HealthCatalysts,Tucson,AZ,USA

BarbaraBarnett

MountSinaiHealthSystem,NewYork, NY,USA

LedaBassit

EmoryUniversity,Atlanta,GA,USA

GraceBendinger

RapidAccelerationofDiagnostics (RADx®)–VentureWell,Hadley, MA,USAFrindleHealth,Newnan, GA,USA

WadeE.Bolton

RADx–VentureWell,Hadley,MA,USA

BoltonConsulting&Services,Delray Beach,FL,USA

SaralynneBrown

MountSinaiHealthSystem,NewYork, NY,USA

YvetteCalderon

MountSinaiHealthSystem,NewYork, NY,USA

CathrynCambria

CambriaRegulatoryConsulting,Atlanta, GA,USA

DevonC.Campbell Prodct,Boston,MA,USA

MiaCirrincione

RADx–VentureWell,Hadley, MA,USA

WilliamClarke

JohnsHopkinsUniversitySchoolof Medicine,Baltimore,MD,USA

MartaC.Cohen

SheﬃeldChildren’sHospital,Sheﬃeld,UK

JohnM.Collins CIMIT,Boston,MA,USA

MichaelK.Dempsey CIMIT,Boston,MA,USA MassachusettsInstituteofTechnology, Cambridge,MA,USA

SamDolphin RADx–VentureWell,Hadley,MA,USA

MarenDowning

RADx–VentureWell,Hadley,MA,USA

ErickEiting

MountSinaiHealthSystem,NewYork, NY,USA

TaniaFernandez

DreamCatcherVentures,SanFrancisco, CA,USA

RADx-VentureWell,Hadley,MA,USA

HarveyV.Fineburg

Gordon&BettyMooreFoundation,Palo Alto,CA,USA

AdolfoFirpo-Betancourt

MountSinaiHealthSystem,NewYork, NY,USA

JenniferK.Frediani EmoryUniversity,Atlanta,GA,USA

LauraL.Gibson

UniversityofMassachusettsMedical School,Worcester,MA,USA

MorganGreenleaf

EmoryUniversity,Atlanta,GA,USA

AnetteE.Hosoi

MassachusettsInstituteofTechnology, Boston,MA,USA

WaleedJavaid

MountSinaiHealthSystem,NewYork, NY,USA

ChristieJohnson Prodct,Boston,MA,USA

EmilyKennedy

RADx–VentureWell,Hadley,MA,USA

ManuelKingsley

QuestusHealthcare,Atlanta,GA,USA

RADx–VentureWell,Hadley,MA,USA

BethanyKranitzky

TheOhioStateUniversityWexner MedicalCenter,Columbus, OH,USA

WilburLam EmoryUniversity,Atlanta,GA,USA

YoungImLee

MountSinaiHealthSystem,NewYork, NY,USA

KevinLeite

RADx – VentureWell,Hadley,MA,USA

JessicaLin

GeorgiaInstituteofTechnology,Atlanta, GA,USA

YangLu IcahnSchoolofMedicineatMountSinai, NewYork,NY,USA

YukariC.Manabe

JohnsHopkinsUniversitySchool ofMedicine,Baltimore, MD,USA

LinaMiyakawa

MountSinaiHealthSystem,NewYork, NY,USA

SunshineMoore

SunshineMooreConsulting,Madison,WI, USA

RADx–VentureWell,Hadley,MA,USA

EmilyMuth

RADx–VentureWell,Hadley,MA,USA

HeathNaquin UniversityCityScienceCenter, Philadelphia,PA,USA

RADx–VentureWell,Hadley,MA,USA

AnnePiantadosi EmoryUniversity,Atlanta,GA,USA

EnriqueM.Rabellino MedScienceServices,Miami,FL,USA

AnuradhaRao EmoryUniversity,Atlanta,GA,USA

MatthewL.Robinson

JohnsHopkinsUniversitySchoolof Medicine,Baltimore,MD,USA

LizRuark covidsafeschools.org,Boston,MA,USA

AdamSamuta

RADx–VentureWell,Hadley,MA,USA

StevenC.Schachter

HarvardMedicalSchool,Boston,MA,USA CIMIT,Boston,MA,USA

AlexandraSmith

RADx–VentureWell,Hadley,MA,USA UniversityofSouthCarolinaSchoolof MedicineGreenville,Greenville, SC,USA

JulieSullivan

EmoryUniversity,Atlanta, GA,USA

PaulTessier CIMIT,Boston,MA,USA

ErikaTyburski

AtlantaCenterforMicrosystems EngineeredPoint-of-Care Technologies,Atlanta, GA,USA

JoseValdesuso RADx–VentureWell,Hadley,MA,USA

EliseoVelasquez

InvestorsofColorNetwork,Boston,MA, USARADx–VentureWell,Hadley,MA,USA

BrianWalsh RADx – VentureWell,Hadley,MA,USA

CassandraWesselman ROSALINDInc.,SanDiego,CA,USA

Foreword

HarveyV.Fineberg

Adeadlypandemicdemandsaresponseatmultiplelevelsofgovernmentandsocietyand acrossmyriadneedsforpublichealthandmedicalcare.AstheCOVID-19pandemictook holdinearly2020,theUSresponsefaltered.Hospitalslackedsufficientpersonalprotective equipmentforstaff and,ascasessurged,somewereoverwhelmedbysickpatients.Optimal careforextremelyillpatientswasuncertain.Thefederalresponselackedaclearleadership structureandchainofcommand.Antiviralswerelacking,andaneffectivevaccinewasyetto bedeveloped.Moreover,theCentersforDiseaseControlandPreventioninitiallydistributedatestkitwithafaultyreagent,settingbackthenationaltestingstrategyforCOVID-19.

Thenation’spremierbiomedicalresearchorganization,theNationalInstitutesofHealth (NIH),focuseditsCOVID-19eﬀortsonthreemaingoalsofresearch:vaccines,therapeutics, anddiagnostics.ByApril2020,theNIHhadactivatedapublic–privatepartnershipto acceleratethedevelopmentofCOVID-19therapeuticsandvaccines.Throughfundingand activecollaboration,theNIHwasinstrumentalinthedevelopmentoftheModernavaccine. Withtheactiveengagementof20companiesandscoresofscientists,theNIHscreened hundredsoftherapeuticcandidates,embarkedonclinicaltrialsformorethanthreedozenof themostpromising,andobtainedsixtherapeuticsapprovedforclinicaluse.Fueledby aspecialcongressionalappropriationinApril2020,theNIHlaunchedtheRapid AccelerationofDiagnostics(RADx®)initiative.Withinsixmonths,theFoodandDrug Administrationgrantedemergencyuseauthorizationtothe ﬁrstpoint-of-care – rapid COVID-19testsfundedthroughRADx – andsincethenmorethanfourdozenRADxsupportedtests(20point-of-care,16laboratory-based,and13home-basedtests)have receivedemergencyuseauthorization.

Thepandemicdemandedunaccustomedspeed,intensity,and ﬂexibilityinresearch.All oftheinstitutesoftheNIHrespondedtothesepandemicexigencies.However,RADxstands outforitsdegreeofinnovativenessandreadinesstoembracenon-traditionalwaysofdoing businessattheNIH.

LedbytheNationalInstituteofBiomedicalImagingandBioengineering,RADxbuilton yearsofexperiencegainedthroughCIMITandthePoint-of-CareTechnologyResearch NetworkthatiscoordinatedbyCIMIT.Ratherthanconsidertheaimtobefundingbrilliant research,RADxadoptedanoutcomes-orientedapproachthatembracedeverystage,from scientiﬁcideathroughproofofconcept,productdevelopment,manufacturing,clinical evaluation,regulatoryreview,andauthorizationforuse.Ratherthantraditionalpeer review,RADxdevelopedashark-tankapproachofpresentation,assessmentofpromise, andinvestment,followedbyaninnovationfunnelwithdevelopmentmilestonesand sequentialwinnowingorintensifyinginvestment.Ratherthanahands-oﬀ approachafter grantapproval,RADxadoptedventure-capital-likecontinuedsupportandcoachingto overcomeanyobstaclesalongtheway.

TheseinnovationsmeantthatRADxwouldseekandfosterideasthathadthepromiseof successandnotsimplylookforreasonsthataprojectmightfail.Thus,RADxdidnotaccept aninevitable “valleyofdeath” forbiomedicalproductdevelopment;RADxestablishedoases ofsupportthatcarriedeasier-to-use,faster,andmorereliablediagnostictestsfromscientiﬁc

ideastoclinicallaboratories,sitesofclinicalcare,andhomes.BecauseofRADx,asmanyas 3billionCOVID-19testshaveenteredtheUSmarket,andrapidhomeandpoint-of-care testshavebecomethenorm.

Thisbookdescribestheconcept,organization,implementation,andresultsoftheRADx initiative.ItprovidesmanycasestoillustratethevariedwaysthattheRADxmodel, combiningthebestofpublicandprivatecapacities,contributedtothesuccess.Itshows howRADxadaptedandlearnedfromfailuresinrealtimetostrengthenitsapproach.The bookpositionsthequestformoreandbetterdiagnostictests – accurate,easytouse,and widelyavailable – againstthebackdropofmultiplepandemicdemandsonclinicalcareand publichealth.TheRADxexperienceholdslessonsnotonlyforthedevelopmentoffuture diagnosticsbutalsoforanysituationinwhichmultiplescientiﬁcscenariosmayyield technologiestohelpmeetanurgenthealthneed.

MorethanthreeyearsafterthestartofCOVID-19,theUnitedStatesandmuchofthe worldappeartohaveweatheredthebruntofthepandemic,althoughthetollonlivesandthe ﬁnancialimpactcontinuetomount,andpost-acutesequelaeofsevereacuterespiratory syndromecoronavirus2(SARS-CoV-2)remainanongoingclinicaldilemma.China,whose zero-tolerancepoliciesheldoﬀ thefullforceofCOVID-19foracoupleofyears,hassince founditselfinthethroesofthepandemicandhaslentitsweighttothegrowing,global burdenofdisease.

Withtime,wecananticipatemanyassessmentsofthepandemicresponseattheglobal, national,andsubnationallevels.Manywillproﬀerlessons,andsomewillbeworthheeding. TheRADxstorytoldheremeetsthathighstandard,worthyofheeding,inpreparingforthe nextpandemicorforanysimilarlysevereandurgenthealththreat.

Preface

WadeE.Bolton

In2019,auniquevirusemergedontheworldscenethatwouldcauseaglobalaffronttoour health-caresystems.Hundredsofmillionsofindividualsbecameinfectedwiththevirus, resultinginmillionsofliveslostandcatastrophic financialdamage.IntheUnitedStates alone,thepandemicwasthemostsignificantmedicalcalamityinthehistoryofournation, surpassingtheliveslostinWorldWarIandWorldWarIIcombinedandevenoutnumberingthecasualtiesofthe1918Spanish flupandemic.Asamemberofthecoronavirusfamily, whichwaslaternamedSARS-CoV-2,thisragingvirusat firstappearedtoresembletwoof itspredecessors,SARSandMiddleEastrespiratorysyndrome(MERS).Thescientific communitysoonlearned,however,thatthedifferencesamongthemwerestark.

ThroughtheNIH’sRADxinitiative,anetworkofprofessionalswasestablishedto respondtothevirusthroughthedevelopmentanddistributionofdiagnosticteststhat couldaccuratelydiagnosethepresenceofthevirusinpatientsamples.Ourassignmenthad noboundaries.Wereachedacrossinternationalborders,collaboratedwiththebravemen andwomeninthe ﬁeld,andwerewelcomedbyacademicandgovernmentinstitutions willingandabletojoininthe ﬁghtagainstthiscommonfoe.Weunderstoodthatthiswas ourabsolutepriority – anationalandglobalmandatewithmillionsoflivesatstake.

Thisbookdocumentshowthelimitsofscienceanddiscoverywerepushedinacollective efforttocontainandmanagethispandemic,fromthedevelopmentofdiagnosticassaysto thesurveillanceofandresponsetoemergingvariants.Theauthorsdescribewhatwasdone differentlytoidentify,develop,anddistributediagnostictestsinrecordtimeandvolume. Weprovidetheframeworkfortechnical,organizational,practical,andoperationalaction itemsthatareessentialtothemanagementofanemergencyhealthcrisis.Wedescribeour lessonslearnedandwhatwewouldhavedonedifferentlytoimprovetheoutcomes.And, critically,eachchapterincludesaroadmapthatdetailsthestepsnecessarytooptimally respondtothepandemic.(Foracompleteroadmapcomprisingalloftheactionsteps plottedovertime,readerswillbeabletoturntoourwebsite, pandemicresponseroadmap .org,onceitislive.)Webelievethiscollectionofroadmapsisthe firstcomprehensive responseplanbasedonreal-lifepandemicexperiences.

Thepublicationofthisbookistimely,astheimpactofCOVID-19iscurrentlyundergoingoverallevaluation.Wearehopefulthattheexperiences,roadmaps,approaches,and frameworkshereinwillserveasscaﬀoldinguponwhichourcolleaguescanbuildwhenthey begintoplantheirresponsetothenexthealthcrisis.

TheWebsite

The pandemicresponseroadmap.org websitewilloﬀeravaluableresourceforindividuals seekingtoenhancetheirunderstandingofpandemicresponsestrategies.Throughan interactiveandcustomizablepandemicresponseroadmap,userswillbeabletogaininsights intothecomplexandevolvingnatureofpandemicsanddevelopcustomizedstrategiesto navigatethemeﬀectively.Ourauthorbiosketcheswillprovidedetailedaccountsofthe trainingandexperiencesofeachauthor,enablingreaderstotrustinandappreciatetheir

uniqueperspectivesandexpertise.Additionally,ourcompiledlistoflessonslearnedduring theCOVID-19pandemicwilloﬀerinsightsintosuccessfulpandemicresponsestrategies andareasforimprovement.Byleveragingthecollectiveknowledgeandexperiencesofour authors,ourwebsiteaimstoexpandupontheknowledgeprovidedwithinthebookpagesto furthercontributetoamoreinformedandeﬀectiveglobalpandemicresponse.

Acknowledgments

Projectteam:StevenSchachter,WadeBolton,EricEvans,TaniaFernandez,Enrique Rabellino,D’lynnePlummer,AlexandraSmith,andMallakTaleb.

RADx®TechCollaborators

AaronBlack,AaronChockla,AbigailConte,AceEdwards,AdamHoffman,AdamSamuta, AdannayaAmadi,AdannayaPathology,AdrianaQuintana,AdrienneHoey,AghaMirza, AhmedBabiker,AhmedHassan,AinatKoren,AlbertLee,AlbineMartin,AlecBoudreau, AlemaJackson,AletheaWieland,AlexGreninger,AlexanderGreen,AlexisBeatty,Ali Haide,AliciaLoffler,AlisonCernich,AllenBreiner,AllenGraham,AllieSuessmith, AllisonBlodgett,AllisonCristman,AllisonEason,AllysonChabot,AlokKapoor, AlpdoganKantarci,AlyssaOwens,AmandaDion-Schultz,AmandaFoster,Amanda Grindle,AmandaGrindle,AmandaMacLeod,AmandaRiley,AmandaStrudwick, AmandaSutton,AmberShowers,AmberThomas,AminulJoelIslam,AmyBaker,Amy Bucher,AmyKrafft,AmyMiarecki,AndreaDepatie,AndreaSjostedt,AndrewAdelman, AndrewDiMeo,AndrewGlenn,AndrewHastings,AndrewNeish,AndrewPerez,Andrew Potter,AndrewWebster,AndrewWeitz,AndyPekosz,AndyWinffel,AngelaStallworth, AniketPatel,AnissaElayadi,AnnChahroudi,AnnGawalt,AnnMartin,AnnaHorney, AnnaLowe,AnnaWood,AnnabelleSt.Pierre,AnnePiantadosi,AnneWyllie,Annette Esper,AnnieMiller,AnnmarieWalsh,AnthonyCurro,AnthonyKirilusha,AnuradhaRao, AnyeloDiaz,ApurvSoni,ArthurBray-Simon,ArunanSkandarajah,ArynneWilburn,Asha Storm,AshleyBanks,AshleyCrawley,AsifRizwan,AtamDhawan,AustinTigerLu,Babar Akhter,BaibaBerzins,BarbaraThompson,BarbaraVanDerPol,BarceyLevy,Benedict Kalibala,BenjaminHelmericks,BernadetteShaw,BethanneGiehl,BethanyTrainor, BethanyWatson,BetsyPeters,BeverlyBricker,BeverlyRogers,BillHeetderks,Bill O’Sick,BillRiley,BobStorey,BonoloMathekga,BradleyHanberry,BrandiLimbago, BrandyMai,BraylonRumph,BrendanMurphy,BrentIngraham,BrettGiroir,Brian Mustanski,BrianWalsh,BrittanyGoldberg,BrookeBeckman,BrookeSeitter,Brooke Staples,BruceBarton,BruceGay,BruceGnade,BruceTromberg,BryanBuchholz,Bryan Du,CadeidreWashington,CaesarMelendez,CaitlinPretz,CandaceDufour,Candice Miller,CangyuanLi,CaraBarnes,CarlKumpf,CarlPark,CarlosAparicio,Carlos Moreno,CarlosPerez,CarolBova,CarolGovern,CarterUsowski,CassieBednarek, CathrynLapierre,CathyCambria,CecileDavis,ChadAchenbach,ChaoQi,Charles Anamelechi,CharlesDaitch,CharlesHart,CharlesHill,CharlesOyesile,Charlette Bronson,CharlotteGaydos,CherylBastian,CherylMaier,CherylShimer,CherylStone, ChiaraGhezzi,ChrisBocus,ChrisBunn,ChrisDesrosiers,ChrisElkins,ChristianFlanery, ChristieCanaria,ChristieJohnson,ChristinaMacauliffe,ChristinaRostad,Christine Cooper,ChristineFarrell,ChristineHanson,ChristineWalter,ChristopherBrooke, ChristopherHartshorn,ChristopherPorter,ChunHuaiLuo,Chung-JungChiu,Cindy Pryor,CindyTeixeira,ClairO’Donovan,ClaudiaHawkins,ClaudiaMorris,Colin Brenan,ColleenKraft,ColleenMatte,ColleenSico,CollinTimm,ColtonJoseph,Connie Arthur,ConnieRivers,ConnorSeabrook,ConradTucker,CorneliusMoore,CourtneyLias, CourtneySabino,CraigLilly,CrystalReinhart,CynthiaHilgren,CynthiaNicholson,Dale xvii

Gort,DanMarshak,DanWattendorf,DaneshThirukumaran,DanielKalman,Daniel Murphy,DanielleDiMezza,DanielleHoward,DanielleOliver,DarashDesai,Darci Edmonson,DarwinSalgado,DavetaBrown,DavidAlter,DavidD.McManus,David George,DavidGiarracco,DavidGoldstein,DavidGottfried,DavidHoaglin,DavidKu, DavidMudd,DavidSanford,DavidSmith,DeborahKelly,DeborahLee,DeniseEhlen, DeniseR.Dunlap,DeniseScholtens,DenizPeker,DennisRose,DevonCampbell,Devon Hartigan,DianaBianchi,DianeLawrence,DianeQuinn,DianeSpiliotis,DigvijaySingh, DilhariPeiris,DinaSimon,DipanwitaBasu,DonCroteau,DonnaMatson,Donna McGrath,DoreenTrotta,DorothyMaxwell,DougSheeley,DouglasBryant,EdithOtabil, EdwardBerger,EdwardEhrman,ElaineKim,ElaynByron,ElenaKoustova,EliasCaro, EliseoPerez-Stable,EliseoVelasquez,ElizabethBulger,ElizabethChristian,Elizabeth Heald,ElizabethOrvek,ElizabethWalsh,EllenClegg,EllieBrent,EmBeauchamp,Emily Cisney,EmilyMuth,EmilySousa,EmmaWojtowicz,EriOrtlund,EricCecco,EricLai,Eric Nehl,EricPadmore,EricStratton,EricaLandis,EricardoEdwards,ErikaTyburski,Erin Iturriaga,EsmerldaMeyer,EthanBerke,EtienneDembele,EugeneRogers,EunMiLee, EvanAnderson,EvanBradley,FajarNuriddin,FarazIlyas,FeliciaQashu,FilippViola, FrancisCollins,FrankCable,FranziskaMeockel,FrederickBalagadde,GabrielaVarela Heslin,GailRadclifee,GallyaGannot,GaryDisbrow,GaryPlace,GarySudusky,Gaurav Mehta,GavinHarris,GeneCivillico,Geoff Bonn,GeoffreySmith,GermánChiriboga, GlennNeuman,GokhanOzalp,GraceBendinger,GraceTran,GrahamThreadhil,Greg Gibson,GregMartin,GregoryMarcus,GretchenArmington,GulNowshad,GuyBenian, HangChen,HansVerkerke,HaroldSullivan,HeathNaquin,HeatherBowers,Heather Tessier,HebaMostafa,HeleneLangevin,HershPatel,HesamHafizi,HibaAbbas,Hilary Dupre,HimaniBisht,HollyAlvarez,HollySommers,HollyTaylor,HopeKrebell,Howard Golub,HurKoser,IanMisner,IlanaGoldberg,J.ChristopherFlaherty,JacobKhouri, JacquelineMartinez,JaiprasathSachithanandhamm,JamesAnderson,JamesPatzke,Jane Holl,JanetFigueroa,JanetHale,JaniceBell,JaniceLegace,JannetteGuarner,Jared Kimbrough,JaredO’Neal,JasmineChaitram,JasonFord,JasonOpdyke,JasonWheeler, JayButler,JeanWelsh,JeanetteDaly,JeanneKeruly,Jeff Evans,Jeff Shuren,Jeff Winner, JeffreyBrocious,JeffreyE.Olgin,JeffreyHolden,JeffreyOlgin,JeffreyWilliams,Jen Afamefuna,JenicaPatterson,JenniferBaker,JenniferBiemer,JenniferCampbell,Jennifer Fediani,JenniferHolme,JenniferJackson,JenniferK.Frediani,JenniferMcKenney,Jeremy Boutin,JeroanAllison,JesandSylve,JessaWaggoner,JessicaIngersoll,JessicaMeade, JessicaOrozco,JessicaScott,JianLou,JillHeemskerk,JillMorgan,JillianMcClain,Jo Hiatt,JoanDavis,JoannaNathan,JoanneAndreadis,JoanneLebrun,JoanneMatthew, JoanyJackman,JocelynMontgomery,JodiBlack,JodyCiolino,JoeDavenport,JohnBarnes, JohnBlackwood,JohnBroach,JohnClick,JohnDiggs,JohnHaran,JohnHealey,JohnLear, JohnLee,JohnMcQuiston,JohnNuckols,JohnP.Broach,JohnParrish,JohnRoback,Jon McGrath,JonathanPatton,JonggyuBaek,JosephBriggs,JosephHutter,JosephOdorisio, JosephValdesuso,JosephWalsh,JoshTolkoff,JoshuaJacob,JoshuaLevy,JoshuaRumbut, JoshuaWolfe,JueChen,JuliaAdams,JuliaTisheh,JuliaZakashansky,JulieFlahive,Julie Norton,JulieStephens,JulieSullivan,JulieWilkinson,JunGuo,JustinBurns,Justin Hardick,JustinMcAteer,JustinTiao,JustinYang,KalpanaRegarajan,KamilahRashid, KaraPalamountain,KaraPenny,KarenAnnLavallee,KarenDel’Olio,KarenGilliam, KarenGriffin,KarenOlsen,KarenWallace,KarlSimin,KateKlein,KateThoma, KaterinaPappas,KatharineEgan,KatherineImmergluck,KatherineLuzuriaga,Katherine Ramirez,KathrynLaneMusall,KathrynMarvel,KatieHambrick,KatieShapcott,Katrina

Bogan,KavitaBabu,KeivanZandi,KelliMalkin,KellyArmy,KellyGorman,KelseyWoods, KenBeall,KerryDemarco,KerryDiBenardo,KevinCoats,KevinLeite,KevinSeiki,Khawar Hamid,KimCaroline,KimNoble,KimPachura,Kim-JudyYou,KimberleeCantin, KimberlySciarretta,KiraMoresco,KiranVerma,K.J.Shaikh,KlemensWengert,Krishna Juluru,KristenHerzegh,KristenWeber,KristiCooper,KristianRoth,KristinLe,Kristina Lowe,KristopherBough,KyleRose,KyleSprow,KylieLanman,KyungMoon,LacyWilson, LaiaHussaini,LarryTabak,LauraBenedit,LauraFerrara,LauraGibson,LauraRose,Laura Sampath,LaurelO’Connor,LaurenBalmert,LaurenHowe,LeaE.Widdice,LedaBassit,Lee Payne,LeonaWells,LeonaWells,LeonardoAngelone,LeticiaRockenbach,LeylaKara,Leyla Rose,LiLi,LieslWarbel,LifangHou,LilliamMartinezBello,LindaSmith,LindseyGieger,Lisa Council,LisaHirchhorn,LisaPonce,LisaPortner,LisaR.Hirschhorn,LisaSmith,LisaWaples, LisaWei,LiuXu,LizDiNenno,LizMcCarty,LizRuark,LoriPbert,LoriRandall,LouisVuga, LucieLow,LuckyJain,LydiaGarciaJacinto,LydiaMcClure,LynnFurtaw,M.DidemAvciogluAyturk,MacArthurBenoit,MackSchermer,MadelineHobbs,MadelineMarx,MadisonConte, MaggieHassan,MaggieLi,MaheshVangala,MamoudouMaiga,MandiBlochberger,Mandy O’Reilly,ManuelKingley,MaraAspinall,MaraHeng,MarayanaiahCeedarla,MarcCharette, MarenDowning,MargaretMcManus,MargaretNeja,MargaretOchocinska,MargoKinneyPetrucha,MariaCordero,MariaDavilla,MariaGrainger,MarianneWeinell,MarissaFayer, MarkBobrow,MarkBonaficio,MarkBonifacio,MarkFisher,MarkGonzalez,MarkGriffiths, MarkGuitarini,MarkHuffman,MarkMarino,MarkPletcher,MarkSmith,MarkSnyder, MarshallR.Collins,MaryAnnPicard,MaryBethTull,MaryCo,MaryDubuque,Mary Fadden,MaryJanetMcCarthy,MaryAnnLambert,MarzanKhan,MassielMota,Matt Durgin,MattO’Connell,MatthewCaputo,MatthewGluckserg,MatthewHart,Matthew Humbard,MatthewMcMahon,MatthewRobinson,MatthewSanders,MaudMavigner, MaureenBeanan,MaureenGarner,MaureenRichardson,MeganSchmidt,MeganShaw, MelaniePeel,MelindaMathis,MelissaFrangie,MelissaHenson,MelissaRamos,Melissa Rotella,MelvaSteps,MiaCirrincione,MichaelBoyce-Jacino,MichaelBrady,Michael Cariseo,MichaelCentola,MichaelDempsey,MichaelHarsh,MichaelHirsh,Michael Huggins,MichaelIademarco,MichaelKochersperger,MichaelKoeris,MichaelLauer, MichaelMasterman-Smith,MichaelNewcomb,MichaelNorton,MichaelPalmer,Michael Wolfson,MicheleListon,MichelleBerny-Lang,MichelleMcConnell,MichellePopler,Mike Ryan,MilagrosRosal,MiriamVos,MonicaLowell,MonicaO’Brian,MorganGreenleaf, MukthaNatrajan,MylaLai-Goldman,NadiaHassan,NancyElder,NancyGagliano,Nancy Mortimer,NancySencabaugh,NaomiBraun,NatalieBruning,NatalieLee,NateWade, NathanielHafer,NatiaSaakadze,NealConnors,NealDickert,NeetaShenvi,NeilMucci, NicholasGallagher,NickD’Aimco,NicoleBenevento,NigistmariamYasin,NikkiPowell, NilsSchoof,NimiFifadara,NiraPollock,NishaFahey,NitikaGupta,NoahPeyser,Noni Byrnes,OladapoOlaitan,OlgaBrown,OlgaHartman,OliverBrand,PaigeEzernack,Pamela McGuinness,PamelaMiller,ParangKim,ParitoshChandwade,PatriciaHelbin,PatriciaWiley, PattiBrennan,PattiO’Neill,PaulBaker,PaulEder,PaulTessier,PaulYoo,PaulinaRebolledo, PekoHosoi,PennyFord-Carleton,PeterD’Entremont,PeterLazar,PeterRice,PeterTobin, PetrSulc,PhilWeilerstein,PunamMathur,QimingShi,QuierraWells,RachaelFleurence, RachelAgoglia,RachelFactor,RachelFink,RachelKrebs,RahulSalla,RanaSaber,Randall Morse,RaoDivi,RashadWood,RashidaFerebee, RayEbert,RaymondCariseo,RaymondFelix Schinazi,RaymondMacDougall,RebeccaCleeton,RebeccaGore,RebeccaKirby,Rebekah Neal,RenSalerno,RenateMyles,ReneeSimon,ReshikaMendia,RhondaGibson,Ribhi Shawar,RicardoRamos,RichardAnderson,RichardCreager,RichardGirards,Richard

Hodes,RichardRothman,RickBright,RickD’Augustine,RickGagliano,RickWoychik,Rik Madison,RishaNayee,RjsekharGuddneppanavar,RobertEisinger,RobertFineberg,Robert Jerris,RobertKircher,RobertL.Murphy,RobertMannino,RobertNobles,RobertScalese, RocioLuparello,RodneyKincaid,RodneyWallace,RonTedesco,RoryCarrillo,Rosemary Humes,RoslynSeitz,RoxaneBurkett,RubenSalinas,RuifengZhou,RussellKempker,Ryan Eckmeier,SadanandGite,SajaAsakrah,SalStrods,SallyMcFall,SamDolphin,Samantha Strickler,SandeepPatel,SandraMaher,SandraOtt,SaraBrenner,SaraCaudillo,SarahBank, SarahEisenberg,SarahFarmer,SarahFey,SarahHernandez,SarahHuban,SarahMcGee, SathmurthyGourisankar,SauntelleByfield,ScottEibel,ScottTanner,SeegarSwanson,Seila Selimovic,SerenaCarroll,ShahidRashid,ShaminyManoranjithan,ShannaBruflodt,Shanna Spencer,ShannonGriffin,ShannonMoore,SharinaPerson,ShaukatSoofi,ShawnMulvaney, ShawnPatel,SheilaBaker,ShirleyConey-Johnson,ShirleyRuiz-Lundgren,SiluHu,Skyler Ward,SofiaMartinez,SoniaGales,SonjaDavis,SonjaDill,SotiriosGeragonis,Sreeram Ramakrishnan,StaceyCarroll,StaceySpies,StacyHellman,StacyTurner,StephanieAdams, StephanieBehar,StephanieMeisner,StephenieLemon,SteveBlanc,StevenSantos,Stewart Ellis,SuminKoo,SunitaGopalani,SunitaPark,SunshineMoore,SusanGregurick,Susan Moreira,SyedNaeem,TamaraMcBrayer,TamaraMcKenzie,TamaraWesley,TamiHagberg, TamilaDover,TammyBeckman,TammyFalla,TaraKnox,TaraLoomis,TaraSchwetz,Tatia Hodges,TaylorGilliland,TempistEvenson,TeresaZembower,ThanujaRamachandra, TheodoreZainal,ThomasGrifa,ThomasJohnson,ThomasPribyl,ThomasVanderford, TiffaniLash,TiffanyWilson,TimStenzel,TimThurman,TimmyMoore-Simas,Timothy Moulton,TimothyVanderford,TobyLowe,ToddMerchak,ToddSherer,TonyBoiers,Tony Haney,TonyVoiers,ToyaMorrison,TraciLeong,TracyMcMahon,TracyWilloughby,Truc Le,UgurCelik,UyenLe,ViNguyen,VickiAnastasi,VictorSine,VictoriaStittleburg,Vidurshi Gupta,VijayDhaka,VijayVanguri,VincentAhonkhai,VintonGrant,VivianaClaveria, VyjayantiKasinathan,W.O’Neal,WaltCarney,WayneWang,WebbStone,WendiKuhnert, WilburA.Lam,WilliamClarke,WilliamDaunch,WilliamHaddad,WilliamPierce,Wolfgang Krull,XaiveraMartinez-Armenta,XavierPeralta,YasminHaider,YolandaZeringue,YuHsiangHsieh,YufeiYu,YukariC.Manabe,YurimaGuilarte-Walker,ZacharyBuono, ZacharyEllison,ZacharyFavakeh,ZihanYang,ZinaBrown,ZiyueWang.

OtherAcknowledgments

BillRodrigues,MarcelleAbell-Rosen,SergioCarmona,JimDensmore,EdwardTharp, BradleyWait,BenWalker,JustinValliere,LisaButler,BrandiTalkington;Huck StrategiesLLC.

Introduction

TaniaFernandez

Theendof2022markedthreeyearssincethe firstreportsappearedinthenewsof apotentiallynovelcoronavirusinaseafoodmarketinWuhan,China.Commencingin December2019,COVID-19 – causedbythesevereacuterespiratorydiseasecoronavirus2 (SARS-CoV-2) – spreadrapidlyacrosscontinents,withthe firstcaseofCOVID-19being reportedintheUnitedStatesasearlyasJanuary20,2020.Twomonthslater,withtheofficial announcementbeingmadebytheWorldHealthOrganization,therewasnodenyingthe realitythatwewereinthemidstofaragingpandemic.

Atitsinception,noonecouldhavepredictedthepowerofthevirus.Itsweptthrough humanity,infectingmorethan700millionpeople,killingmorethan6.9millionpeople across215countries,cuttingacrosscaste,creed,andcolor.

Thisbookisatributetothe “warriors” whoworkedinthetrenchesdayandnightto combatthevirusandwagethedeadlywaragainstthepandemic.Itismeanttoserveas asoberingreminderofthesacriﬁcesmadebysomany.Wededicatethisbooktothemillions oflivesthatwerelosttoCOVID-19andtofrontlineworkersacrosstheglobewhosacriﬁced theirlivesinthelineofduty.

Thisisourstoryofhowhumanitycametogetherduringanincrediblychallengingtime touniteforcesand fightacommonenemy.Itisastoryofreflectionsandlessonslearned, arecordofwhatwedidrightandwhatwecouldhavedonebetter,but,aboveall,thisis astorythatiswritteningratitudetotheunconquerablespiritofhumankindandthe relentlesspursuitofscientificknowledgetoservehumanity.

Thisbookchroniclesthepowerofinnovation,theacceleratedcommercializationof diagnostics,thebirthofnewbusinessmodelsandcreative ﬁnancingventures,theperseveranceandcommitmentofentrepreneurs,andtheagilityandresourcefulnessofgovernment institutionsastheyadaptedtomeettheimminentneedsofthepandemicandservethe community.

Coronavirusesarenotnewtohumankind.Humanityhaswitnessedthreedeadlypandemicsinthetwenty-firstcenturyalone,allofwhichwereassociatedwiththisgroupof viruses.In2002,theworldwitnessedthe firstlethalcoronavirus-induceddisease,whichwas namedsevereacuterespiratorysyndromecoronavirus(SARS-CoV).Adecadelater,in2012, adifferentcoronavirusoutbreakunraveledintheMiddleEast,earningthenameMiddle Eastrespiratorysyndromecoronavirus(MERS-CoV).Despiteourseemingfamiliaritywith thisgroupofviruses,theglobalcommunitywasunpreparedwhenanovelcoronavirus reareditsuglyheadandsweptthroughhumankindwithaferocitylastwitnessedonly duringtheSpanishinfluenzapandemicof1917causedbytheH1N1virusandoftenreferred toasthegreatestmedicalholocaustinhistory.

Despitepreviousappearances,thiscoronaviruswaslabeledasnovelbecause acomparisonoftheviralgenomerevealedthatithadonly79.5%homologywithSARSCoVand40%homologywithMERS-CoV.Thus,itwasbattletimeagain.Wehadno armamentariumto ﬁghtthevirusoranyspecializedknowledgeofwhatweweredealing with.OurunderstandingoftheevolutionofSARSCoV-2andhowitspreadwasparticularly unclearduringtheearlystagesoftheCOVID-19pandemic.Misconceptionsandmyths aboutitsoriginanditsmodeoftransmissionragedlikewildﬁresacrosscontinents,fueling panicandchaos.

Thepandemichadmadeitswayintothelifeofthemasses,andthescientiﬁccommunity wasforcedtomeetthedemandsofquestioningandangrycommunitiesdemanding answers.Whateversideofthefenceonewasonwithregardtothequalityofscientiﬁc rigoronsocialmedia,itcannotbedeniedthatthemediaservedtodisseminateknowledge andinformationatanunprecedentedspeed.

Intheworldthatweliveintoday,whereCOVID-19,socialdistancing,lockdowns, contacttracing,superspreaderevents,antigentests,andpolymerasechainreaction(PCR) testshaveallbecomecommonhouseholdparlance,letusnotforgetthat,inDecember2019, theworldwasadiﬀerentplace.Awarenessofpandemicswasatanall-timelow,despitethe occasionalvisionarymessagesofcautionthatwerevoicedbyaselectfewbutlargely neglected.

Thedepthandbreadthofscientificknowledgethatwehaveamassedsincethatfatalday thatSARS-CoV-2interruptedhumanityservesasatributetoallthescientists,clinicians, andhealth-careworkerswhoworkedtirelesslyatanunprecedentedpacetoadvance coronavirusresearch.DuringitsearlyspreadinJanuary,thousandsofviralgenomeswere rapidlysequencedbyresearchlaboratoriesaroundtheworldandsharedinopen-access databasessuchastheEpiCoVdatabasefromtheGlobalInitiativeonSharingAllInfluenza Data(GISAID)andtheOurWorldinDataCOVID-19dataset.Withinamonthofthe releaseoftheSARSCoV-2genome,theCDChaddevelopedthe firstSARS-CoV-2diagnostictestkitwhichgotFDAEUAapprovalonFebruary4,2020.

Aglimmerofhopearosethatwidespreadtestingandearlydetectionmightserveto interveneindiseaseprogressionandthuscounteracttheincreasingmortalitythathumanity waswitnessing.Accordingly,manycountriesrushedtoimplementpopulation-basedtestingtomonitorspreadandimplementquarantiningtoreduceviraltransmission.This createdenormouspressureforhigh-quality,reliableteststobedevelopedandcommercializedatrecord-breakingpace.Theplanetmorphedintothelargestglobaltestinggroundfor humanity.Governmentsacrosstheworldrosetotheoccasion,astheyhavetraditionally done,tofundresearchandinnovation.FromsequencingtheSARS-CoV-2genomeand sharingitwiththeworldtocharacterizingmethodsofviralentryandspread,aswellas ongoingsurveillanceofanassaultofviralvariantsanddealingwiththeconfusionandutter despairofthosewhowereasymptomaticallyspreadingthevirus,thescientiﬁccommunity workedtirelesslytopushtheboundariesofunderstandingthebiologyofthevirus.

Thechaptersinthisbookarewrittenbyawiderangeofauthorswithvaryingexperiencesandexpertise,whohaveworkedacrossthespectrumfromresearchanddevelopment tocommercializationofCOVID-19diagnostics.Giventhemultidisciplinarynatureofthis initiative,eachchapterhasbeenwrittenbyauthorswithrelevantexpertiseandprovidesan in-depthnarrativefromtheirownuniqueperspectives.Thechaptershavebeencompiledto takethereaderonajourneywithusaswechronicletheearlystagesofthepandemic,the historicalevents,andtheeﬀectivenessofthedecision-makingprocessesduringcrucial

phasesofthepandemic.Wedelvebrieﬂyintotheimmunologyofthevirusanditsrapid evolutionthroughmutagenesisandtouchuponthecontroversialtopicofimmunitytothe virus.

IntheUnitedStates,SARS-CoV-2spreadrapidly,andwithitgrewtheinabilitytokeep pacewiththeincreasingdemandsforCOVID-19diagnostictesting.InApril2020,as mortalitycontinuedtosoarandtheneedfortestingwithintheUnitedStatesbecame imminent,theNationalInstitutesofHealth(NIH)receiveda$1.5billionappropriation fromCongresstoexpandtestingcapacityintheUSA.Thus,itwasthat,whiletheworld continuedtooperateinachaoticfrenzy,anewinnovativeprogramwasbornwithin ﬁve daysafterthelegislationwassignedintolaw.

TheNIHlaunchedtheRapidAccelerationofDiagnostics(RADx®)program.TheRADx Techinitiativewascreatedtosupportthedevelopment,validation,production,andcommercializationofaccurate,point-of-care,andhometests,aswellastoimproveexistingclinical teststhatcoulddetectSARS-CoV-2.Thisbrainchildinitiativepusheddiagnostics,amuchneglectedsector,totheforefrontthroughafocusonthecompressionofadiagnosticprototype-to-productlaunchfromover ﬁveyearstounderayear.Manyofthechaptersinthisbook arewrittenbyauthorswhowerepartoftheRADxinitiativeandworkedinthetrenches.These chaptersgointointricatedetailoneachaspectofthejourney,fromdevelopmenttodeployment,andwhatittooktoacceleratediagnosticcapacityinatimeofcrisis.

Overall,theRADxTechinitiativewasanunprecedentedprogramthatinvestedahuge amountofcapitalintoCOVID-19diagnosticsacrossthespectrum,fromtestsperformedin referencelaboratoriestopoint-of-carediagnosticsandover-the-counterhometests.The programusedarigorous “deepdive” diligenceprocessanda “sharktank” modelrunby leadingindustryexpertstoselectcompaniesandprojectswithinnovativetechnologiesthat hadthepotentialtoscaleupandaddressthetestingneedsindifferentsegmentsofsociety. Beyondthecapitalinvestments,RADxTechprovedtobeafertilegroundfortheevolution ofapublic–privatepartnershipmodelsuchastheindustryhadnotwitnessedbefore. Combiningthebestofbothworlds,itsetoutonitsmissionnotjustto financeinnovation incompaniesandde-risktechnology,buttoprovidecompanieswithanecosystembuiltto maximizesuccessincommercialization.Itsfocusonexternalverificationandvalidation throughkeyinstitutions,data-drivengo/no-godecisions,stringenttimelines,andoutcomes wasresponsibleforthesuccessoftheprogram.

AnotheruniqueaspectoftheinitiativewastheleverageofthePoint-of-CareTechnology ResearchNetwork(POCTRN),runbytheNationalInstituteofBiomedicalImagingand Engineering(NIBIB),whichthroughthreecyclesofpriorNIHfundinghadpreviously identiﬁedacriticalgapindiagnosticdevicedevelopmentaroundtheclinicalusecase.Thus, ascompaniesdevelopedtheirtechnologiesforCOVID-19tests,theywereguidedbyexperts intheareasofinfectiousdiseaseandemergencymedicine;ambulatory,pediatric,andadult clinicians;medicaldirectorsofcertiﬁedlaboratories;diagnosticdevelopers;andmarketing expertswithreal-worldexperience.Atthetimeofwritingthisbook,hundredsofmillionsof COVID-19testshavebeendevelopedandmarketed.

Itwasinitiallythoughtthat,withSARS-CoV-2beingwelladaptedtohumans,therewas minimalneedforconcernaboutmutationsamongcirculatingviruses(becauseofthe historicallyslowmutationrateofcoronavirusesandtheirinherentself-editingmechanism). Thischangedduringthelatermonthsof2020,whenthe ﬁrstreportsappearedofemergent SARS-CoV-2variantsthatwereassociatedwithincreasedtransmissibilityanddisease severity.

Diagnostictests,whichwerebasedontheoriginalWuhansequenceofSARS-CoV-2, werefoundtobeaﬀectedbythesemutations.TherepeatedemergenceofnewSARS-CoV-2 variantspresentedchallengestothedevelopmentofhigh-performingdiagnostics.The RADxVariantTaskForce – aninterdisciplinarygroupcomposedofrepresentativesof federalagencies,diagnosticdevicemanufacturers,privateandpublicbioinformaticscompaniesandorganizations,largelaboratoryorganizations,andacademicinstitutions – was thuscreatedasaprogramwithinthelargerRADxinitiativethatfocusedonassessingRADx technologiesagainstvariants.

Theclinicalmanagementchapter(Chapter3)focusesonpatientcareduringatimeof absolutecrisisandthesigniﬁcantshiftinclinicalpracticefromusingevidence-based medicinetobeingforcedtouseexperimentalmethodsoftreatment.Ithighlightsthe innovationinhealth-caredeliverymodelsashospitalleaderssoughttoincorporatetelemedicinetowidenpatientreachwhilenotcompromisingonquality.

AquotefromGeorgeSantayana(TheLifeofReason,1905)comestomind: “Thosewho donotrememberthepastarecondemnedtorepeatit.” So,letusnotforget.Letusnever ceasetorememberthesacrificeofdoctors,health-careworkers,andfrontlineresponders acrosstheglobe.Humanitywillalwaysbegratefultothemfortheirsacrificeduringthese unprecedentedtimes.Thisbookcapturescasestudiesofhowstrongandselflessleaders madeittheirmissiontofocusonthecareofpatientsinatimewhentherewerenoruleson howtocombatthisenemy.

Canwepreventthenextpandemic?Aswecontinuetoreflectonthatquestion,welook backnotjustatthemistakesthatweremadeduringthepandemicbutalsoatwhatwedid rightandthekeycontributionsthatweremadeinthisperiod.Afewofthenoteworthy successesincludebutarenotlimitedtocontrollingsupply-chainbottlenecks,therapid commercializationofdiagnosticsinatimeofcrisis,theunprecedentedrolloutofCOVID19testing,vaccinedevelopment,acceleratedregulatoryapprovals,andensuringthataffordabletestsweremadeavailableasmuchaspossible.Akeydifferentiatorofthisbookisthe factthat,ineachchapter,readerswill findmeticulouslydetailedroadmapsthatarespecific tothechapter.Wehopethatthesewillserveasusefultoolsforthenextgenerationofhealthcareleaderstocreate,implement,andexecuteoperationalstrategiesinthefaceofchaosand uncertaintyduringsuccessivediseaseoutbreaks.

Wearecognizantofthefactthat,inthisbook,wehaveanalyzedthepandemicthrough whatcouldbeconsideredaveryUS-centriclens.Whilepartofthiswaschoice,alargepartof itwasnecessity.Tobeabletocommunicatewithourreaderswiththeexperienceand expertisethatisrequiredtotellthisstory,wehadtowriteitfromthebattlefieldweoperated from,whichwastheUnitedStates.Innowaydowemeantodiminishtheheroiceffortsof othernationsthatfoughtthisbattle,andtheyshouldbeapplauded.Wherepossible,wehave referencedglobaleffortsanddrawnattentiontotheminselectchapters.

Apandemicaffectsvariousaspectsofsociety.Theclosureofessentialandnonessential businesses,restrictionsontravel,requiringindividualstoisolatetocombatrisingratesof mortalityandmorbidityalltooktheirtoll,andsocietyfacedexistentialthreatsaseconomies begantoshutdown.Variednationalresponsestothethreatofthevirus,aswellaseconomic andracialdifferencesacrossnations,ledtosocietaldisparitiesandvastlydifferentpandemic impactsacrosstheglobe.Thishasnotbeenignoredandisalsoafocusofthisbook.

Thereisnodoubtinanyone’smindthattheeﬀectofthepandemichavebeensevere,and wearestillwitnessingandwillcontinuetowitnessitslong-termdamagetosociety worldwide.Thepowerofsharingscientiﬁcdata,thestrengthofpartnerships,thecreativity

ofcollaborations,andtherefusaltoadmitdefeatinthepresenceofacommonenemyshould neverbeforgotten.Thesememorieswillserveuswellforbuildingabetterandmore resilientworld.

Throughthisbook,wehopetoaddressthemaincomponentsofthepandemicasit evolvedandtoprovidestrategiesandguidelinesforthemanagementofoutbreaksbeyond COVID-19,thusservingasalegacyformanyfuturegenerations.

1 EarlyDetection,Response,and SurveillanceoftheCOVID-19 PandemicCrisis

EnriqueM.Rabellino,AlexandraSmith, andMartaC.Cohen

Introduction

Thischapterprovidesfoundationalknowledgeoftheoccurrences,events,anddiseasemanifestationsduringtheearlystagesoftheCOVID-19pandemic,includingtheresponsesand measuresthatwereundertakentocontainthetransmissionofsevereacuterespiratory syndromecoronavirus2(SARS-CoV-2),thevirusthatcausesCOVID-19.Theimportance ofearlyinterventionisdiscussedthroughoutthischaptertoillustratetheimpactthattimely action – or,inmanycases,inaction – hadonthedevelopmentofthepandemic.Thischapter exploresthedatacollectionandanalysismechanismsutilizedtomonitordiseasespreadin diﬀerentgeographies.Thenecessityofinformationthatisderivedfromearlydiseasevigilance andsubsequentsurveillanceprogramsisstressed.Thischronologicalaccountisintendedto createaroadmapforhealthandgovernmentalauthoritiestofollowforfutureundertakings, programs,anddecision-makingprocessesattheearliestphasesoffuturepandemics.

DiseaseOutbreak

Thespreadofinfectiousdiseasesaffectsbothindividualsandentirecommunities.Early detectionofanewoutbreakiscrucialsothatcontainmentmeasurescanbeimplemented quicklyenoughtominimizetheneedforlarge-scalequarantine,especiallywhenresources arelimited.Whenprimarycare,publichealth,laboratories,andinvolvedcommunities collaborateeffectively,earlyidentificationandmitigationinitiativesareachievable.This sectionoutlinestheinitialdetectionoftheCOVID-19outbreakandtheresponsesof governments,publichealthofficials,andcommunities. Figure1.2 isdesignedtohelp visualizethesignificantoccurrencesduringtheearliestphasesoftheCOVID-19pandemic.

FirstCases

OnDecember19,2019,acaseofpneumoniaofunknownoriginwasdetectedinWuhan, China,acityof11millionpeopleandthecapitalofHubeiprovinceincentralChina.By December29,2019,fourmorecaseshadbeenreportedtotheChineseCenterforDisease ControlandPrevention(CCDC).1 AllinitiallyreportedcaseswererelatedtotheWuhan SouthChinaSeafoodMarket(HuananSeafoodWholesaleMarket).Thesecaseshadbeen identifiedthroughasurveillancemechanismfor “pneumoniaofunknownetiology,” aconceptdesignedtoallowtimelyidentificationofnovelinfectiousorganismsintroduced followingthe2003SARS-CoVoutbreak.2 Duetovaryingdiseaseseverityandclinical manifestations,thesecasesattractedtheattentionoflocalphysicians.Whilelittlewas knownaboutthecauseoftheseinfections,therewereindicationsofapossiblenew emergingvirusthatdivergedfromtheclassicalinfluenzavirus.

PANDEMIC ROADMAP: SURVEILLANCE AND INITIAL RESPONSE

Evaluate clinical manifestations

Monitor symptomatology and build database

Preliminary evaluation of available data

Notify health authorities (local, national, international)

Isolate and identify unknown virus

Promote and implement sanitary measures for disease control

Maintain surveillance systems to evaluate severity of outbreak and health impact

Identiﬁcation of human-to-human transmission

Assessment of disease infectivity and transmissibility

Figure1.1 Thisroadmapdepictsthevitalactivities,theirchronology,andanestimatedtimeframeinmonths.In thecaseoftheSARS-CoV-2pandemic,month1wasDecember2019,themonthinwhichtheviruswasisolated, sequenced,identiﬁed,andpublished.

Roughly10dayslater,themedicaladministrationoftheWuhanMunicipalHealth Commission(http://wjw.wuhan.gov.cn/)issuedanddistributedadocumentannouncing theoutbreak,reporting27newcasesofpneumonia,mostlyinstallholdersattheWuhan SouthChinaSeafoodMarket.Sevenofthesepatientswereincriticalcondition.Various hospitalsinWuhanheldemergencysymposia,wheretheydeﬁnedasuspectedcaseas apatientwhometallfourofthefollowingcriteria:fever,withorwithoutrecorded temperature;radiographicevidenceofbilateralpneumonia;lowornormalwhiteblood cellcountorlowlymphocytecount;andnoimprovementinsymptomsafterthreedaysof antimicrobialtreatment,asperstandardclinicalguidelines.Apatientwhometthe ﬁrst threecriteriaandhadanepidemiologicallinktotheWuhanSouthChinaSeafoodMarket couldalsobeconsideredasuspectedcase.3

Dec 19: First cases of pneumonia with unknown origin detected

Jan 1: The WHO creates an incident management support team; no speciﬁc recommendations

Jan 3: Chinese government formally notiﬁes the CDC and China isolates new virus

Jan 5:

Dr. Yong-Zhen Zhang posts early virus sequence to GenBank

Jan 20: First US conﬁmed case (Washington State)

Early Jan: Institute of Viral Disease Control conﬁrms novel virus

Jan 15: Hong Kong and Singapore issue alerts to travelers from Wuhan and establish quarantine

Feb 3:

• The USA declares a public health emergency

• The WHO proposes its Strategic Preparedness and Response Plan

• Cases of COVID-19 in Asia, Europe, North America, and Oceania

Early Feb: Global air travel restricted

Mar 1:

Worldwide distribution of COVID-19

Mar 11: The WHO declares a COVID-19 pandemic

Dec 29: Four cases reported by the CCDC and linked to Wuhan marketplace

Dec 30: Wuhan municipality announces outbreak

Jan 7: The CDC creates an incident management system; it issues a watch level 1 and a travel notice for travelers to Wuhan

Jan 12: Genetic information available to the WHO

Mid-Jan: Cases conﬁrmed in 30 Chinese provinces; Wuhan lockdown

Jan 31:

WHO issues global health emergency

Jan 22: The WHO Emergency Committee issues a package of technical guidance

Figure1.2 Pandemicevolution:fromearlydetectiontothedeclarationoftheCOVID-19pandemic.

Feb 25: The CDC considers that COVID-19 is progressing towards a pandemic status

Mar 15:

The US government declares COVID-19 a national emergency

Mar 3: 80 151 conﬁrmed cases in mainland China and internationally over 10 566 cases in 72 countries

CCDC,ChineseCenterforDiseaseControlandPrevention;CDC,USCentersforDiseaseControlandPrevention;WHO,WorldHealthOrganization.

Localauthoritiesrespondedbyinitiatingvirus-typingstudies,implementingpopulation isolation,andclosingthemarket.WhilemostpatientswerelinkedtotheWuhanmarket,it soonbecameevidentthathuman-to-humantransmissionhadbeenoccurringsincemidDecemberandthatthenumberofcaseswasdoublingevery7.4days.

Earlyreportsreferredtotheoutbreakas “viralpneumonia,” suggestingthatbacterial agentshadbeenruledout.Althoughtheexactvirusthatcausedtheoutbreakwasunknown, thesimilarityinsymptomatologytothepreviousSARS-CoVandMiddleEastrespiratory syndromecoronavirus(MERS-CoV)outbreaksledhealthoﬃcialstohypothesizethatitwas anotherSARS-CoVoutbreak.

Initially,Chinesehealthoﬃcialswerefreetoshareinformationaboutthenewlyemerginginfectiousdisease;however,China’sfederalauthoritiesquicklybeganinhibitingglobal medicalandscientiﬁccommunication.TheChinesegovernmentbegantocensuredoctors who,inDecember2019,raisedthealarmaboutthispneumoniaofunknownorigin.For example,attheCentralHospitalofWuhan,ayoungophthalmologistexpressedhisconcernstocoworkersaboutavirusthathefeltresembledSARS-CoV,adiseasethatoriginated inChinaandspreadtofourcountriesin2003.Thepolicesummonedandadmonishedhim, togetherwithsevenotherdoctors,onJanuary3,2020.Hewasinstructedto “stopmaking falsecomments” andinvestigatedfor “spreadingrumors.”3 Tragically,hecontracted COVID-19and,onFebruary7,2020,hepassedawayattheageof33.4

ByJanuary1,2020,accordingtotheWorldHealthOrganization(WHO)Newsroom, “thecausalagenthadnotyetbeenidentifiedorconfirmed.”5 Furtherrequestsweremade totheChineseauthoritiesforinformationthatwouldenableassessmentoftheriskposedby thevirus.Onthesameday,theWuhanSouthChinaSeafoodMarketwasclosed,andthe ChineseNationalHealthCommissionsetdailymeetingstomonitorpotentialpneumonia epidemics.Whileitwasclearthathumanswereinfectedwithpneumoniaofunknown etiology,theinitialtheoriesseemedtosuggestalinktoawholesale fishandliveanimal market,indicatingpossibleexposuretoanimals.Uptothispoint,informationaboutthe situationwasonlyreachinglocalandinternationalcommunitiesinformallyorthrough newsreleasedbythepress,andtheyhadreceivedlimitedinformationtodetermineand monitorthepotentialrisks.3,5 TheWHOassembledanincidentmanagementsupportteam, whichrecommendedcontinuedpublichealthmeasuresandsurveillanceofinfluenzaand severeacuterespiratoryinfections.Theserecommendationsdidnotincludeanyspecific measuresfortravelers.

OnJanuary3,2020,theChinesegovernmentformallynotiﬁedthedirectoroftheUS CentersforDiseaseControlandPrevention(CDC)oftheoutbreak,revealingthat44 patientswithpneumoniaofunknownetiologyhadbeenreported,11ofwhomwere criticallyill,withtheremaining33instablecondition.3, 6 InJanuary2020,Chinesescientists attheNationalInstituteforViralDiseaseControlandPreventionannouncedthediscovery ofanewcoronavirus.7 Thisnovelcoronaviruswasthepathogeniccauseoftheviral pneumoniaofunknownetiology,designatingthediseaseasanovelcoronavirus-infected pneumonia.

Respondingtoasurgeinpneumoniacaseswithunknownetiology,onJanuary7,2020, theCDCestablishedan “incidentmanagementsystem” andissuedwatchlevel1travel precautionsforWuhan,China.TheCDCrecommendedthatvisitorstoWuhanavoid contactwithsickpeople;avoidanimals(aliveordead),animalmarkets,andproductsthat originatedfromanimals(suchasundercookedmeat);andwashtheirhandsoftenwithsoap andwater.Additionally,theCDCadvisedanyonewhohadtraveledtoWuhanandfeltsick