Extremely Rapid H7N9 Immunogenicity Analysis and Vaccine Design April 13 2013 Annie De Groot M.D. CEO/CSO www.epvax.com 1
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
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.
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
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
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 hVp://www.ncbi.nlm.nih.gov/pmc/arMcles/PMC3130614/ Schanen et al. Vaccine 2011;29:3299-309
What about 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.
“Immunogenicity Scale” Immunogenic proteins Non Immunogenic proteins
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. See De Groot and MarMn, Clinical Immunology, 2009 - -60 - - -70 -
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
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 24
A beber/faster way to make ﬂu vaccine? BeVer 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
T cells = Immune System Body Armor T cell response cannot prevent InfecMon but . . . T cell response can arm against Disease
FastVax: Vaccines on demand Rapid deployment when genome sequence is in hand • High throughput computing This can be • Immunoinformatics prebuilt!! • Vaccine design algorithms • Vaccine Production • Delivery device Pilot program Funded by DARPA • Animal safety/tox/immunogenicity/validation • Deployment by established distribution systems 27
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
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
Published Benchmark 2009 De Groot and MarMn. Reducing risk, improving outcomes: Bioengineering less immunogenic protein therapeuMcs. Clinical Immunology 2009. 131, 189-‐201.
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 31
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
Building ICSs EpiAssembler – Final Immunogenic Consensus Sequence Balance Score+Conserva?on: Highest conserved epitopes Selec?on for score Best Op?on are poorly immunogenic
GD-‐IDV FormulaMons (plaporm independent) DNA – chain of epitopes, or ICS-‐opMmized whole proteins ICS-‐opMmized proteins in VLP pepMde in liposomes
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, email@example.com Anne S. De Groot CEO/CSO firstname.lastname@example.org
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
EpiVax: Four Core Strengths Media Contact: Anthony Marcello, BDA, email@example.com 40 ConﬁdenMal