_人禽流感疫苗研发进展课件

Vaccines for Pandemic Influenza 流感大流行疫苗储备株研究进展 Dong jie China NIC China CDC Family: Orthomyxoviridae （正粘病毒科） Three types: A, B, C SS negative-sense RNA viruses （单股副链RNA病 毒） 8 (or 7) gene segments（8 或7节段） Enveloped viruses （囊膜病毒 ） Influenza Viruses（流行性感冒病毒） Influenza A Viruses Subtyped based on surface glycoproteinsSubtyped based on surface glycoproteins hemagglutinin (HA) and neuraminidase (NA)hemagglutinin (HA) and neuraminidase (NA) current human subtypes: H1N1, H3N2 current human subtypes: H1N1, H3N2 甲型流感病毒依据表面糖蛋白甲型流感病毒依据表面糖蛋白HAHA和和NANA分亚型，人群中流行的甲型流感包括分亚型，人群中流行的甲型流感包括H1N1, H3N2H1N1, H3N2 。 Birds reservoir for all HA and NA subtypesBirds reservoir for all HA and NA subtypes：（鸟类是甲型流感病毒的自然宿主）：（鸟类是甲型流感病毒的自然宿主） H1 - H17 H1 - H17 N1- N9N1- N9 Infects multiple mammalian species Infects multiple mammalian species （甲型流感可以感染多种哺乳动物）（甲型流感可以感染多种哺乳动物） humans, swine, horses, whales, seals, cats, and dogshumans, swine, horses, whales, seals, cats, and dogs （人，猪，马，鲸，海豹，猫和狗）（人，猪，马，鲸，海豹，猫和狗） H5 and H7 subtypes include viruses that are highly pathogenic for domestic poultryH5 and H7 subtypes include viruses that are highly pathogenic for domestic poultry （H5H5和和H7H7的某些亚型对家禽是高致病性的）的某些亚型对家禽是高致病性的） Antigenic Drift（抗原漂变） Gradual alteration (by point mutation) of HA and/or NA within a subtype（渐变，点突变） Inability of antibody (to previous strains) to neutralize mutant virus （以前病毒的抗体无法中 和突变病毒） Occurs in both influenza A and B viruses （甲乙型流感 病毒均可发生） Causes periodic epidemics（导致周期性的流感流行） Rate of occurrence: 50% from previous strains（与以前病毒相 比有大于50%差异） 17 HA subtypes 9 NA subtypes Influenza A reservoir Influenza A Viruses in Humans 1918195719681977 Spanish Influenza Asian Influenza Hong Kong Influenza H1N1H2N2H3N2 H1N1 ? 19972003 1999 H5N1 H9N2 H7N7 H5N1 What can cause Pandemic Influenza? New HA: Human influenza A virus with a novel hemagglutinin or a novel hemagglutinin and neuraminidase gene.（新的HA） Susceptibility: Lack of immunity to this novel virus, in a large proportion of the population.（易感性） Transmissibility: Demonstrated ability of the virus to cause disease and spread from person-to-person. （可传播性） Human infection with avian influenza viruses (2004) 人感染禽流感病毒情况 YearPlaceVirus subtype Cases (death) 1995UKH7N71 1997Hong KongH5N118 (6) 1999Hong KongH9N22 2003H5N1H5N12 (1) 2003NetherlandsH7N784 (1) 2003Hong KongH9N21 2004CanadaH7N32 2004EgyptH10N72 From （禽流感H5N1全球感染情况） H5N1 influenza in animals other than poultry -2004 除家禽以外感染H5N1的动物 Bird（禽类） - Ducks and geese（鸭和鹅） - Crows ,sparrows（乌鸦，麻雀） - Peregrine falcon, eagle（猎鹰，鹰） Cats（猫科） - Domestic cats（家猫） - Tigers/leopard（虎/美洲豹） Pigs（猪） Man （人） Cumulative Number of Confirmed Human Cases of Avian Influenza A/(H5N1) Reported to WHO 14 August 2007 （WHO确诊诊人禽流感病例） Country 20032004200520062007Total casesdeathscasesdeathscasesdeathscasesdeathscasesdeathscasesdeaths Azerbaijan000000850085 Cambodia000044221177 China110085138322516 Djibouti000000100010 Egypt00000018102053815 Indonesia 000020135545282410382 Iraq000000320032 Lao Peoples Democrati c Republic 000000002222 Nigeria000000001111 Thailand0017125233002517 Turkey00000012400124 Viet Nam332920611900209542 Total4446329843115795735320193 Total number of cases includes number of deaths. WHO reports only laboratory-confirmed cases. All dates refer to onset of illness. Corporate links E-mail scams | Employment | FAQs | Feedback | Other UN sites | Privacy | RSS feeds World Health Organization 2007. All rights reserved WHO 流感大流行预警3级 Number of Episodes of Illness, Healthcare Utilization, and Death Associated with Moderate and Severe Pandemic Influenza Scenarios Characteristic（特征） Moderate (1958/68-like) （中等） Severe (1918-like)（严重） Illness（疾病）90 million (30%)90 million (30%) Outpatient medical care（门诊医学监护） 45 million (50%)45 million (50%) Hospitalization（住院）865,0009,900,000 ICU care （ ICU 监护）128,7501,485,000 Mechanical ventilation （机械通气） 64,875 745,500 Deaths（死亡）209,0001,903,000 Options for Vaccines for Pandemic Influenza 流感大流行疫苗株的选择 Conventional inactivated vaccine : wt virus（野毒：常规灭活疫苗） Conventional inactivated vaccine: a reassortant virus containing HA and NA from wt virus and internal genes from A/PR/8/34 (PR8) virus（传统的重配疫苗：HA和NA 来源于野毒，其它内部6节段来源PR8 ） Live attenuated cold-adapted (ca) vaccine: a reassortant prepared with master ca strain A/Ann Arbor/6/60 (AAca) （活的减毒冷适应疫苗株：方法同上，来源于种子株 A/Ann Arbor/6/60 ） “Surrogate” non-pathogenic virus antigenically similar to pandemic strain, perhaps as a high growth reassortant （与大流行株抗原类似的非致病性替代株） Purified expressed HA protein（纯化的经表达的HA蛋白） Reassortant virus with PR8 or AAca using reverse genetics（以PR8 或者 AAca反向 遗传方法重配的毒株） Choice of Vaccines: Pros and Cons疫苗选择的优缺点 Method（方法）Advantage（优点）Disadvantage（缺点） Inactivated wt virus（灭活的野毒）Quick （快）Safety concern (if highly pathogenic) May not grow efficiently（安全考虑） Inactivated PR8 reassortant virus（减 毒的PR8重配株） Approved and accepted（已经批准 ） High growth（高产） Safety concern (if highly pathogenic) （安全考虑） Cold adapted AAca reassortant virus （冷适应重配株） Approved and accepted（已批准） Could induce cellular immunity（可 诱导细胞免疫） Safety concern (if highly pathogenic) （安全考虑） Inactivated surrogate virus (wt or reassortant)灭活的替代株 Safe（安全） Approved and accepted（已批准） Virus may not be available （没有适 合的病毒） Recombinant HA protein（重组的HA 蛋白） Safe（安全）Poorly immunogenic（差的免疫原性 ） Reassortant (PR8 or AAca) virus generated by reverse genetics（反向 遗传重配毒株） Quick（快速） Safe （安全） Intellectual property issue（知识产权 ） Low supply of certified cell lines（生 产细胞系缺乏） GLP practice to be applied（GLP操 作） PR8(H1N1) G9 (H9N2) Mixture of viruses Anti-H1N1 Abs+ H9N2-PR8 (6:2) Generation of Reassortant Virus（经典的病毒重配方法） Screening by RT/PCR plaque forming capability in CEF cells with or without trypsin（重配株的生长特性 ，空斑形成能力） Genotype and sequence of the HA and NA genes（HA，NA序列 分析和基因分型） Pathogenicity in chickens （对鸡致病性） Pathogenicity in mammals (mice and/or ferrets)（哺乳动物致病性 包括鼠和/或雪貂） Antigenicity of the reassortant vaccine reference virus （HI）（重 配疫苗病毒抗原性检测） Efficacy of protection from challenge with wild-type virus in mouse model（野毒攻击检测疫苗的保护性） General Approach to the Evaluation of Candidate Vaccine Viruses（疫苗候选株评价方法） d60d46d42d14d0 d-1 Vaccines:VN1203/PR8 VN30408/PR8 Indo05/PR8 Vi