918年，由甲型H1N1流感病毒引發(fā)的“西班牙流感”爆發(fā)流行，在全球超過(guò)5億人感染，造成5千萬(wàn)到1億人死亡，死亡人數甚至超過(guò)了第一次世界大戰和第二次世界大戰死亡人數的總和，可謂是世界歷史上最嚴重的流行病疫情。而今，在“西班牙流感”暴發(fā)100周年之際，中國疾病預防控制中心主任高福院士應邀為國際頂級學(xué)術(shù)期刊《細胞》撰寫(xiě)評述文章“From‘A’IVto‘Z’IKV:AttacksfromEmergingandRe-emergingPathogens”，用生動(dòng)的語(yǔ)言和詳實(shí)的數據系統地評述了全球新發(fā)突發(fā)傳染病形勢及應對策略。
該文對于新發(fā)突發(fā)病原進(jìn)行了歷史性回顧，尤其開(kāi)篇從今年流感流行、紀念1918大流行100年作為切入點(diǎn)，然后延伸到包括中東呼吸綜合征（MERS）、埃博拉在內的新發(fā)突發(fā)傳染病，還重點(diǎn)介紹了發(fā)現很早、但是直到最近幾年才對人引起嚴重感染的寨卡。高福院士巧妙地用了從A（禽流感）到Z（寨卡）這樣的題目，既體現了新發(fā)再發(fā)病毒的不斷涌現及暴發(fā)的不確定性，又預示了人類(lèi)最終能戰勝病毒。
Figure1HumanInfectionswithSubtypesofInfluenzaAViruses
在對抗這些新發(fā)突發(fā)病原的研究和防控過(guò)程中，我們看到了我國科學(xué)家近年來(lái)在傳染病防控領(lǐng)域所取得的驕人成績(jì)，也看到了我國基礎研究及防控隊伍的不斷壯大及大國的責任和擔當。最后，高福院士提出，控制傳染病的兩個(gè)重要要素：持續監測與基礎研究。病毒傳播是沒(méi)有國界的，因此必須開(kāi)展國際合作。高院士呼吁全球的科學(xué)家、臨床醫生及公共衛生專(zhuān)家等一起來(lái)攻克新發(fā)突發(fā)病原，并著(zhù)重介紹了即將全面啟動(dòng)的全球病毒組計劃（GlobalViromeProject，GVP）、建立非洲CDC網(wǎng)絡(luò )等戰略部署，將對新發(fā)突發(fā)病原發(fā)起“主動(dòng)出擊、全面出擊”，主動(dòng)鑒定出病毒威脅，并采取必要的措施來(lái)預防下一次的大流行病。
高院士呼吁啟動(dòng)全球病毒組項目
此外，高院士對由世界銀行、世界衛生組織以及日本和德國政府共同發(fā)起的流行病應急融資基金（PEF），以及由挪威政府、比爾和梅林達.蓋茨基金會(huì )、惠康信托基金會(huì )和世界經(jīng)濟論壇共同建立的流行病預防創(chuàng )新聯(lián)盟（CEPI）給予高度評價(jià)。這類(lèi)創(chuàng )新的全球性融資機制，將有效保護全世界免遭致命性流行病影響，并加速
疫苗研發(fā)進(jìn)程。人類(lèi)需要不斷認知病原。高院士指出對病毒的致病性、跨種傳播等深入的基礎研究是傳染病有效防控的根本，也亟待更多的關(guān)注和基金資助。
中國微生物學(xué)會(huì )病毒學(xué)專(zhuān)業(yè)委員會(huì )主任委員郭德銀評論文章雖然篇幅不長(cháng)，但高屋建瓴，視野寬廣，信息豐富，重點(diǎn)突出。文章內容構思巧妙，題目“從A（禽流感）到Z（寨卡）”寓意深長(cháng)，一是說(shuō)明新發(fā)突發(fā)病毒的多樣性和復雜性，二是意指從對病原監測到完全控制病原的期望。文章首先重點(diǎn)介紹當前正在流行并不斷新發(fā)再發(fā)的流感病毒的起因、危害和防控措施，然后依次介紹SARS和MERS冠狀病毒、埃博拉病毒、寨卡病毒等的歷史與現狀，強調了活禽市場(chǎng)關(guān)閉、新技術(shù)應用（如高通量基因組測序）、國內外合作、早期檢測與持續監測、尤其是基礎研究在防控新發(fā)突發(fā)病毒方面的重要性。
高福院士在文章中指出經(jīng)過(guò)SARS之后，中國已經(jīng)建立起高效的病原監測與防控體系。而中國疾病預防控制中心作為政府舉辦的實(shí)施疾病預防控制與公共衛生技術(shù)管理和服務(wù)的國家級專(zhuān)業(yè)機構，自成立以來(lái)通過(guò)不斷鞏固相關(guān)基礎研究，大力推進(jìn)疾病預防控制的應用研究，在重大傳染病的防治和疾病預防控制的基礎、前沿技術(shù)研究方面取得了豐碩成果，并以此為支撐，在疾控基礎平臺體系建設、新發(fā)突發(fā)傳染病應對、重大傳染病和慢性病防控等方面取得了突出成績(jì)。
高福院士在文中呼吁要銘記歷史教訓，避免悲劇再次上演，要持續加強在基礎研究方面的投入，以此來(lái)積極促進(jìn)公共健康政策和創(chuàng )新合作舉措的有效施行。該文章對于我國病原學(xué)研究和傳染病防控具有重要價(jià)值，對進(jìn)一步推動(dòng)“健康中國”戰略、“一帶一路”倡議以及構建人類(lèi)命運共同體具有重要意義。
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,witha
smallportionofB/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.
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