醫(yī)學(xué)英語課件資料：The Future of Vaccines

1、The Future of VaccinesWhere we are today- Under 5 Mortality3Global distribution of the relative risk of an EID eventZoonotic from wild-life Zoonotic non wildlifeDrug resistant pathogens Vector borne pathogensJones et al Nature 451, 2008The common characteristics of EID Most of them were zoonotic ori

2、gins; Most of the agents belonged to viruses; These viruses have not become established in humans; RNA viruses occupied large proportion;Specific drugs, diagnostic kits or vaccines are not available. 4The most important EIDs in the first decade of the 21st centurySARS2003S. ChinaHPAI H5N11996-NowS.

3、ChinaH1N1/20092009MexicoMERS2012Saudi ArabiaH7N92013E. ChinaEbola2014W. Africa5Influenza ecosystem in ChinaMa C et al, JVI, 2015Virus Emergence & Reassortment7Poultry gene pool(farms & markets)Domestic ducksGene pool interfaceNatural gene pool (migratory ducks) Chicken & other poultry2002 2015+Incre

4、ased Demands for VaccinesMajor worldwide infectious diseasesHIV, TB, MalariaBioterrorism threatsSmallpox, plague, anthraxEmerging infectious diseasesWest Nile Virus, Ebola, SARS, pandemic flu,.Improved versions of existing vaccinesFlu, hCMV, Novel applications of vaccine approachCancer, Animal vacci

5、nesFoot and Mouth Disease, equine flu.Immunity against pathogensNative immunity (non-specific) like leucocyte eating pathogens and lacto-ferrin interfering nutrition process of pathogenAcquired immunity (specific ) antibody cell-mediated immunityHow can a host get specific immunityImmunity obtained

6、after infection ( in most case the infection is a process without symptoms)Immunity obtained through artificial procedure to pass immune substance like antibodyImmunity obtained through vaccinationCurrently available vaccinesInactivated vaccineAttenuated vaccineSubunit vaccineVaccine made from toxin

7、s and/or other acelluar components of pathogensRecombinant vaccineInactivated vaccineKilled pathogens through heating or chemical procedureThe strengthens of inactivated vaccine: safe low cost and easy to operate The weakness of inactivated vaccine: poor stimulation to Cell-medicated ImmunityAttenua

8、ted vaccineLiving pathogens with low virulence through long term multiplication like BCG or in vitro technologyStrengthens of attenuated vaccine:Effective stimulation to Cell-medicated Immunity and induction of surface immunityWeakness of attenuated vaccine: High cost in terms of production and cold

9、 chain Potential risk for immunocompromised individuals and retro-mutationSplit vaccinesThe most feasible product is split vaccine for prevention of influenza infectionThe product is not very different from inactivated vaccine but delete components which are not essential for immunity induction and/

10、or responsible for adverse events (AE)Toxoid vaccine Toxoid vaccine is made by de-toxication of bacterial toxins like tantenus toxoid and diphtheria toxoidStrengthens of toxoid vaccine: safe, and good efficacy to induce antibodyWeakness of toxoid vaccine: poor immune memory Recombinant vaccineCompon

11、ent of pathogen created through recombinant technology like HBsAg expressed by yeast vectorStrengthens of recombinant vaccine: safe, easy to deliverWeakness of recombinant vaccine: insufficient immunogenicity, high cost in R/D and production Vaccines: examples of challengeOct. 22, 1999: use of the o

12、ld Rota vaccine no longer recommended due to safety concernJan. 1, 2000: exclusive use of inactivated polio vaccine in USFlu vaccine: shortages in 2000-01 seasons but large doses return unused in 2001-02. But again, major supply shortage in 2004-05 season.Oct, 2008: failure of Mercks HIV vaccine tri

13、al (increased infection in vaccinees).demand for future vaccineSafe (increasingly higher standard)Antibody protection alone is not enough (new knowledge from cell mediated immunity)Low cost and stableFlexible and easy to modifyWhat are needed:Innovative thinking (empirical vs. scientifically approac

14、hes)Non-conventional strategy (out of delivery based system)New technology (gene vaccine, pseudovirus particle and new adjuvant)A delivery method-centered approach is no longer sufficient for vaccine discoveryLive attenuated vaccines (OPV)Why does it work very well? Inactivated vaccines (flu)Why doe

15、s it not work very well? Or even high AE?Subunit vaccines (HBV, HPV)Why does conformation matter and why adjuvants? Polysaccharide and conjugated vaccinesHow to develop antibody against non-protein antigensGene-based vaccines (DNA, viral vector)How to balance Ab and CMI responsesImmunology will be m

16、ore integrated into vaccinology in the 21st centuryTradition statement 1vaccine = immune protectionTradition statement 2vaccine is an empirical scienceCritical question:Can we make vaccine discovery a more rational design process based on the induction of protective immune responses?Significant prog

17、ress in the last 10 yearsT cell mediated protection induced by vaccinesTypes of T cell responses (cytokine profile) Th1 vs. Th2From Antibody to B cellsChallenges to measure B cells directlyBottleneck: Ag specificity & phenotypic markers New ways of measuring AbFunctional antibodiesIn vitro NAb = in

18、vitro protection? Current model of B-cell differentiationAging and response to vaccineInter-vaccine differenceIndividual differenceVaccination-delivering related differenceUnderlying diseases may have negative impacts on the vaccination responseGut flora, a potential pathway to solve the problem?Ant

19、ibody titers against Vaccinia WRAmannao, 2007. NEJMAntibody titers against varicella-zoster virus Rod strainAntibody titers against Tetanus toxin C-fragmentAntibody titers against diphtheria toxinAdjuvants （佐劑）Discovery of Toll-like receptors (TLR)revolutionized the adjuvant researchFurther explore

20、innate immunityAccelerated research on new adjuvantTry to differentiate adjuvant effects to adverse eventsAdjuvants enhance the protection provided by vaccinesPulendran B, Ahmed A. Cell 2006; 124:849-863Antigen onlyTimeAntigen + adjuvantImmune responseCategories of AdjuvantsBruno, 2007. Nature Micro

21、biology103104105106107Adjuvant groupsV-specific IgG titersAdjuvant groupsV-specific antibody (mg/ml)Adjuvant effect of synthetic monophosphate lipid (MPL),a potent TLR-4 ligandRecombinant V protein of Y. pestis (plague)C57BL/6 mice Antigen processing and presentationPreviously ignored in vaccine fie

22、ldCritical for gene-based vaccinesAntigen engineering becomes criticalGag-expressing DNA vaccine constructsAntigen identification and optimizationReverse vaccinologyMenB vaccine: based on protein, not sugarBioinformatics approach to narrow down the selectionMore to come (e.g. vaccines against MRSA,

23、plague.)DNA vaccine is a great toolAntigen optimizationAntigen natural conformation (in pathogens)Antigen post-translational processingAntigen in vitro productionAntigen formulationIntegratted Immunology for Vaccine R/DTo determine the roles of T cell immunityCausal relationship to protection?What a

24、re more predictable biomarkers?A new look at B cell immunologyLong term memory is keyRe-define functional antibodies Re-emerging interest in adjuvantExplosive grow in the next few yearsAvoid surprise of adverse events!New thinking leads to new breakthroughAntigen processing, prime-boost and antigen selectionInequitable burden of diseaseA Call for the Decade of Vaccines3916 September 2022Call to donors, g