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Vaccine development!

Immune system overview in 10 minutes The non-immunologist guide to the immune system Morten Nielsen Department of Systems Biology DTU. Vaccine development!.

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Vaccine development!

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  1. Immune system overview in 10 minutesThe non-immunologist guide to the immune systemMorten NielsenDepartment of Systems BiologyDTU

  2. Vaccine development! The arm of Sarah Nelmes, a dairy maid, who had contracted cowpox. Jenner used material from her arm to vaccinate an eight year old boy, James Phipps. (1798).

  3. Vaccine review

  4. Vaccines can eradicate pathogens and save lives

  5. Vaccines have been made for 36 of >400 human pathogens +HPV & Rotavirus Immunological Bioinformatics, The MIT press.

  6. Immune system • Innate – fast… • Addaptive – remembers… • Cellular • Cytotoxic T lymphocytes (CTL) • Helper T lymphocytes (HTL) • Humoral • B lymphocytes Epitopes Figure by Eric A.J. Reits

  7. MHC Class I pathway Figure by Eric A.J. Reits

  8. MHC-I molecules present peptides on the surface of most cells Figure courtesy Mette Voldby Larsen

  9. CTL response Figure courtesy Mette Voldby Larsen

  10. Encounter with death

  11. Figure by Anne Mølgaard

  12. HLA binding motif SLLPAIVEL YLLPAIVHI TLWVDPYEV GLVPFLVSV KLLEPVLLL LLDVPTAAV LLDVPTAAV LLDVPTAAV LLDVPTAAV VLFRGGPRG MVDGTLLLL YMNGTMSQV MLLSVPLLL SLLGLLVEV ALLPPINIL TLIKIQHTL HLIDYLVTS ILAPPVVKL ALFPQLVIL GILGFVFTL STNRQSGRQ GLDVLTAKV RILGAVAKV QVCERIPTI ILFGHENRV ILMEHIHKL ILDQKINEV SLAGGIIGV LLIENVASL FLLWATAEA SLPDFGISY KKREEAPSL LERPGGNEI ALSNLEVKL ALNELLQHV DLERKVESL FLGENISNF ALSDHHIYL GLSEFTEYL STAPPAHGV PLDGEYFTL GVLVGVALI RTLDKVLEV HLSTAFARV RLDSYVRSL YMNGTMSQV GILGFVFTL ILKEPVHGV ILGFVFTLT LLFGYPVYV GLSPTVWLS WLSLLVPFV FLPSDFFPS CLGGLLTMV FIAGNSAYE KLGEFYNQM KLVALGINA DLMGYIPLV RLVTLKDIV MLLAVLYCL AAGIGILTV YLEPGPVTA LLDGTATLR ITDQVPFSV KTWGQYWQV TITDQVPFS AFHHVAREL YLNKIQNSL MMRKLAILS AIMDKNIIL IMDKNIILK SMVGNWAKV SLLAPGAKQ KIFGSLAFL ELVSEFSRM KLTPLCVTL VLYRYGSFS YIGEVLVSV CINGVCWTV VMNILLQYV ILTVILGVL KVLEYVIKV FLWGPRALV GLSRYVARL FLLTRILTI HLGNVKYLV GIAGGLALL GLQDCTMLV TGAPVTYST VIYQYMDDL VLPDVFIRC VLPDVFIRC AVGIGIAVV LVVLGLLAV ALGLGLLPV GIGIGVLAA GAGIGVAVL IAGIGILAI LIVIGILIL LAGIGLIAA VDGIGILTI GAGIGVLTA AAGIGIIQI QAGIGILLA KARDPHSGH KACDPHSGH ACDPHSGHF SLYNTVATL RGPGRAFVT NLVPMVATV GLHCYEQLV PLKQHFQIV AVFDRKSDA LLDFVRFMG VLVKSPNHV GLAPPQHLI LLGRNSFEV PLTFGWCYK VLEWRFDSR TLNAWVKVV GLCTLVAML FIDSYICQV IISAVVGIL VMAGVGSPY LLWTLVVLL SVRDRLARL LLMDCSGSI CLTSTVQLV VLHDDLLEA LMWITQCFL SLLMWITQC QLSLLMWIT LLGATCMFV RLTRFLSRV YMDGTMSQV FLTPKKLQC ISNDVCAQV VKTDGNPPE SVYDFFVWL FLYGALLLA VLFSSDFRI LMWAKIGPV SLLLELEEV SLSRFSWGA YTAFTIPSI RLMKQDFSV RLPRIFCSC FLWGPRAYA RLLQETELV SLFEGIDFY SLDQSVVEL RLNMFTPYI NMFTPYIGV LMIIPLINV TLFIGSHVV SLVIVTTFV VLQWASLAV ILAKFLHWL STAPPHVNV LLLLTVLTV VVLGVVFGI ILHNGAYSL MIMVKCWMI MLGTHTMEV MLGTHTMEV SLADTNSLA LLWAARPRL GVALQTMKQ GLYDGMEHL KMVELVHFL YLQLVFGIE MLMAQEALA LMAQEALAF VYDGREHTV YLSGANLNL RMFPNAPYL EAAGIGILT TLDSQVMSL STPPPGTRV KVAELVHFL IMIGVLVGV ALCRWGLLL LLFAGVQCQ VLLCESTAV YLSTAFARV YLLEMLWRL SLDDYNHLV RTLDKVLEV GLPVEYLQV KLIANNTRV FIYAGSLSA KLVANNTRL FLDEFMEGV ALQPGTALL VLDGLDVLL SLYSFPEPE ALYVDSLFF SLLQHLIGL ELTLGEFLK MINAYLDKL AAGIGILTV FLPSDFFPS SVRDRLARL SLREWLLRI LLSAWILTA AAGIGILTV AVPDEIPPL FAYDGKDYI AAGIGILTV FLPSDFFPS AAGIGILTV FLPSDFFPS AAGIGILTV FLWGPRALV ETVSEQSNV ITLWQRPLV

  13. Sequence logos • Height of a column equal to I • Relative height of a letter is p • Highly useful tool to visualize sequence motifs HLA-A0201 High information positions http://www.cbs.dtu.dk/biotools/Seq2Logo

  14. HLA polymorphism

  15. HLA specificity clustering A0201 A0206 A0101 B0702

  16. More MHC molecules: more diversity in the presented peptides • 1% probability that MHC molecule presents a peptide • Different hosts sample different peptides from same pathogen.

  17. Pathogen variability • Pathogen variability • Millions of viral particles within a given host • Pathogen diversity • Different viral subtypes circulating in different parts of the world

  18. HIV subtypes (Gag protein) C AE B A D

  19. Epitope identification 56 (1.5%) 9mer are conserved among all 15 Clade A gag sequences

  20. Viralescape/variation The virus of today is different from the virus of tomorrow (Viral escape) ??? ?? ???? Figure courtesy Mette Voldby Larsen

  21. Vaccine design. Polytope construction Linker NH2 M COOH Epitope cleavage C-terminal cleavage New epitopes Cleavage within epitopes

  22. DNA vaccine

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