中国疾控中心主任高福院士在Cell发表新发突发传染病评论文章

 

该文对于新发突发病原进行了历史性回顾，尤其开篇从今年流感流行、纪念1918大流行100年作为切入点，然后延伸到包括中东呼吸综合征（MERS）、埃博拉在内的新发突发传染病，还重点介绍了发现很早、但是直到最近几年才对人引起严重感染的寨卡。高福院士巧妙地用了从A（禽流感）到Z（寨卡）这样的题目，既体现了新发再发病毒的不断涌现及暴发的不确定性，又预示了人类最终能战胜病毒。

 

Figure1HumanInfectionswithSubtypesofInfluenzaAViruses

 

在对抗这些新发突发病原的研究和防控过程中，我们看到了我国科学家近年来在传染病防控领域所取得的骄人成绩，也看到了我国基础研究及防控队伍的不断壮大及大国的责任和担当。最后，高福院士提出，控制传染病的两个重要要素：持续监测与基础研究。病毒传播是没有国界的，因此必须开展国际合作。高院士呼吁全球的科学家、临床医生及公共卫生专家等一起来攻克新发突发病原，并着重介绍了即将全面启动的全球病毒组计划（GlobalViromeProject，GVP）、建立非洲CDC网络等战略部署，将对新发突发病原发起“主动出击、全面出击”，主动鉴定出病毒威胁，并采取必要的措施来预防下一次的大流行病。

 

高院士呼吁启动全球病毒组项目

 

此外，高院士对由世界银行、世界卫生组织以及日本和德国政府共同发起的流行病应急融资基金（PEF），以及由挪威政府、比尔和梅林达.盖茨基金会、惠康信托基金会和世界经济论坛共同建立的流行病预防创新联盟（CEPI）给予高度评价。这类创新的全球性融资机制，将有效保护全世界免遭致命性流行病影响，并加速疫苗研发进程。人类需要不断认知病原。高院士指出对病毒的致病性、跨种传播等深入的基础研究是传染病有效防控的根本，也亟待更多的关注和基金资助。

 

中国微生物学会病毒学专业委员会主任委员郭德银评论文章虽然篇幅不长，但高屋建瓴，视野宽广，信息丰富，重点突出。文章内容构思巧妙，题目“从A（禽流感）到Z（寨卡）”寓意深长，一是说明新发突发病毒的多样性和复杂性，二是意指从对病原监测到完全控制病原的期望。文章首先重点介绍当前正在流行并不断新发再发的流感病毒的起因、危害和防控措施，然后依次介绍SARS和MERS冠状病毒、埃博拉病毒、寨卡病毒等的历史与现状，强调了活禽市场关闭、新技术应用（如高通量基因组测序）、国内外合作、早期检测与持续监测、尤其是基础研究在防控新发突发病毒方面的重要性。

 

高福院士在文章中指出经过SARS之后，中国已经建立起高效的病原监测与防控体系。而中国疾病预防控制中心作为政府举办的实施疾病预防控制与公共卫生技术管理和服务的国家级专业机构，自成立以来通过不断巩固相关基础研究，大力推进疾病预防控制的应用研究，在重大传染病的防治和疾病预防控制的基础、前沿技术研究方面取得了丰硕成果，并以此为支撑，在疾控基础平台体系建设、新发突发传染病应对、重大传染病和慢性病防控等方面取得了突出成绩。

 

高福院士在文中呼吁要铭记历史教训，避免悲剧再次上演，要持续加强在基础研究方面的投入，以此来积极促进公共健康政策和创新合作举措的有效施行。该文章对于我国病原学研究和传染病防控具有重要价值，对进一步推动“健康中国”战略、“一带一路”倡议以及构建人类命运共同体具有重要意义。

 

From“A”IVto“Z”IKV:AttacksfromEmergingandRe-emergingPathogens

 

GeorgeF.Gao

 

100yearsaftertheinfamous“Spanishflu”pandemic,the2017–2018fluseasonhasbeensevere,withnumerousinfectionsworldwide.Inbetween,therehavebeencontinuous,relentlessattacksfrom(re-)emergingviruses.Tofullyunderstandviralpathogenesisanddevelopeffectivemedicalcountermeasures,wemuststrengthencurrentsurveillanceandbasicresearchefforts.

 

Thisyearmarksthecentenaryofthe“Spanishflu”pandemic,themostdevastatingviralpandemicinhistorycausedbyanH1N1influenzaAvirusthatinfectedover500millionandkilledbetween50and100millionpeople.Weknowtoexpectafluseasoneveryyear;thequestionisalwayshowsevereitwillbe.Withhighnumbersofinfluenzainfectionsreportedworldwideduringthisseason,weareagainremindedofthepublichealththreatstemmingfromapotentialinfluenzapandemic.TheUSCentersforDiseaseControlandPrevention(CDC)reportedthatthisisthefirsttimeinthepast15yearsthatallstatesintheentirecontinentalUSAhavereportedwidespreadfluactivityduringthesameweek.InChina,thereportednumberofflucaseshaveincreasedover2-foldcomparedtothefluseasonsinthepastseveralyears—thesecond-highestrecordednumber,justafterthe2009pandemicH1N1(pH1N1)—andmanypatientshavebeenhospitalizedwithsevereclinicalsymptoms.Theseeventshaveraisedconcernsthatweareindangerofanotherflupandemic.Circulatingfluvirusesarequitediversethisyear—includingthe“swineflu”2009-pH1N1,H3N2,andinfluenzaB/VictoriaandB/Yamagata—andarespreadacrossvariousgeographicallocations.TheH3N2subtypeisdominantintheUKandtheUSA,butamixedpoolofpH1N1,H3N2,andinfluenzaB/Yamagata,withasmallportionofB/Victoria,havebeenreportedinChina.Auniversalinfluenzavaccinetocombatsuchmutation-pronevirusesisurgentlyneededyetstillfarfromreach,despitetheglobalefforts.Despitebesteffortstoanticipatetheemergentstrains,vaccinesvaryfromyeartoyearintermsofefficacy,withthisyear’sprovidingonlymoderateprotection.

 

HumaninfectionswithdifferentsubtypesofavianinfluenzaAviruses(AIVs)havebeenconsistentlyreportedsinceH5N1AIVwasreportedinHongKongduring1997(Yuenetal.,1998).InfectionswithAIVtypicallyresultinhighcasefatalityrates(CFRs)rangingfrom～30%to～70%,andatleast14influenzaAvirussubtypes—includingthethreeseasonalfluviruses,H1N1,H2N2,andH3N2—havereportedlyinfectedhumanstodate(Figure1).Ofnote,influenzaAvirushasasegmentedgenomewith8genomicsegmentsencodingatleast10–16proteins,twoofwhicharehemagglutinin(HA)andneuraminidase(NA).Therearecurrently16(+2)HAgenesand9(+2)NAgenes(+2meanstwomoreHAorNAfrombat-derivedinfluenza-likeviruses,forwhichonlygenomicsequencesareavailable,butnoalivevirushasyetbeenisolated;Wuetal.,2014).ThecombinationofHAandNAwouldtheoreticallyyield144subtypesofHxNyviruses.Duetothemigratorybirds’travelandlivepoultrytrade,whichincludesthetransportofpoultryandoperationoflivepoultrymarkets(LPMs)throughoutChinaandSoutheastAsia(Gao,2014),weshouldexpectmorehumaninfectionswithAIVsinthefuture.AIVsmaysupplygenomicsegmentsforreassortmentwithcirculatingseasonalinfluenzavirusestogenerateanovelpathogenwithhighCFRandpandemicpotential.Aswecan’tyeteradicateseasonalflu,effortstochangethetraditionallivepoultrytrade—forexample,thetraditionalLPMs—inordertorestricttheflowofdomesticpoultrymigrationmayhelpdecreasetheprobabilityoftheemergenceofnovelAIVsubtypes,eventhepotentialpandemicviruses.

 

ThenumbersofhumancasesinfectedbydifferentsubtypesofinfluenzaAvirusreportedworldwideareshowninhistogram(WHO,2017a).Thexaxispresentsthetimepoints(year)ofthefirstreportedcaseforeachsubtypevirus.Theyaxispresentsthetotalnumbersofreportedhumancasestodate.Thecasenumbersofhuman-infectingH1N1,H2N2,andH3N2areextraordinarilylargeandarenotavailableforexactcountsduetoinfluenzapandemicssuchasthe1918H1N1Spanishflu,1957H2N2Asianflu,and1968H3N2HongKongflu.

 

Fluisn’talone.Coronavirusisanotherfamilyofemergingpathogenswithpublichealthconcern.Adevastatingbutquicklyconqueredoutbreakofsevereacuterespiratorysyndromecoronavirus(SARS-CoV)during2003transformedChina’sapproachtooutbreakcontrol.Asophisticatedsurveillancesystemhassincebeenputintoplace.Whileprimarilygovernmentled,thereisextensivecollaborationwithvariousinstitutesintheacademic,industry,andhealthcarefieldstoproduceawide-ranging,comprehensivenetworkthatissueswarningsofanimpendingoutbreakattheearliestopportunity.AsexemplifiedbytheChineseAcademyofSciencesCenterforInfluenzaResearchandEarly-warning(CASCIRE)network,inadditiontoChineseNationalInfluenzaCenter/WHOCollaboratingCenterforReferenceandResearchonInfluenzaunderChinaCDC,suchasystemcandrivebasic,applied,andtranslationalresearchoninfectiousdiseasecontrolandprevention(Bietal.,2017).Arelatedcoronavirus,theMiddleEastrespiratorysyndromecoronavirus(MERS-CoV),emergedintheMiddleEastduring2012andhasonoccasioncausedsporadicinfectionswithimportedcasesfromreturningtravelers,someofwhichgoontoinfectothers.OnesuchinstancewastheimportationofaMERS-CoVcaseintoChinafromSouthKoreaduring2015(Suetal.,2015),inwhichthetravelerwaspromptlyidentifiedandquarantined,preventingfurtherinfections.DuetotheongoingnatureoftheMERS-CoVoutbreak,wearelikelytoencountermorecoronavirusinfectionsinthefuture.Preparationsshouldbemadeaccordinglythroughthedevelopmentofbothvaccinesandantivirals.

 

Ebolavirus(EBOV),firstidentifiedinCentralAfricaduring1976,unexpectedlystruckWestAfricaduring2013–2015,impactingseveralcountriesinNorthAmerica,Europe,andAfrica.Afterearlierincidents,effortswereunderwaytodevelopvaccinecandidates;however,thesewerechallenged,astheviruswasatfirstsuspectedtohaveahighermutationratethatmightnegativelyimpacttheefficacyoftheEBOVvaccinecandidatesunderclinicaltrials(Gireetal.,2014).Toaddressthisquestiondirectly,atotalof175whole-genomesequenceswereobtainedfromviralisolates,andthemutationratewasdeterminedtobesimilartothatofpastEBOVoutbreaks(Tongetal.,2015).Therefore,currentexperimentalvaccinesshouldstillbeefficacious.Duringthisepidemic,applicationofgenomicsequencingtechnologygreatlyfacilitateddiseasecontrol.Molecularepidemiologyandpathogenesisstudies,inadditiontothedevelopmentofeffectiveantivirals,suchastheZMappantibodycocktailandthevesicular-stomatitis-virus(VSV)-andadenovirus(Ad5,chAd3)-basedvaccines,werethekeymeasuresfortheeffectivecontrolofthesepathogens.

 

WhiletheworldwasstillcelebratingthesuccessoffinallyconqueringEBOVafteraprotracted2-yearbattle,Zikavirus(ZIKV)struckwiththefirstcasesreportedinBrazilaftersmalloutbreakspreviouslyreportedinMicronesia(YapIsland)andFrenchPolynesiain2007and2013,respectively(Figure2).Asanobscurepathogen(butknowntohumanssince1947),theZIKVisolatesfromthe2015–2016epidemicwerefoundtopossessnewcharacteristics(Grubaughetal.,2018).Thevirusquicklyspreadgeographicallywithatleast84countries/regionsaffected(Figure2).AcoordinatedglobalresponseeventuallyledtotheconclusionoftheepidemicinNovember2016,butlong-termcomplicationsstemmingfromZIKVinfectionsareyetbeingreportedfromconvalescentpatients.

 

LocationswherebigeventsofZikavirusinfectionoccurredwereindicatedinred.Theseeventsaredescribedinboxesandnumberedaccordingtothetimesequence.ThedashedarrowlinesrepresentthespreadingroutesofZikavirusduringthe2015–2016outbreak.RegionswithevidenceofZikavirustransmissionarecoloredinyellow,exceptforthefivered-coloredonesasmentionedabove.Chinaiscoloredinlightyellowduetotheimportedcasesin2016andtheisolationofZikavirusinlocalvector,althoughnotinthe84countrieswithZikavirustransmissionaccordingtotheWHOclassification(WHO,2017b).

 

AftertheZIKVepidemic,outbreaksofyellowfevervirus(YFV)occurredacrossAngolaandBrazilin2017.TheviruswasimportedtoChinaasChineseworkersreturnedfromAngola(Chenetal.,2016).Almostsimultaneously,RiftValleyfevervirus(RVFV)wasalsoimportedintoChinafromAngolathroughareturningtraveler.Theseeventshighlightedthedifficultyinaccuratelypredictingthetimeandlocation,aswellastheidentity,ofthecausativepathogenbehindthenextoutbreak.Indeed,EBOVandZIKVwerebothconsideredneglected,tropicalre-emergingpathogens,SARS-CoVandMERS-CoVwerenovel,emergingpathogens,andinfluenzavirusesweretypicallyre-emergingpathogenswithnewpropertiesderivedfromgeneticevolutionandreassortments.

 

Amyriadofcontributingfactorssuchasurbanization,globalization,andclimatechangewillimpactthepathogenicityandtransmissionofcertainpathogens,aswellasthedistributionoftheirreservoirhosts.Thisrealityplacesadditionalemphasisontheimportanceofproactivecountermeasures,suchaspathogensurveillanceandvaccinedevelopment,aswellastheneedforreactivecountermeasures,suchasantiviraltherapy.

 

Asacommunityofscientists,clinicians,publichealthexperts,andcaregivers,wehavesofarbeenabletoanswerthechallengesposedbyaspectrumofpathogensrangingfrom“A”vianinfluenzavirusto“Z”ikavirus.Eachhastakentimeandasomewhattailoredapproach.Wecanexpectsternertestsinthefuture,andsomeofthelessonslearnedmustbecarriedforward.Sincethespreadof(re-)emergingvirusesisnotconfinedbygeographicboundaries,itisclearthatcollaborativesolutionsacrossnationsareneededtosolvetheseglobalproblems.Effortsinthisveinaregettingofftheground.Internationalpartnerships,suchastheGlobalViromeProject(Carrolletal.,2018)forvirushuntingworldwideandtheestablishmentofaCDCnetworkinAfricawithassistancefromtheUSCDCandChinaCDC,willgreatlyimproveourcapacityforsurveillance,contributingto,ideally,aworldwidesysteminthe“bigdata”eraofthe21stcentury.ThePandemicEmergencyFinancingFacility(PEF),launchedbytheWorldBankincollaborationwiththeWorldHealthOrganizationandthegovernmentsofJapanandGermany,aimstoprovideover$500milliontocoverdevelopingcountriesagainsttheriskofoutbreaks.TheCoalitionforEpidemicPreparednessInnovations(CEPI),foundedbytheNorwaygovernment,theBill&MelindaGatesFoundation,theWellcomeTrust,andtheWorldEconomicForumaimtoprovideacoordinated,bench-to-bedsideapproachfor(pre-)clinicalvaccinedevelopmentanddelivery.Theaboveexamplesshowthatwearebeginningtolearnourlessons,butwemustnotforgetthatbasicscientificresearchintobothhigh-profileandobscurepathogensformsacrucialbasisfortheeffectiveimplementationofinformedpublichealthpoliciesandinnovativecollaborativeinitiatives.Robustinvestmentintobasicresearch(i.e.,viralpathogenesis,interspeciestransmission,etc.)shouldbeencouragedtoachieveafullymulti-facetedapproachtocombatingfuturepandemics.

 

Acknowledgments

 

WorkinG.F.G.’slaboratoryispartysupportedbytheStrategicPriorityResearchProgramoftheChineseAcademyofSciences(grantno.XDPB03)andtheNationalNaturalScienceFoundationofChina(NSFC,grantno.81621091).MythanksgotoDrs.HaoSongandLianpanDaifortheirhelpofpreparingthefiguresandDrs.GaryWong,DayanWang,TaoChen,YuhaiBi,WilliamJ.Liu,YiShi,andZhongjieLifordiscussions.