医学英语课件资料：BASIC OF VACCINOLOGY

1、BASIC OF VACCINOLOGY| 1| 2ContentHistory of vaccine developmentFrom Jenner to PasteurMilestones of the history of vaccinationImpact of vaccination on diseasesBasics of vaccinesVaccines and vaccine classificationThe vaccine immune responseAdverse reactions to vaccinationHib vaccine: from single vacci

2、nes towards combination vaccinesHib diseases: invasive infectionsPRP: transform from T cell-independent to T cell dependentDTaP based combination vaccinesInfluenza vaccines: the most varied vaccine still under improvementInfluenza and its complicationsConventional influenza vaccinesDiverse influenza

3、 vaccinesVaccines of futureChimeriVax and development of Dengue vaccineThe vaccine development cycleConclusion“The golden mirror of medicine(医宗金鉴)”（1742）listed four forms of inoculation against smallpox practiced in China since 1695: The nose plugged with powdered scabs laid on cotton wool (浆苗法) Pow

4、dered scabs blown into the nose (旱苗法) The undergarments of an infected child put on a healthychild for several days (痘衣法) A piece of cotton smeared with the contents of a vesicleand stuffed into the nose (水苗法)Variolation (人痘)：A Chinese invention痘衣法旱苗法| 3To protect against smallpox, writings citing t

5、he use of inoculation and variolation go back to the 10th century in China.Variolation was introduced into England by Lady Mary Montagu in 1721, on her return from ConstantinoplePlotkin “Vaccines” 6th edition| 4Cowpox (牛痘)：the naissance of vaccinationCowpox was a sporadic disease occurring in rural

6、counties of England, transmitted from cow to man, but not life threatening. Local wisdom said that a person who had contracted cowpox was immune to smallpox.1796 surgeon Edward Jenner took this village folklore and experimented with it, using the pus from the cow pox pustules for variolation.This va

7、ccination was the first naturally attenuated vaccin for manCreation of the word vaccination vacca is Latin for cow| 5The story of modern vaccines started from here On 6 July, 1885, a nine-year-old boy, Joseph Meister, had been bitten many times by a rabid dog in his village two days before. Louis in

8、jected the vaccine into Joseph twelve times over the course of ten days. Josephs bites healed, without having contracted rabies.| 6Louis Pasteur: the father of modern vaccines1870, Louis Pasteur creates the first live attenuated bacterial vaccine (chicken cholera)1884 , Pasteur creates the first liv

9、e attenuated viral vaccine (rabies)1885, Pasteur first uses rabies vaccine in a human| 7Pasteur and his disciplines in 18941909 Creation of BCG, the first live attenuated bacterial vaccine for humansCalmetteGuerinRamonMilestones in the History of Vaccination1923: Development of diphtheria toxoid vac

10、cine (inactivation with formalin) (Ramon)1926: Development of tetanus toxoid vaccine based on same principles (Ramon & Zoeller)Great success of vaccine development in 20th century 1909 BCG (Calmette & Gurin) 1923 Diphtheria toxoid vaccine (Ramon) 1926 Tetanus toxoid vaccine (Ramon & Zoeller)1932: Us

11、e of first yellow fever vaccine1936: Development of inactivated influenza A vaccine in embryonated eggs1950s: Development of inactivated polio vaccine (Salk) and live attenuated polio vaccine (Sabin)1950-1970: Development of live attenuated strains for measles (Edmonston), rubella (Wistar RA27/3), m

12、umps (Jeryl Lynn) and varicella (Oka)1986: Licensure of first recombinant vaccine (Hepatitis B)1990: Licensure of first polysaccharide conjugate vaccine (Haemophilus influenzae b)1991: Licensure of first acellular pertussis vaccine| 8 41 vaccines are available to protect against 26 infectious diseas

13、es.1700180019001910192019301940195019601970198019912000rabiessmallpoxtyphoiddiphtheriatuberculosistetanuscholerapertussisinfluenzayellow feverIPV (polio Salk)OPV (polio Sabin)measlesmumpsrubellameningococcuspneumococcushepatitis Bhepatitis AHib Pa combo HA/HBpre-industrial eraindustrial eraHPVRotaye

14、ars| 910Vaccination is the 20th centurys greatest public health triumph after improved access to clean, safe drinking water More than 2.5 million lives(1) are saved in the world every yearbut more than 2 million people still die(1) due to a lack of access to existing vaccines(1)WHO Global immunizati

15、on data. January 2009Value of Vaccines11Vaccines save livesMillions of cases of disease preventedSmallpox has been eradicatedBefore eradication in 1980, smallpox threatened 60% of the worlds population, and killed 1 out of 4 people infected (1) Polio infections have fallen globally by 99% since 1988

16、 (2) An estimated 5 million people have escaped paralysisMeasles mortality has decreased by 74% worldwide between 2000 and 2007 (3) WHO Factsheet n 288 March 2005Global Polio Eradication Initiative (GPEI). Global Situation - Jan 2009WHO 10 Facts on Immunization Oct 2009 /features/factfiles/immunizat

17、ion/en/index.html12Vaccination is one of the most cost-effective health care investments availableIn the United States, cost-benefit analysis indicate that every dollar invested in a vaccine dose saves US $2 to US $27 in health-care expenses (1) A past study estimated that a one-week supplemental im

18、munization activity against measles carried out in Kenya in 2002 would result in a net saving in health costs of US$12 million over the following ten years; during that time it would prevent 3 850 000 cases of measles and 125 000 deaths (2) WHO. Immunization against diseases of public health importa

19、nce fact sheet n 288. March 2005 WHO - Factsheet n 288 March 2005Vaccines save moneyImportance of sustainable vaccination| 13| 14ContentHistory of vaccine developmentFrom Jenner to PasteurMilestones of the history of vaccinationImpact of vaccination on diseasesBasics of vaccinesVaccines and vaccine

20、classificationThe vaccine immune responseAdverse reactions to vaccinationHib vaccine: from single vaccines to combination vaccinesHib diseases: invasive infectionsPRP: transform from T cell-independent to T cell dependentDTaP based combination vaccinesInfluenza vaccines: the most varied vaccine stil

21、l under improvementInfluenza and its complicationsConventional influenza vaccinesDiverse influenza vaccinesVaccines of futureChimeriVax and developement of Dengue vaccineThe vaccine development cycleConclusionVaccine A suspension of attenuated or killedmicroorganisms orantigens derivedfrom them Vacc

22、aProteinPolysaccharideSurface AgToxinDefinition of VaccineFor the PREVENTION or the TREATMENT ofINFECTIOUS DISEASES| 15Bacterial VaccinesViral VaccinesLive Vaccines BCG Diphtheria Tetanus Pertussis Meningo Pneumo Hib Typhim Vi Measles Mumps Rubella Varicella OPV Yellow Fever Influenza Hepatitis B He

23、patitis A IPVRabiesKilledVaccines Typhoid CholeraVaccine Classification| 16ATTENUATED = LIVEINACTIVATED = KILLEDInactivated Vaccines and Attenuated Vaccines The vaccine contains one or several antigens which can stimulate the Immune System, without Infection. The vaccine constituents are inactivated

24、 no any disease risk The vaccine contains a LIVE micro-organism which is able to multiplyin the host to stimulate the Immune System. This live micro-organism is attenuated to avoid any disease manifestation NO pathogenic effect Imitates the natural infection Multiplication AFTER administration NO pa

25、thogenic effect Keep the antigenic structure NO multiplication after administration May provide humoral and mucosal immunity Require fewer doses Longer lasting protection Cannot revert to pathogenicity No transmission to contacts Easier to produce| 17 WHOLE CELL : BCG Pertussis Cholera Live typhoid

26、TOXOID : Tetanus Diphtheria Pertussis toxin SURFACE Ag : Acellular pertussis POLYSACCHARIDE : Meningo Pneumo Typhim Vi CONJUGATE POLYSACCHARIDE : Hib WHOLE VIRUS : Measles Mumps Rubella Varicella Poliomyelitis IPV OPV Yellow Fever Rabies Hepatitis A SPLIT VIRUS : Influenza RECOMBINANT SURFACE Ag : H

27、epatitis BBacterial Vaccines and Viral VaccinesVIRALBATERIAL| 18The basic immune response| 19The basic confirmation of immune response after vaccination is the : But other cell-mediated mechanisms may cooperate : i.e. BCGThe antibody level after vaccination must be :above the protective antibody lev

28、el (when it is known) and/orincreased (usually 4-fold) from the initial level.Immune response after vaccinationantibody level| 20 Example of an inactivated vaccineExample of a live vaccine1st dose2nd 3rd (dose)boosterprotective Ab levelprotective Ab levelnatural naturalbooster boosterrevaccination1s

29、tBooster Effector| 21Factors modifying the immune response after vaccinationFactorsEffectsVaccinesNature of vaccinesLive inactivated One exception: oral polioCold chain (2-8C) Oral polioAge of vaccinee Polysaccharide non conjugateMaternal antibodies Live vaccinesImmuno deficienciesVariableInactivate

30、d vaccinesCo-infection Oral polioAdjuvant (hydroxide aluminum) Toxoids (diphtheria , tetanus)Antigenic load/ToxoidsViral strain or MumpsInjection route (Intra dermal)Rabies, influenzaGenetic factorsNon respondersHep B| 22The Immunization ScheduleThe Immunization Schedule may be considered effective

31、if specific antibodies are developed by at least 95% of vaccinated individuals.Determining factors Epidemiology of the disease the age at greatest exposure The severity of disease at different age groups Variations in the child ability to immunologically respond to the vaccine stimulationInfants abi

32、lity to acquire immunity : Passively transferred maternal antibodies persist during the first 6 to 12 months of life and protect the infant against certain infections They may inhibit the immune response induced by vaccination against measles, rubella, or mumps, particularly in the first 6 months of

33、 life| 23Adverse reactions to vaccinationsLocal reactions : Redness, tenderness, pain, Common, transient and benign Nodule at the injection site (5-10%) which may turn into aseptic abscessSystemic reactions : Feverish syndrome for 1-2 days( TF, pertussis, rubella, measles) Eruption Severe anaphylaxi

34、s is exceptionalIndurationEruptionPurpuraUrticaria| 2425The definition of AEFIAdverse Event Following Immunization1 (AEFI)：Reactions or events suspected to be related to vaccinationIt includes those which are not caused by vaccines, or falsely made correlation to vaccinesSide effects following immun

35、ization 2 ：Effects damage vaccinees tissues, organs and functions whileVaccine in question conformed to pharmacopeiaVaccine administration process was correctNo fault of stakeholders1. 全国疑似预防接种异常反应监测方案卫办疾控发201094号2. 预防接种的反应和处理（第三版）The causes of AEFIAEFINature of vaccinesAdministrationIndividual fact

36、orsIndicationsContra indicationsInjection routeDosageCold chainUnsafe injectionOngoing diseasesAllergyImmunosuppressionPsychological factorsStrainsPurityProductions TechnologyAdjuvantsExternal agentsInactivation errorDrugs| 26Contraindications for vaccinationIncreasing purification and concentration

37、 have considerably lowered the risks incurredIt is important to limit the number of contraindicationsFeverInfectious diseaseRecurrence of chronic diseaseUnder immuno-inhibitor | 27| 28ContentHistory of vaccine developmentFrom Jenner to PasteurMilestones of the history of vaccinationImpact of vaccina

38、tion on diseasesBasics of vaccinesVaccines and vaccine classificationThe vaccine immune responseAdverse reactions to vaccinationHib vaccine: from single vaccines to combination vaccinesHib diseases: invasive infectionsPRP: transform from T cell-independent to T cell dependentDTaP based combination v

39、accinesInfluenza vaccines: the most varied vaccine still under improvementInfluenza and its complicationsConventional influenza vaccinesDiverse influenza vaccinesVaccines of futureChimeriVax and developement of Dengue vaccineThe vaccine development cycleConclusion| 29STRAINSTARGET AGEPATHOGENIC POWE

40、RCapsulatedYoung children95% under 5 years oldInvasive infectionsmeningitis, pneumoniasepticemia, epiglottitistype btypesa, c, d, e, fYoung childrenAs above but rare Non capsulatedChildrenAdultsLocal infections :bronchitis, otitis,sinusitis, conjunctivitisCapsulatedPlotkin S. Vaccine, 3rd ed. 1999;

41、183-221 WHO, Position paper on Hib vaccines H. influenzae strain characteristicsHibPharyngeal colonizationBacteremiaPharynxBloodCNS LungsBactericidal response PRP capsule protection Elimination of non-capsulatedH. influenzae strainsPneumoniaMeningitisSepticemiaEpiglottitisArthritisOsteomyelitisCellu

42、litisBlood-brain barrierBorderon JC, Arch de Ped, 1995; 2(3) : 249-54Haemophilus Influenza of type B (Hib) invasiveness| 30By FOTHERGILL and WRIGHT (1932) % Meningitis Incidence Number (x104) of killedbacteria per ml of blood Incidence of Hib meningitis according to age and bactericidal activity in

43、the serum(Years)Adult123456705101520253035- 35- 30- 25- 20- 15- 10- 5- 0Susceptible period2 months5 yearsHib pathogenesis| 31Hib Schematical morphologyBacterial membrane and cell wallPlasmidintracellularextracellularcapsularpolyoside P.R.P.proteinL.P.SCAPSULE EXTERNALMEMBRANECapsuleBacterial DNAPlot

44、kin S. Vaccine, 3rd ed. 1999; 183-221 PRP = polyribosylribitol phosphate(多聚核糖基核糖醇磷酸盐)| 32Why PRP is not protective?Poor and immature response to PRP : response is T cell-independent. No efficacy in children 2 months of age Elicits memory and booster effectTTPRPPRPprotein carrierconjugate vaccine: PR

45、P-T(T-dependent response)+Tetanus ToxoidHow to transform Ag from T-independant to T-dependant| 34PRP-T: ImmunogenicityFritzell B. Immunol Med 1991; 8 : 176-183GMT (g/ml)Minimum protective level (0.15 g/ml)Long term protective level (1 g/ml)Multicenter immunogenicity studies of HIB combined with DTP-

46、IPV administered at 3-4-5 and 18 months to 412 children in Franceinjection| 35Hib vaccines widely used all over the worldAct-Hib is a WHO pre-qualified vaccine since April 19983Act-Hib was first registered on 06th February 1992 in France and is currently licensed in 103 countries4To date over 225 mi

47、llion doses were distributed5Countries where Act-HibTM is registered (as of 27/07/2011)| 37HBVHBVOPVOPVOPVDTPDTPDTPMenHBVHibHibHibPrevenarPrevenarPrevenarIPVIPVIPVThe reverse of great success of vaccine: A child will receive 18-20 doses before 2 years of age*Vaccine combination: combination of multi

48、ple antigens in the same syringe in a single administration, at one administration siteVaccine association:administration of two or more vaccines at different anatomical sites during the same medical visitThe way of reducing vaccine shotsHistory of Combination Vaccines40DTaP based pediatric combinat

49、ion vaccinesTwo or more componentsVaccine prevents multiple diseases or one disease caused by different types of the same organismCombined by the manufacturer or medical personnel prior to administration DTaPHibIPVHBOthersDTaP as the backbone on which to add:Adapted from Plotkin et al. Vaccines, 200

50、8 Pre-requisites for development of Combination VaccinesThe product must be stable for 18-24 months.Each vaccine component must be recommended to be given at the same age.Local and systemic adverse effects must be at an acceptable level.The immune response to each component must be at a protective l

51、evel.Immunologic interactions must be acceptable.The product should be simple to use.Nature of the vaccine valencesPurified proteins, toxoids, bacterial PS, protein-conjugated bacterial PS, inactivated purified whole virus, VLP, fusioned proteins, Quality and content of the additives present in the

52、vaccineAdjuvant Al salts, preservative, stabilizer, pH and osmolarity adjustersProduct presentation and pharmaceutical form (liquid or lyo)Stability of the drug product (vaccine) and of its drug substancesReady-to-inject (liquid) vaccineTo be rehydrated (lyo) vaccine (by a diluent or by another liqu

53、id vaccine)41| 42Combination vaccines: safe, effective and convenient 第4剂1215月龄第4剂第4剂第4剂18月龄第1剂第3剂6月龄第3剂第3剂5月龄第2剂第3剂第2剂第3剂4月龄第1剂第2剂第1剂第2剂3月龄第1剂第1剂2月龄第2剂1月龄第1剂0月龄第1剂出生24小时内流脑A疫苗肺炎疫苗Hib疫苗百白破疫苗脊灰疫苗（IPV)卡介苗乙肝疫苗 疫苗种类接种起始年龄DTaP-IPV-Hep B-Hib vs. Pentaxim+Engerix B(2, 4, 6 mnt +15 mnt Pentaxim booster)HEXA

54、XIM: 6 in 1 full liquid combinationHEXAXIMTetanusIPVHepatitis BPertussisDiphtheriaHib| 43Into EPIAcceleration of DTaP-IPV based Combined Vaccines in NIP and EPI 60YSplit,Sub unitIntradermalVirosome,AdjuvantLife attenuatedSanofiJ&J, GSK, NovartisPfizerSanofi, GSK,Novartis,SolvayBetter protection| 52H

55、igh doseSanofiIntra muscularIntra dermalIntra nasalDifferent Vaccines for different targetsQuadra valentSanofi,GSKMF59-adjuvanted Influenza Vaccine1.175 mg1.175 mg9.75 mgPBS0.5 mlSubunit InfluenzaANTIGENS15ug eachM. Dupuis et al. Vaccine 2000, Vol 18: 434-439An oil-in-water emulsion Squalene: obtain

56、ed from shark liver in humans as a natural metablite of cholesterol and as a normal component of cell membrane in droplets, stabilized by the addition of two emulsions: Tween 80 and Span 85 no depot effect: MF59 and antigens are cleared independently from the muscle| 53Activate dendritic cells and i

57、ncreased antigen uptake at the site of injection : MF59 Induces a significant influx of macrophagesIncrease efficiency of antigen presentation to T-cells after migration to draining lymph nodes: MF59 typically induces a T-helper 2-type immune response54Fluzone High Dose Product ProfileLicensure Lice

58、nsed in Dec 2010 in USDescription:High dose, trivalent, influenza vaccine60 g antigen (4 times the antigen load of Vaxigrip)Pre-filled 0.5 ml syringeTarget population:Adults 65 years and olderDosage and administration:Identical to standard dose (SD) influenza vaccine: 1 dose, 60 g/0.5 ml doseAdverse

59、 Events:Systemic safety and local reaction similar to current IM vaccinePain comparable to current IM vaccine Immunogenicity Profile:Superior immunogenicity profile to Fluzone IM influenza vaccineA clinical efficacy study (relative to Fluzone) being done, with expected results in 2016Fluzone HD vs.

60、Fluzone SDStudy in adults age 65 yrsDifferent Routes of Vaccine Administration via the Skin| 551。Nicolas JF, Guy B, Expert Rev Vaccines 2008;7:1201-14 9.2。Laurent A, et al. Vaccine 2007; 25: 642330. 10 .3。Lambert PH, Laurent PE, Vaccine 2008; 26:319732083.4。Nestle FO, Nickoloff BJ. J Clin Invest 200