1. Institute for Immunology and Informatics (iCubed) D. Spero icubed overview 2011 URI Biotechnology Program in Providence The College of the Environment and Life Sciences University of Rhode Island www.immunome.org URI Alumni Board 2012

2. GAIA Vaccine Foundation Project West Africa (Bamako, Mali) http://www.GAIAVaccine.org

3. Institute for Immunology and Informatics (iCubed) Our Mission: To design safer, efficacious vaccines and therapeutics to prevent and cure human and animal disease using novel computer-based (informatics) immunology tools Focus: Accelerated vaccine discovery for infectious diseases and biodefense D. Spero URI Alumni Board 2012

4. The iCubed Leadership Annie De Groot, M.D. Research Professor and Director iCubed CEO EpiVax Inc. Expertise: Immunology, Immunoinformatics, Vaccine Research, Infectious Diseases, Autoimmunity, Biotechnology Denice Spero, Ph.D. Research Professor and Co-director iCubed Former President of Developing World Cures, Inc. Vice President Drug Discovery Boehringer Ingelheim Pharmaceuticals, Inc. Pharmaceutical Leader, Experienced Drug Developer Expertise: Drug metabolism and pharmacokinetics, Drug Safety, Drug Formulation, Organic Chemistry, Autoimmune Diseases, Developing world diseases, Pharmaceutical industry

5. Why Are Vaccines so Important? Vaccines are the single most cost effective means of controlling the spread of infectious disease No public health tool has improved global health more than vaccines D. Spero URI Alumni Board 2012

6. The Goal- Prevent Disease

7. Why are Vaccines a Hot Commodity ? After years of beating a retreat from making vaccines, the world's biggest drug companies are piling back in. Vaccines are giving the drug business a shot in the arm....For example, Johnson & Johnson paid $441 million for a stake in Crucell, a Dutch vaccine firm, and...... just last week, Roche snatched up Illumina for $5.7B. Through the deal, Roche would pick up technology to read the genetic makeup of tumors, boosting the potential for targeted personalized medicine in this area, as Bloomberg notes. What are some of those medicines? Well, of course, Vaccines.

8. Whole (live/killed) vaccines Subunit vaccines Genome- Derived, Epitope Driven (GD-ED) Vaccines Better understanding of vaccine MOA Improve vaccine safety and efficacy The Focus: Better, Faster Vaccines Accelerate Vaccine Design The Evolution of Vaccines Vaccines are evolving rapidly Can we make them even Faster – Safer – Better?

9. “Old Style” Vaccines Shake... and bake – That was then

10. How the Flu Vaccine is made Sanofi Pasteur 50 year old technology, growing influenza virus in chicken embryos- doesn’t work with avian flu.

11. Molecular biology High throughput sequencing Genomics / proteomics Bioinformatics Computational power Accelerating Drivers

12. Whole (live /killed) vaccines Subunit vaccines Genome- Derived- Epitope-driven vaccines Accelerating Vaccine Design From Genome to Vaccine

13. Vaccine Design Tools and Techniques http://www.epivax.com/platform 13 iVAXToolkit

14. Strain 1 Strain 3 Strain 2 core genome dispensable genes strain-specific genes pangenome Comparative Genomics Impacts Vaccine Immunogen Selection Comparative Genomics

15. Protective epitopes Potentially detrimental cross- reactive epitopes Potentially detrimental cross- reactive epitopes Safer: remove conserved epitopes

16. 16 Conservatrix: Overcome the Challenge of Variability HIVHCVInfluenza Conserved Epitope-allows protection vs. more strains w/ fewer epitopes. CTRPNNTRK Overcome Strain Variation- Conservatrix

17. Confidential 17 August 25, 2011 Epitopes Conserved over Time & Space

18. DNA Vector DNA insert Intended Protein Product: Many epitopes strung together in a “String-of-Beads” Reverse Translation: Determines the DNA sequence necessary to code for the intended protein. This DNA is assembled for insertion into an expression vector. Protein product (folded) Making the Vaccine

19. DNA – chain of epitopes, or peptide in liposomes ICS-optimized proteins in VLPICS-optimized whole proteins Vaccine Formulations Other Formulations

20. IVAX Toolkit: In use by Researchers funded by the NIH Cooperative Centers for Human Immunology CCHI 20 iVAX Toolkit On Line Access

21. iVAX – for Neglected Tropical Diseases Protozoan Infections – African Trypanosomiasis – Chagas Disease – Leishmaniasis Bacterial & Viral Infections – Buruli Ulcer – Dengue – Leprosy – Trachoma** Helminth (Worm) Infections – Soil-Transmitted Helminth Infections Ascariasis** Hookworm** Trichuriasis** – Schistsosomiasis** – Lymphatic Filariasis** – Onchocerciasis** – Dracunculiasis **indicates one of “The Big Seven” NTDs

22. Neglected Tropical Diseases

23. Leading Causes of Life-Years Lost to Disability and Premature Death

24. DISEASE Lower Respiratory Infections HIV/AIDS Unipolar Depression Diarrheal Disease Ischemic Heart Disease Neglected Tropical Diseases Cerebrovascular Diseases Malaria Road Traffic Accidents Tuberculosis DALYs 91.4 million 84.5 million 67.3 million 62.0 million 58.6 million 56.6 million 49.2 million 46.5 million 34.7 million 38.7 million Funding Per DALY $0.62 Global Burden of Infectious Disease

25. Burk/Tuly/ MP Current Vaccine Design Pipeline Epitope Discovery Epitope Validation Construct Design Immuno-genicity HIV/TB Epitope Discovery Epitope Validation Construct Design Immuno-genicity Tularemia Epitope Discovery Epitope Validation Construct Design Immuno-genicityAnimal Model Validation Monkeypox Epitope Discovery Epitope Validation Construct Design Animal Model Validation H. pylori Epitope Discovery Epitope Validation Construct Design Animal Model Validation VEE/Wee Epitope Discovery Epitope Validation Construct Design Animal Model Validation Immuno-genicity 25

26. Vaccine Immunogenic Epitopes Shared Immunogenic Epitopes smallpox vaccinia Immunome-Derived Monkeypox Vaccine: VennVax

27. Prime-Boost Immunization with VennVax 27 Immunization Sacrifice 3 mice Week 16 1. epitope DNA vaccine prime 2. epitope peptide boost 1. control DNA prime 2. control peptide boost Week 8-10 IFN-  multiplex ELISA Aerosol challenge

28. Survival of VennVax-Vaccinated Mice After Aerosol Challenge 28 0 20 40 60 80 100 100% survival of Vaccinated mice vs. 17% of placebo Moise et al. Vaccine. 2011; 29:501-11

29. Therapeutic H. pylori Vaccination Week 0 Week 6 Week 12-19 Week 51 IFN-gamma and IL-4 ELISpot Histology 1. epitope DNA vaccine prime IM 2. epitope peptide boost IN H. pylori SS1 H. pylori SS1 H. pylori SS1 H. pylori SS1 lysate IN 1. epitope DNA vaccine prime IN 2. epitope peptide boost IN 1. control DNA prime IN 2. control peptide boost IN H. pylori SS1

30. *** P<0.001 ** P<0.01 *** P<0.001 HelicoVax Eradicates H. pylori Infection This result accomplished in just over 24 months... Moss et al, Vaccine 2011;29:2085-91

31. Whole (live /killed) vaccines Subunit vaccines Personalized Vaccines Next Step in Vaccine Evolution?

32. PigMatrixFishMatrix And....

33. “That was then”: How the Flu Vaccine is made Sanofi Pasteur 50 year old technology, growing influenza virus in chicken embryos

34. This is Now! The iCubed “Gene to Vaccine” Approach No whole viruses or bacteria: Fast and targeted! Genome of the pathogen Select pathogen proteins String peptides together to make a vaccine Select peptides that will interact with the human immune system

35. Pathogen Genome(s) Genome-Derived Vaccine Components Genome-Derived Vaccine Components Faster! The “Gene to Vaccine” – 60 days Funding from DARPA for this approach to be announced this week!

36. A bold statement: Personalized vaccines will be a reality in 10 to 15 years. How so? Because the technology that can design safe, effective vaccines already exists, right here at URI. Moving vaccine development from 20 years to 20 minutes is the next step. What is needed ? Vision. Leadership. Financial and Infrastructure Support. “Yes we can!” We are able to make better, safer and faster vaccines, and also develop a workforce that is prepared to bring that dream to fruition.

37. New Challenges/ New Opportunities Emerging Infectious Disease Threats Unprecedented infectious disease threats (population density, global travel, global warming, widespread bioengineering technology and capabilities) Advances in genomics, microbiology and immunology create an opportunity to re-think current processes

38. How are we meeting the challenge? iCubed Research Areas Applying New Tools to Design New, Safer and Faster Vaccines:  Biodefense - defending our military and our communities  Infectious diseases - Hepatitis C, H. pylori, emerging ID  Cancer - New collaborations with cancer experts  Tropical Diseases - Developing world and Southern US  FarmVax - Fish, swine, chickens to protect our food, protein sources

39. Hepatitis C virus (cirrhosis and liver cancer) H.pylori (gastric carcinoma) Tick-borne diseases (Lyme Disease) Vaccine Delivery by targeting immune cells Multipathogen vaccines against biowarfare agents Flu and the aging immune response Eastern and Western Equine Encephalitis Virus Vaccines for Aquaculture Dengue Virus Hemorrhagic Fever Diagnosis Lysostaphin Selected Current Grants

40. Providing students with the right skill set Immunology Vaccinology Protein Manufacturing Entrepreneurship Neglected Tropical Disease Training Vaccine Renaissance Conference

41. The Business Side of iCubed Vision: To Build URI as the Major Center for Next Generation Vaccine Discovery in the World  Entrepreneurial Model  Primarily self-funded through grants and overhead return  Seeking Private Funding to: Expand research projects Support faculty and laboratory space

42. iCubed Trajectory  Opened 2008 – 3 full time staff, several part time faculty  As of 2012 - 15 scientists and staff  Many Collaborations: Brown/Lifespan, Dartmouth, UConn, NIH (LPD) USDA (ARS), DoD, Peru (Cayetano Heredia), Thailand, Indonesia (Eijkman Institute)  Awarded grants since inception: $11.3 M dollars

43. Institute for Immunology and Informatics Lifespan, URI, EpiVax 2009 Translational Research on Immunome-Derived Accelerated Vaccines Projects at the Institute for Immunology and Informatics In collaboration with EpiVax

44. The iCubed Team