Extremely rapid h7 n9 vaccine design by epivax

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Extremely rapid h7 n9 vaccine design by epivax

  1. 1. Extremely  Rapid  H7N9  Immunogenicity   Analysis  and  Vaccine  Design   April  13  2013  Annie  De  Groot  M.D.    CEO/CSO  www.epvax.com       1  
  2. 2. Adapted  from  a  Presenta?on  to  NIAID   Universal  Flu  Vaccines:  Now  More  than  Ever   EpiVax  has  a  flu  SBIR  that  was  scored  and  we  are  wai?ng  for  a  decision  about  funding  21  March  2013  Presented  by  Annie  De  Groot  MD    to  Rachelle    Salomon,  NIH,  NIAID,  DMID  EpiVax:  Lenny  Moise,  Frances  Terry,  Bill  MarMn  Mindy  Cote,  Ryan  Tassone,  Howie  LaMmer  Lauren  Levitz,  ChrisMne  Boyle  VGTI:  Ted  Ross   2  
  3. 3. Emergent  H7N9  disease  in  China  
  4. 4. The  Problem:  Ongoing  Transmission   H7N9%Cases%and%Deaths%/%WHO%Report% As  of  4/12/2013   50# 70%# 45# 60%# 40# 35# 50%# 30# 40%# 25# 20# 30%# 15# 20%# 10# 10%# 5# 0# 0%# 1+Apr# 3+Apr# 4+Apr# 5+Apr# 6+Apr# 7+Apr# 8+Apr# 9+Apr# 10+Apr# 11+Apr# AVERAGE# Total#Cases# Total#Deaths# New#Cases/Day# Mortality#Rate# hRp://www.who.int/csr/don/2013_04_12/en/index.html   hRp://pandemicinformaMonnews.blogspot.com   hRp://crofsblogs.typepad.com  
  5. 5. WHO  Report  Graph   This  picture   shows  the   geographically   wide  distribuMon   of  flu  cases  -­‐   suggesMng   widespread   distribuMon  of  the   virus  rather  than   a  point  outbreak.      
  6. 6. Time  to  consider  T  cell  epitopes?     hRp://www.ncbi.nlm.nih.gov/pmc/arMcles/PMC2936654/  
  7. 7. The "New" Flu (H1N1 2009 California)
  8. 8. 2009  Worry:  CDC  -­‐  No  Cross-­‐reacMve  Ab  •  Preliminary  studies  of  individuals  showed   that  anMbodies  induced  by  seasonal   influenza  vaccinaMon  were  not  cross-­‐ reacMve  with  novel  H1N1.  •  What  if  the  T  cell  epitopes  were  cross-­‐ reacMve?  Would  that  help?      Centers  for  Disease  Control  and  PrevenMon.  Serum  anMbody  response  to  a  novel   influenza  A  (H1N1)  virus  a`er  vaccinaMon  with  seasonal  influenza  vaccine.  MMWR   Morb  Mortal  Wkly  Rep  2009;58(19):521–4.    
  9. 9. Second  Exposure   Response  if  Exposure  or   Related  or   strain  is  VaccinaMon   Unrelated  Strain   idenMcal.  .  .  Or   if  cross-­‐reacMve    .  .  .  if  no   T  cell  epitopes   cross-­‐ reacMve     T  cell   response   IniMal  response  to   exposure  or   vaccinaMon  
  10. 10. EpiVax  Predicted  Cross-­‐Protec?on   hRp://www.ncbi.nlm.nih.gov/pubmed/19660593  
  11. 11. Iden?fied  immunogenic  and  conserved  Sequences  –  Predicted  Cross  Protec?on   Immunogenic Enough  Cross-­‐ T cell protecMve  Epitopes   epitopes that  Seasonal  Flu   vaccinaMon  or   exposure  may  protect   Conserved T-Cell Epitopes De Groot et al. Vaccine 2009;27:5740-7
  12. 12. Valida?on  that  cross-­‐conserved  T  cell  epitopes  are  an?genic   “Immunized”  with  Brisbane  HA  whole  Flu  vaccine  -­‐    Response  to  X-­‐Conserved  T  cell  epitopes   HA394-411 0.09 0.034 No Ag Culture Antigen 0.027 1.19 6.44 Brisbane HA CD154 IFNγ 4.7 hRp://www.ncbi.nlm.nih.gov/pmc/arMcles/PMC3130614/   Schanen et al. Vaccine 2011;29:3299-309
  13. 13. The ”Stealth" Flu (H7N9 2013 Shanghai)
  14. 14. New  Case  in  Beijing   H7N9%Cases%and%Deaths%/%WHO%Report% 60# 70%# 50# 60%# 50%# 40# 40%# 30# 30%# 20# 20%# 10# 10%# 0# 0%# # # # # # r# r# r# r# r# r# r# r# GE pr pr pr pr Ap Ap Ap Ap Ap Ap Ap Ap +A +A +A +A RA 1+ 3+ 4+ 5+ 6+ 7+ 8+ 9+ 10 11 12 13 E AV Total#Cases# Total#Deaths# New#Cases/Day# Mortality#Rate# New  Case  in  Beijing  
  15. 15. H7N9  Morbidity  and  Mortality   Quick  numbers...   •  Total  confirmed  human  cases  of  influenza   A  virus  H7N9:  49     •  Total  deaths  aRributed  to  infecMon  with   influenza  A  virus  H7N9:  11     •  Case  Fatality  Rate  (CFR):  22%     •  Average  Mme  from  illness  onset  to  first   confirmaMon  of  H7N9  (days):  10     •  Average  age  of  the  H7N9-­‐confirmed  cases   (including  deaths;  years):  60     •  Median  age  of  the  H7N9-­‐confirmed  cases   (including  deaths;  years):  65     •  Mode  age  of  the  H7N9-­‐confirmed  cases   (including  deaths;  years):  74     •  Average  age  of  the  deceased  (years):  59     •  Males:  70%  of  cases,  82%  of  deaths     hRp://pandemicinformaMonnews.blogspot.com   hRp://www.uq.edu.au/vdu/VDUInfluenza_H7N9.htm  
  16. 16. What  About  H7N9?  Novel  or  Conserved?   H7N9   CirculaMng  Flu   Very  Poor  Cross-­‐ConservaMon  –  Only  within  Internal  Proteins  
  17. 17. Which  H7N9  Proteins   Ian  Mackey  hRp://www.uq.edu.au/vdu/ VDUInfluenza_H7N9.htm  
  18. 18. Conserva?on  Analysis  H7N9  
  19. 19. Conserva?on  Analysis  H7N9  
  20. 20. This  is  a  unique  virus  •  Low  conservaMon  of  HA,  NA  surface  proteins   is  not  surprising  •  Internal  proteins  are  more  conserved  •  And  –  HA  is  has  unusually  low  immunogenicity  •  May  explain  why  infecMon  is  widespread:  •  Difficult  to  make  anMbodies  to  the  HA  
  21. 21. How  do  we  measure  Immunogenicity?     Vaccine  anMgen   epitope   epitope   epitope   1    +    1    +    1        =    Response   Immune  response  to  a  vaccine  anMgen  can  be  predicted  by  measuring   the  number  of  T  cell  epitopes  contained  in  the  anMgen  with   immunoinformaMcs  tools.    
  22. 22. “Immunogenicity  Scale”   Immunogenic   proteins   Non     Immunogenic   proteins  
  23. 23. New  H7N9  Flu  is  Predicted  to  be  POORLY  IMMUNOGENIC   -  80 - www.EpiVax.com -  70 - -  60 - -  50 - Hemagglu?nin   -  40 - A/Brisbane/59/2007(H1N1)   -  30 - -  20 - Neuraminidase   A/Perth/16/2009  (H3N2)   -  10 - Average  Epitope  Content   -  00 - (Random  Expecta?on)   A/Brisbane/59/2007(H1N1)   -  -10 - A/Shanghai/1/2013  (H7N9)   -  -20 - A/Perth/16/2009  (H3N2)   -  -30 - A/Shanghai/1/2013  (H7N9)   Immunogenicity  based  on  T   -  -40 - helper  epitope  content  per  amino   -  -50 - acid.  Performed  by  Ardito,  Terry,     De  Groot  and  MarMn,  April  2013   -  -60 - -  -70 -
  24. 24. Spread  to  Beijing  on  4/13/13   This  figure  was  published  online  at   hRp://www.epivax.com/blog/h7n9-­‐ shanghai-­‐2013-­‐the-­‐new-­‐stealth-­‐virus/     Hemagglu?nin   Neuraminidase  
  25. 25. Spread  to  Beijing  on  4/13/13  Spread  to  Henan  on  4/14/  13  
  26. 26. Poten?al  Solu?on?     As  of  4/13/2013  
  27. 27. EpiVax  Vaccine  Toolkit:  iVAX   27  
  28. 28. Fully  integrated    From  genome  to  vaccine   •  EpiMatrix – maps T cell epitopes •  ClustiMer - Promiscuous / Supertype Epitopes Seamless  Vaccine   •  BlastiMer - Avoiding “self” - autoimmunity Design   •  Conservatrix – Identifies Conserved Segments   Integrated  toolkit  is   •  EpiAssembler - Immunogenic Consensus Sequences unique  to  iVax   •  Aggregatrix – Optimizing the coverage of vaccines •  VaxCAD - Processing and Assembly 28  
  29. 29. A  beier/faster  way    to  make  flu  vaccine?     BeRer  understanding    of  vaccine  MOA   Egg-­‐based/Cell   Genome-­‐ Whole  (live/ Culture  Based   Derived,  Epitope   killed)  flu   Whole  Ag  (HA)   Driven  (GD-­‐ED)   vaccines   vaccines   Vaccines   Improve  vaccine   safety  and   efficacy   Accelerate   Vaccine  Design   Genome-­‐derived  Epitope-­‐driven  Influenza  Vaccines  (R21  /  NIAID  /  NIH  
  30. 30. T  cells  =  Immune  System  Body  Armor   T  cell  response  cannot  prevent  InfecMon  but  .  .  .     T  cell  response  can  arm  against  Disease  
  31. 31. FastVax: Vaccines on demand   Rapid  deployment   when  genome   sequence  is  in  hand     •  High throughput computing Prebuilt   •  Immunoinformatics •  Vaccine design algorithms •  Vaccine Production •  Delivery device Pilot  program     Funded  by  DARPA   •  Animal safety/tox/immunogenicity/validation •  Deployment by established distribution systems 31  
  32. 32. 20  hours  -­‐  April  05  –  April  06  2013  Extremely  Rapid  H7N9  Vaccine  Design   April  05,  2013:  Obtain  H7N9  Sequences  (4  human-­‐sourced;  GISAID)     Obtain  all  available     H7N9  sequences   EpiMatrix  Analysis:  IdenMficaMon  of  H7N9  Class  I  and  Class  II  Epitopes   Compare  with  previous  epitopes  (IEDB)   And  other  H7N9  strains;  create  final  list   20  hours  (Logged).   101  H7N9  ICS*  Class  II  Epitopes  +  586  Class  I  Epitopes       Eliminate  Epitopes     highly  conserved  with  Human   Design  vaccine:  12  hours  (Logged).   April  06,  2013:  H7N9  Vaccine:  Two  Constructs,  Class  I  and  Class  II  
  33. 33. Predic?ng  Epitopes  that  Drive   Immune  Response  is  our  Exper?se   HLA (Human MHC), are comprised of MHC II Pocket a limited number of pockets. EpiMatrix predicts how well a side chain will bind to a specific pocket. MHC II Peptide Epitope 8 class II Archetype matrices which taken together incorporate 95% of human populations (and pockets) Mature worldwide. APC Each 9-mer/10-mer is analyzed for binding potential to each of those 8 allele matrices. The  EpiMatrix  Score  describes  how  well   .Southwood et al. J. Immunology 1998 the  pepMde  “fits”  into  the  pockets  Sturniolo et al. Nature Biotechnology, 1999 EpiVax  
  34. 34. Published  Benchmark  2009  De  Groot  and  MarMn.  Reducing  risk,  improving  outcomes:  Bioengineering  less  immunogenic  protein  therapeuMcs.  Clinical  Immunology  2009.  131,  189-­‐201.  
  35. 35. Epitope  Clusters  =  Immunogenic   •  A Key Discovery – Epitopes are Clustered in Protein Sequences DRB1*0101 DRB1*0301 DRB1*0401 DRB1*0701 DRB1*0801 DRB1*1101 DRB1*1301 DRB1*1501 •  T-cell epitope clusters make excellent vaccine candidates: –  compact; relatively easy to deliver as peptides; highly reactive in-vivo 35  
  36. 36. Building  ICSs  EpiAssembler  –  Final  Immunogenic  Consensus  Sequence  STRAIN 01 Q X S W P K V E Q F W A K H X W N X I S X I Q Y LSTRAIN 02 Q A S W P K V E X F W A K H M W N F I S G I Q Y LSTRAIN 03 Q X S W P K X E Q F W A K H M W N F I S G I Q Y XSTRAIN 04 Q A S W X K V E Q F W A K H M W N F X S X I Q Y LSTRAIN 05 Q X S W P K V E Q F W A K H M W N F I S G I Q Y LSTRAIN 06 Q A S W P K X E Q F W A X H M W N F I S G I Q Y XSTRAIN 07 Q X S W P K V E Q F W A K H M X N F I S G I Q Y LSTRAIN 08 Q A S W X K V E Q F W A K H M W N F I S G I Q Y LSTRAIN 09 Q X S W P K X E Q F W A K H M W N F X S X I X Y XSTRAIN 10 Q A S W P x R V E Q F W A K H M W N F I X G I Q Y LSTRAIN 11 Q A S W P K V E Q F W A K H M W N F I S G I Q Y LSTRAIN 12 Q A S W X K V E Q F W A X H M W N F I S G I Q Y XSTRAIN 13 Q A S W P K V E Q F W A K H M W N F I S G I Q Y LSTRAIN 14 Q A S W X K X E Q F W A K H M W N F I S X I Q Y LSTRAIN 15 Q A S W P K V E X F W X K H M W N F I S G I Q Y LSTRAIN 16 Q X S W P K V E Q F W A K H M W N F I X G I Q Y LSTRAIN 17 X A S W X K V E Q F W A K H M W N F I S G I Q Y XSTRAIN 18 Q X S W P K X E Q F W A K H M W N X I S G I Q Y LSTRAIN 19 Q A S W X K V E Q F W A K H M W N F I S X I Q Y LSTRAIN 20 Q A S W P K V E Q F W A X H M W N F I S G I Q Y L F W A K H M W N F W P K V E Q F W A M W N F I S G I Q Q A S W P K V E Q N F I S G I Q Y L Q A S W P K V E Q F W A K H M W N F I S G I Q Y L
  37. 37. Building  ICSs  EpiAssembler  –  Final  Immunogenic  Consensus  Sequence   Balance  Score+Conserva?on:   Highest  conserved  epitopes   Selec?on  for  score   Best  Op?on   are  poorly  immunogenic  
  38. 38. Safer: remove conserved epitopes   Human Potentially detrimental cross- reactive epitopes Pathogen     Potentially detrimental cross- Protective reactive epitopes epitopes
  39. 39. VaxCAD  VaxCAD   will   idenMfy   juncMonal   epitopes   and   rearrange   chosen   epitopes   to   reduce   juncMonal  epitope  formaMon   39  
  40. 40. EpiMatrix Cluster Score -10 0 10 20 30 40 50 HP4117 HP4179 HP4007 HP4111 HP4018 HP4070 HP4034 HP4193 HP4065 HP4181 HP4157 HP4060 HP4068 HP4164 HP4160 HP4175 HP4127 Epitope Cluster Score HP4120 Junctional Cluster Score HP4126 HP4154 HP4168 HP4119 Peptides in Default order in construct HP_IIB HP4100 HP4001 HP4061 Create  String  of  Beads-­‐Vaccine   EpiMatrix Cluster Score -10 0 10 20 30 40 50 HP4117 HP4061 HP4181 HP4111 HP4018 HP4070 HP4060 HP4157 HP4065 HP4001 HP4193 HP4034 HP4068 HP4168 HP4160 HP4175 HP4127 Epitope Cluster Score HP4126 Junctional Cluster Score HP4007 HP4154 HP4164 HP4119 HP4100 Peptides in Optimized order in construct HP_IIB HP4120 HP417940  
  41. 41. GD-­‐IDV  FormulaMons    (plaqorm  independent)   DNA  –  chain  of  epitopes,  or   ICS-­‐opMmized  whole  proteins   ICS-­‐opMmized  proteins  in  VLP   pepMde  in  liposomes  
  42. 42. EpiVax  is  eager  to  help  •  Seasoned  Research  Team  •  Validated  Vaccine  Design  Tools  •  H7N9  Analysis/Vaccine  design  complete  •  Constructs  sent  for  producMon  •  Other  services:   –  Analyze  exisMng  H7  vaccines  for  conservaMon   –  Advise  on  vaccine  design   EpiVax  Contacts:     Anthony  Marcello,  BDA,  amarcello@epivax.com     Anne  S.  De  Groot  CEO/CSO  annied@epivax.com  
  43. 43. Ac?ve  Collaborators  /  Vaccines   Alan  Rothman   Bill  MarMn   Carey  Medin   Ted  Ross   Lenny  Moise   Andres  GuiMerrez   Frances  Terry   Danielle  Aguirre   Leslie  Cousens   Joe  Desrosiers   Ryan  Tassone   Thomas  Mather   Don  Drake,  Brian  Schanen   Howie  LaMmer   Wendy  Coy   David  Weiner   Mindy  Cote   Loren  Fast   Lauren  Levitz   ChrisMne  Boyle   Hardy  Kornfeld   Connie  Schmaljohn   Jinhee  Lee   Lesley  C.  Dupuy   Mark  Poznansky   Sharon  Frey   Tim  Brauns   Liisa  Selin   Mark  Buller   Pierre  LeBlanc   Jill  Schreiwer    
  44. 44. EpiVax:  Four  Core  Strengths   Media  Contact:  Anthony  Marcello,  BDA,  amarcello@epivax.com     44 ConfidenMal  

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