疫苗研究中的的反向疫苗学-共66张课件

疫苗研究中的的反向疫苗学

ReverseVaccinologyinVaccineResearch疫苗研究中的的反向疫苗学

ReverseVaccinoJenner策略:模拟自然感染过程

-病原体的致病性和保护性可以分离

病原体减毒病原体灭活病原体抗原多肽交叉病原体*容易模拟

*免疫致病*免疫致敏基因临床试验反向疫苗策略\技术Rappuoli,R.,Covacci,A.Science2019;302(5645):602Jenner策略:模拟自然感染过程

-病原体的致病性和保护细菌病毒寄生虫真菌蛋白质抗原体液免疫细胞免疫YYB细胞YYYYY抗体(((ThCTLT细胞清除病原清除病原或病变细胞>1017种抗原*预防性疫苗-传染病*改变了人类疾病谱*延长了人类平均寿命*治疗性疫苗

-传染病和非传染病*可进一步改变人类疾病谱*可进一步延长寿命死亡:>>战争死亡人数

健康:活跃人群-平均寿命社会经济影响:>>战争肿瘤Tcellclone1012

TCRheterogenicity1018Self-non-selfHarmful-nonharmfulDangersignal

细菌病毒寄生虫真菌蛋白质抗原体液免疫细胞免疫YYB细胞YYY治疗性疫苗的研究策略

-疾病过程可以用抗原(表位)特异性免疫反应干预上调或下调特异性CTL

-免疫保护主要依赖细胞免疫的疾病

*慢性持续性胞内感染

*肿瘤

*自身免疫性疾病(负调疫苗)

etc诱生特异性抗体

*抗原明确的认知性疾病

etc治疗性疫苗的研究策略

-疾病过程可以用抗原(表位)特异性免疫疫苗研究中的的反向疫苗学-共66张课件BiotechMedicinesinDevelopment

ProductCategory19891993201920192000

AngiogenesisInhibitor----------------6Antisense--------599CellularTherapy------------2016ClottingFactors2133----CSFs76533Erythropoitins41133GeneTherapy----1173825GrowthFactors29112117hGH34755Interferons1211111212Interleukins12101396McAb2550717485(59)RecHumanProteins356814RecSolubleReceptor22664Signalling------------34Vaccines1320407798Others1023455383Total95143234350369BiotechMedicinesinDeve现代生命科学的一个重要特点在于：

实验数据的急速和海量积累计算机运算速度:18个月增长一倍

DNA序列数据:14个月增长一倍现代生命科学的一个重要特点在于：

实验数据的急速和海量积累疫苗研究中的的反向疫苗学-共66张课件Immunoinformatics—thenewkidintown免疫学是一门复杂科学：

*immunesystemcomponents:e.g.immunoglobulins,lymphocytereceptors,or

cytokines,…

*thecomplexityoftheregulatorypathways

*network-typeinteractions

目前获得的数据只是一小部分，数据在指数增长

Computationalanalysishasthereforebecomean

essentialelementof

immunologyresearchwitha

mainroleofimmunoinformaticsbeingthe

managementandanalysisofimmunological

data

Immunoinformatics—thenewkid生物信息学－

正在改变整个生物医学的研究模式Biologyinthe21stcenturyisbeingtransformedfromapurelylab-basedsciencetoaninformationscienceaswell.(Nature,2019)“那种倾毕业精力研究一个基因、一条代谢途径、一种生理周期的时代已经过去。还会有学者这么做，但他们将只代表一种研究风格，而不再是学术主流。”生物信息学－

正在改变整个生物医学的研究模式Biology

DatabaseInsilicoexperimentTargetedexperimentDatawarehousingprovidesaframeworkforthisprocesswu,2019DatabaseInsilImmunoinformatics—thenewkidintown进一步的数据分析，是将免疫学问题转变为计算机（模型）问题，通过解决计算问题解读出生物学意义

immunoinformatics的基础：

immunologicaldatabases

sequenceanalysis

structuremodelling

mathematicalmodellingoftheimmunesystem

simulationoflaboratoryexperiments

statisticalsupportforimmunological

experimentation

andimmunogenomics.

Immunoinformatics—thenewkid候选基因预测抗原处理与

MHC亲和力候选多肽MHC结合实验证实抗原呈递自身免疫抗原处理预防实验癌症病人

重复正常志愿者细胞毒T细胞库谱免疫反应A2TgmiceCK分析Tetramer治疗实验确定肿瘤抗原临床试验*确定天然抗原的天然表位*天然表位在疾病过程中的作用

*如何克服对天然抗原的免疫耐受

*如何考虑疫苗组分(含改造天然表位)

*如何启动表位特异性反应FromReverseBiologytoReverseVaccinology候选基因预测抗原处理与

MHC亲和力候选多肽MHC结合实验证一、确定天然抗原的天然表位:

-预测:免疫信息学方法/新的预测方法

-探测:新的实验技术二、天然表位在疾病过程中的作用

-免疫病理学研究

表位特异性反应在疾病过程中的作用如:病毒清除/肝损害三、如何克服对天然抗原的免疫耐受

-“天然抗原加倍”失败

“通过模拟抗原(mimogen)克服对天然抗原(antigen)的耐受”四、如何考虑疫苗组分(含改造天然表位)

-CTL表位的异质性与分类

-天然表位的缺陷与改造(APL)五、如何启动表位特异性反应

-mimogen的设计

-Th1极化佐剂

_递送系统一、确定天然抗原的天然表位:

-预测:免疫信息学方法确定天然抗原的天然表位1.新的表位预测方法1.B-cellepitope:

antigeicityindex-WuY,etal.ChiSciBull2019;40(9):7612.Thelpercellepitope:

5-aatemplate-WuY,etal.ImmunolJ1993;9(2):137

electropologicaldescriptor–LinZ,etalLettPeptSci2019;9(6):273

3.CTLepitope:

-molecularsimulation-GengM,etal.ChinSciBull

2019;48(18):1962

-3D-QSAR–LinZ,etal.JComputbiol

2019;11(4):683

-moleculardynamics-(submitted)

-SCORE-(submitted)确定天然抗原的天然表位1.新的表位预测方法1.B-cell疫苗研究中的的反向疫苗学-共66张课件Thcellepitopeprediction-electropologicaldescriptorζ=(ζ1,ζ2,ζ3,ζ4,ζ5,ζ6,ζ7,ζ8,ζ9,ζ10)(1.6)Thcellepitopeprediction-elSample:EkRestrictedThepitope:LTALGAILKKK

ζ=(0.7338,0.2322,0.0546,0.0335,0.0317,0.0274,0.0620,0.0530,0.0442,0.0053)

Interactionbetweentheneighboraminoacidresidues：L-T、T-A、A-L、L-G、

G-A、A-I、I-L、L-K、K-K、K-K

Interactionamongaminoacidswithoneaminoacidresidueinterval：L-A、T-

L、A-G、L-A、G-I、A-L、I-K、L-K、K-KSample:EkRestrictedThepitoy=0.9114-0.9457ζ2+1.4313ζ3-3.6876ζ7-9.9270ζ8+24.1798ζ10(1.9)Examination:byrandomsamplingy=0.9114-0.9457ζ2+1.4313ζ3-3.NoYexpYallYpredNoYexpYallYpred1＋＋＋15－－－2＋＋＋16－－－*3＋＋＋17－－－4＋＋＋*18－－－5＋＋＋19－－－6＋－－20－－－*7＋＋＋21－－－8＋＋＋*22－－－9＋＋＋23－－－10＋＋＋24－＋＋*11＋＋＋25－－－12＋＋＋*26－－－13＋＋＋27－－－14＋＋＋28－－－*NoYexpYallYpredNoYexpYallYpredHLA-A2-MAGE-2112-120complexYellowband:α1domain&α2domainofHLA-A2Blueband:β2microglobulinCTLepitopeprediction-MolecularsimulationHLA-A2-MAGE-2112-120complexCT

ThepredictedfittingandbindingsitesofdifferentMage-2sequencestotheHLA-A*0201SequenceDistance(P2-P9)H-bondsNon-boundenergySovent

accessiblearea(Å2)P2P9MAGE-2（112-120）KMEELVHFL19.877-18082.11.2(0.63%)0(0%)MAGE-2(171-179)PISHLYILV17.847-18193..20.89(5.1%）0(0%)MAGE-2(220-228)KIWEELSML18.735-18513..20(0%)4.8(2.8%)MAGE-2(271-279)FLWGPRALI17.926-18080..93.3(2.1%)1.6(0.9%)Thepredictedfittingandbin

ThepredictedfittingandbindingsitesofdifferentMZ2-DsequencestotheHLA-A*0201

PeptideH-bondsSoventaccessibleareaineachresidue(Å2)Numberofatomiccontacts

P1P2P3P4P5P6P7P8P9P2P9

M184.550.4712.68142.89164.1926.5427.1464.570.47

933

M2915.080.4714.2079.46119.2927.7337.9429.782.10933

M3815.620.4714.3984.04108.9417.1127.3348.392.57941

M41240.462.8732.8040.24107.4531.3936.6655.164.82922

Thepredictedfittingandbin

CTLepitopebindstothecleftofHLA-0201CTLepitopeprediction-QSARCTLepitopeprediction-疫苗研究中的的反向疫苗学-共66张课件KIFGSLAFLwithpIC50(exp)=7.478

pIC50(cal)=4.5945+(0.002×102.78)+…+(-0.00760×154.35)

+(0.4898×0.53)+…+(-1.2287×0.10)=7.444Example:pIC50=a0+(b1×ISA1+…+b9×ISA9)+(c1×ECI1+…+c9×ECI9)

KIFGSLAFLwithpIC50(exp)=7.4NoPeptide(origin)SequenceFIapIC50scorebscorec1TRAG-3(37-45)HACWPAFTV0.615.5504-23.554.712TRAG-3(4-12)GLIQLVEGV1.027.2677-22.2812.883TRAG-3(58-66)ILLRDAGLV1.807.6175-19.85100.044TRAG-3(57-65)SILLRDAGL1.097.4092-23.258.605MAGE-2(112-120)KMVELVHFL0.896.9395-21.77115.936MAGE-2(171-179)PISHLYILV0.956.9954-21.7925.987MAGE-2(220-228)KIWEELSML1.618.0233-21.1835.458MAGE-2(271-279)FLWGPRALI1.447.8897-19.87105.889MAGE-3(108-116)ALSRKVAEL1.107.1581-22.04194.3210MAGE-3(174-182)HLYIFATCL1.087.0691-21.30128.3911MAGE-3(201-209)LLIIVLAII1.127.1739-22.521.1812MAGE-3(271-279)FLWGPRALV1.908.1336-19.47968.4313NY-BR-1(167-175)MLLQQNVDV1.6448.1177-19.58307.9814NY-BR-1(1043-1051)YLLHENCML1.2837.3216-20.20100.3215NY-BR-1(1274-1282)NMWLQQQLV1.0566.9159-19.74358.11ComparisonofFIandpIC50inaseriesofCTLepitopesintumorantigens

NoPeptide(origin)SequenceFIapICTLepitopeprediction-SCORE

K0c1c2c3c4c5c6statistics3.402-0.1350.1000.2210.5260.988-0.129Standardcoefficients0-0.6770.2830.3310.8840.911-0.564CTLepitopeprediction-SCORECTLepitopeprediction–moleculardockingCTLepitopeprediction–molecuMeleculardocking:CTLepitopewithinTaxproteinofHtlv-1toHLA-I)Meleculardocking:PocketA

(CEA691)PocketA

(CEA691Y1)PocketA(CEA691)PocketA(CEA疏水相互作用：弱较强氢键作用网络：/N末端强大的氢键作用网络共轭π键：/Trp167与P1P2SAS：1.40Å2

0.93Å2

pIC50：6.52

7.15CEA691CEA691Y1ETotal：

-112.3kcal·mol-1

-138.6kcal·mol-1与MHCI类分子的亲和力CEA691<CEA691Y1药物疏水相互作用：弱BenefitsfromImmunoinformatics-Canreducethetimeandeffortinvolvedinscreening

potentialT-cellepitopesbyapproximately10-to20-fold

-ProteinscanbescannedandinvitroT-cellconfirmation

canbeobtainedinamatterofweeks,insteadofyearsForexample,EpiVaxandtheTB/HIVResearchLaboratorycompletedthemappingofHLAB*07

epitopesintheWNVgenomein10weeksBenefitsfromImmunoinformatic

Internet-accessibleclassI-restrictedT-cellepitopemappingtools

Ctlpre

3/MoleculardynamicsJCB2019

Internet-accessibleclassI-rInternetprogramsforthepredictionofantigenprocessingProgram

PredictionofAddressPROTAPMHC

BIMAS+www-bimas.dcrt.nih.

gov/molbio/hla_bindHLAligand+MAPPP++mpiib-

berlin.mpg.de/MAPPPMHC-pathway+++mhc-pathwayMHCPred+jenner.ac.uk/MHCPred

NetChop+cbs.dtu.dk/services/NetChopNetMHC+cbs.dtu.dk/services/NetMHCPAPROC+paproc.dePREDEP+bioinfo.md.huji.ac.il/marg/Teppred/mhc-bindProPred-I++imtech.res.in/raghava/propred1/index.htmlRANKPEP++/Tools/rankpep.htmlSVMHC+sbc.su.se/svmhc/new.cgiSYFPEITHI+syfpeithi.de

Internetprogramsforthepred2.表位新的探测方法超抗原表位新的探测方法-合成

肽加用辅助分子

[HuW,etal.InfectImmun,2019,66(10):4971-

4975]

短肽共价键包被技术

[WuY,etal.ImmunolJ,2019;10(3):88-93]短肽免疫斑点杂交检测法

[WuY,etal.ImmunolJ,2019;10(1):17-21]

yeast-display

[LiangYF,etal.ClinChem2019;51(8):1382-96]2.表位新的探测方法超抗原表位新的探测方法-合成

ClinCanRes：2019;9(5):1850CellRes2019；11(3)：203JVirol

2019;749(9):5568InterJCancer2019;107（1）：167ChinSciBull2019;48(18):1962InfectImmun2019;66(10):4971ImmunolInvest2019;25:405……

Identicationofnovelepitopesandmimotopes

[altogether>55epitopes]Viralantigens:HBV,HRV,Sars-Cov,RV

Tumorantigens:MAGE-2,MAGE-3,MAGE-1,

TRAG-3,NY-BR-1,CML28,etcClinCanRes：2019;9(5):1850天然表位在疾病过程中的作用*病人为对象:如急性\慢性\恢复期乙型肝炎病人

肝损害\病毒载量

*表位特异性细胞免疫反应:

如:Tetramer

EliSpot,ICC,51Crrelease,Facs,

proliferation,differentiation,activation,polarization天然表位在疾病过程中的作用*病人为对象:如急性\慢性\恢复期Thereweremoreperforinpositivecells(mainlybystandTcells)inpatientswithhighlevelofALT

thaninthepatientwithlowlevelofALT.Pt4

ALTh

Alco

DNA0Pt3

ALTh

DNAhPt5ALTh

DNALPt5RALTLDNALThefrequencyofperforinpositivecelloutoflymphocytesincirculation(directexvivo)Thereweremoreperforinposit表位存在异质性[ImmunolLett2019;92:253-258]

[Gastroenterol2019，Submitted]

可以象抗体识别表位类似分类:

优势保护性、非优势保护性

优势非保护性、非优势非保护性

存在优势保护性非溶破性表位

[JVirol,2019，79(9):5568-5576]表位存在异质性[ImmunolLett2019;92:实验证实非溶破性CTL表位

RankpositionlengthsequencescorewithBIMASscorewithSYFPEITHI

187-959SYVNTNMGL5760262117-12610EYLVSFGVWI400023

3131-1399AYRPPNAPI2880234131-14010AYRPPNAPIL345620

ResultsofpredictionofpotentialCTLepitoperestrictedwithH-2Kd实验证实非溶破性CTL表位

Rankposition疫苗主分的考虑（表位）预防性治疗性优势性优势性

保护性保护性保守性保守性长期记忆长期记忆?

非溶破性

APL疫苗主分的考虑（表位）预防性三、如何克服对天然抗原的免疫耐受

1.Strategy:

“通过模拟抗原(mimogen)克服对天然抗原

(antigen)的耐受”AntigenEpitope

EpitopeAntigen(mimogen?)2.Challengeinscience:

reverseimmunology3.Challengeintechnology:

antigenengineering三、如何克服对天然抗原的免疫耐受

1.Strategy:

Epitope-basedvaccinedesign(EBVD)ImmunoinformaticsproteoimcscandidateAgepitopemappingimmunopathologyCandidateepitopesAPLMimetics…AntigenengineeringSynthesis

&

purificationScreening

invitro

invivo

inpatient’sDeliverysystem

CandidatevaccineClinicaltrial[WuY,etal.TheImmunologist2019,9(S):985-989][WuY,etal.ActaAcademiaeMedicinaeMilitaryTertiae.2000;20:917-918]

Epitope-basedvaccinedesign(ERecognitionofepitope

(A)

epitopepeptideisusuallymuchlonggerinpMHCIIthaninpMHCI(13~25vs8-10)

peptidesinallMHCIhavetheirN-andC-terminianchoredintotwosimilarpoketsofMHCI,span20Ă

longerpeptidebulgeoutinthemiddle

peptideinpMHCII:smooth/cnacvedawayfromTCR/bettershapecompelementarity/twiceinatomiccontacts/additionalcontactslargelyaccountedforbypMHCIIratherthanTCR-MHCII

(B)

Murine

Human

(MolecularImmunology38,2019:1039)Recognitionofepitope

(A)

epi疫苗研究中的的反向疫苗学-共66张课件TRP-2WTSVYDFFVWL-20.73471.177.401TRP-21YYVYDFFVWL-19.80471.177.704TRP-22LSLYDFFVWL-19.798054.547.953TRP-22MSMYDFFVWL-19.484610.647.852

TRP-21Y2LYLYDFFVWL-18.868054.548.256TRP-21Y2MYMYDFFVWL-18.554610.648.149a:polynomialmethod;b:quantitativemotifmethodc:QSAR

APLsSequenceScoreaScorebScorecImmunoinformatics-APLforTCRTRP-2WTSVYDFFVWL-TRP-2WTSVYDFFVWL0.351.32TRP-22LSLYDFFVWL0.082.49TRP-22MSMYDFFVWL0.132.15TRP-21Y2LYLYDFFVWL0.041.45TRP-21Y2MYMYDFFVWL0.191.82HBV(18-27)FLPSDFFPSV0.192.00APLsSequenceFIa/H-2KbFI/HLA-A2.1OVA(257-264)SIINFEKL3.080.10AffinityofpeptidestoHLA-A2.1orH-2Kbmolecules

TRP-2WTSVYDFFVWL0.351.32TRPComparisonofthestabilityofthecomplexofTRP-2(180-188)

wildpeptideorAPLswithHLA-A2ComparisonofthestabilityofAPLcouldinducemoreIFN-andgranzymeBinPBMCAPLcouldinducemoreIFN-anAPCtargeting&enhanceantigenuptakeEnhancementoftranscription&translationEnhanceAgdeliverytoproteasomeMHC-PassemblyinER&transporttothecellsurface

RecognitionTargetingprotforcellmembrancedisplayorsecretionUpregulationofMHCI如何在体诱导Th1/CTL反应?APCtargeting&enhanceantige抗原颗粒化-表位噬菌体展示HBV的Phage-displayedparticle

-Vaccine2019;19:2918肿瘤的Phage-displayedparticle

-InterJCancer2019;98:748HBV的ISCOMs

-WorldJournalastroenterology2019;8:294抗原颗粒化-表位噬菌体展示HBV的Phage-displa抗原颗粒化-模拟病毒研究HBV的mimovirusLiuH,etal.ImmunolLett2019,89:167肿瘤的mimovirus

WuY,etal.JVirol2019;76(20):10264抗原颗粒化-模拟病毒研究HBV的LiuH,etal.3.抗原颗粒化-转基因植物口服疫苗轮状病毒转基因口服疫苗

LiJ,etal.Virology2019；313:337-3453.抗原颗粒化-转基因植物口服疫苗轮状病毒转基因口服疫苗

抗原颗粒化-Semilikiforestvirus-basedtumorvaccineNiB,etal.Inductionofspecifichumanprimaryimmune

responsetoaSemilikiforestvirus-basedtumorvaccinein

atrimeramousemodel.

CancerImmunolImmunother2019;54(5):489-98NiB,etal.InductionofP815TumorImmunitybyDNA-BasedRecombinantSemlikiForestVirusor

RepliconDNAExpressingtheP1AGene.

CancerDetect

Prev2019;28(6):418-425

NiB,etal.InductionofP815TumorImmunitybyDNA-BasedRecombinantSemlikiForestVirusor

RepliconDNAExpressingtheP1AGene.

CancerDetect

Prev2019;28(6):418-425

抗原颗粒化-Semilikiforestvirus-baImmunoinformatics-mimogenforHBVKindsofepitopeRefinedepitopeNumberofepitopePermutationandcombinationofepitopesUnderphase-II-IIIclinicaltrial国际上第一个模拟抗原疫苗

国内第一个CTL疫苗

国内第一个多肽疫苗

国内第一个脂质体疫苗Immunoinformatics-mimogenfor颗粒(抗原)疫苗的呈递机理

-ER靶向抗原交叉呈递特征和机制

■：OVA257-264-KDEL□：OVA257-264●：OVA257-264-TEWTEurJImmunol

2019；34(12):3582-95颗粒(抗原)疫苗的呈递机理

-ER靶向抗原交叉呈递特征和颗粒(抗原)疫苗的呈递机理

Thesedatasuggestthatendocytosedphageparticlesmaybeprocessedandcross-presentedinorganellespositiveforphagosomeandendoplasmicreticulum(ER)markersviaaclassicalERMHCclassIloadingmechanism.EurJImmunol2019;35(7):2041-50颗粒(抗原)疫苗的呈递机理

ThesedatasuggeVaccine[+免疫调节]SongJ,etal.SustainedSurvivinExpressionfromOX40CostimulatorySignalsDrivesTCellClonalExpansion.

Immunity

2019;22:621–31JiaZ,etal.Effectiveinductionofanti-tumorimmunitybyimmunizationwithplasmidDNAencodingTRP-2plusmeutralizingofTGF-betta,CancerImmunolImmunother2019;54(5):446-52

ChenY,etal.Cross-talkbetweencomplementsystemandTcellsthroughB7-H1onhumanrenaltubularepithelialcellsininflammation.JCI2019(submitted)Vaccine[+免疫调节]SongJ,etal.S在SCI收录期刊发表主要论著目录

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