Vaccine Manufacturing and Clinical Trial Services for Diarrheal Disease Product Development

1. Vaccine Manufacturing and Clinical Trial Services for Diarrheal Disease Product Development Rodolfo M. Alarcón, PhD Enteric and Hepatic Diseases Branch Division of Microbiology and Infectious Diseases (DMID) Enteric and Hepatic Diseases Branch EHDB, NIAID, NIH, DHHS Vaccines & Vaccination July 27-29, 2015 Brisbane, Queensland, Australia

2. Overview • Introduction to NIH/NIAID/DMID/EHDB • Organization and Mission • EHDB pathogen list and area of focus • EHDB PO contacts • DMID grant, preclinical, and clinical support services • DMID clinical services • EHDB Phase IV Rotavirus Vaccine Trial

3. NIH Organization 27 IC’s (Institutes and Centers) Each with its own Goals, Programs, Approaches http://www.nih.gov/icd/ http://www.nih.gov/about/ National Institute of Allergy and Infectious Diseases (NIAID) — Est. 1948 NIAID research strives to understand, treat, and ultimately prevent the myriad infectious, immunologic, and allergic diseases that threaten millions of human lives.

4. How is NIH Organized? • Director’s Office – sets policies, represents NIH to Congress, public, has modest discretionary $, etc. • Institutes and Centers (I/C’s) – Each has focus, e.g., NCI, NIAID, NHBLI, NIDDK, etc. • Develop Specific Programs and Priorities • Intramural and Extramural • Intramural conducts research • Extramural - Administer funding awards • Center for Scientific Review (CSR) – special function to review grants via study sections (sometimes called Scientific Review Groups or SRG’s) directed by Scientific Review Officers (SRO’s).

5. National Institutes of Health Office of the Director National Institute of Allergy and Infectious Diseases National Institute on Aging National Institute on Alcohol Abuse and Alcoholism National Institute of Arthritis and Musculoskeletal and Skin Diseases National Cancer Institute National Institute of Child Health and Human Development National Institute on Deafness and Other Communication Disorders National Institute of Dental and Craniofacial Research National Institute of Diabetes and Digestive and Kidney Diseases National Institute on Drug Abuse National Institute of Environmental Health Sciences National Eye Institute National Institute of General Medical Sciences National Heart, Lung, and Blood Institute National Human Genome Research Institute National Institute of Mental Health National Institute of Neurological Disorders and Stroke National Institute of Nursing Research National Institute of Biomedical Imaging and Bioengineering National Center for Complementary and Alternative Medicine National Library of Medicine National Center on Minority Health and Health Disparities National Center for Research Resources Fogarty International Center Clinical Center Center for Information Technology Center for Scientific Review Peer Review

6. Extramural Research Staff Program Staff • Responsible for the programmatic, scientific, and/or technical aspects of a grant Review Staff • Responsible to NIH for scientific and technical review of applications • Center for Scientific Review (CSR) • Regular and Ad Hoc Study Sections Grants Management Staff • Responsible for ensuring that all required business management actions are performed by the grantee and the federal government in a timely and appropriate manner both prior to and after award.

7. Overall NIH Budget Intramural GrantsandContracts

8. NIAID: Find us on the web http://www.niaid.nih.gov

9. NIAID Research: A Dual Mandate Credit: AS Fauci

10. Division of Microbiology and Infectious Diseases Office of the Director Clinical Research Coordination International Research in Infectious Diseases Office of Clinical Research Affairs Office of Genomics and Advanced Technologies Office of Regulatory Affairs Office of Clinical Research Resources Office of Biodefense Research Affairs Office of Scientific Coordination and Program Operations Bacteriology and Mycology Branch Enteric and Hepatic Diseases Branch Sexually Transmitted Infections Branch Respiratory Diseases Branch Parasitology and International Programs Branch Virology Branch NIH/NIAID

11. Robert Hall: Enterics, Hepatic, toxins ENTERIC AND HEPATIC DISEASES BRANCH Fred Cassels Branch Chief Christian Gonzalez Product Manager Susan Payne Health Specialist TBD Admin HEPATIC ENTERIC CLINICAL DIAGNOSTIC Shahida Baqar: E. coli, Stx, ricin,Bacterioides Robert Hall: Vibrio, Aeromonas Rajen Koshy: HCV, HBV, HAV, HEV, HDV TBD Clinical Project Mgr Gabi Feolo Clinical Project Mgr Melody Mills: Helicobacter, Listeria, Shigella, normal flora Rahsan Erdem Medical Officer Bill Alexander: Salmonella, Yersinia Rodolfo Alarcon: Enteric Viruses – NoV, RV Product Development Ryan Ranallo: Clostridia spp., Campylobacter, SEB

12. Find your PO http://www.niaid.nih.gov/about/findingpeople/dmid/Pages/ehdb.aspx

13. Diarrheal Disease • Diarrheal disease is the second leading cause of death in children under five years old. • It is both preventable and treatable. • Each year diarrhea kills around 760,000 children under five. • Diarrhea is a leading cause of malnutrition in children under five years old. • A significant proportion of diarrheal disease can be prevented through safe drinking-water and adequate sanitation and hygiene. • Globally, there are nearly 1.7 billion cases of diarrheal disease every year. Credit: WHO

14. Hepatitis • Hepatitis viruses B and C cause acute and/or chronic infection and inflammation of the liver. • Major causes of severe illness and death. • The global burden of disease due to acute hepatitis B and C and to cancer and cirrhosis of the liver is high (about 2.7% of all deaths) • Forecast to become a higher ranked cause of death over the next two decades. • 57% of cases of liver cirrhosis and 78% of cases of primary liver cancer result from hepatitis B or C virus infection. Credit: WHO

15. Hepatitis • An estimated two billion people worldwide have been infected with hepatitis B virus • 360 million have chronic (long-term) liver infections. • 620 000 people die every year as a result of hepatitis B virus infection. • A vaccine against hepatitis B has been available since 1982. • Some 150 million people are chronically infected with hepatitis C virus • 350,000 people are estimated to die from hepatitis C-related liver diseases each year. • Vaccination is one of the strategies used to prevent hepatitis infection. • Vaccines exist against hepatitis A and B. • Effective candidate vaccines for hepatitis E prevention exist. • Progress has been shown in developing candidate vaccines against hepatitis C Credit: WHO

16. Research Steps in Vaccine Development 15 – 20 years or more Discovery and Product Development Research Credit: AS Fauci

17. How does the NIH support Vaccine Development? Credit: AS Fauci

18. NIAID Support Mechanisms Across the Product Development Pipeline Resource Centers Contract Resources Clinical Trial Support: VTEU, other Mechanisms Vaccine Discovery Target ID & Validation Preclinical Development Clinical Development R01, R21, R03 STTR/SBIR, STTR/SBIR-AT-NIAID R34/U01 Partnerships

19. Peer-reviewed grants and contracts to public or private institutions and for-profit and non-profit organizations Investigator-initiated grants Basic and Partnerships - R01, R21, R03 Clinical – R34/U01 Targeted initiatives supporting both grants and contracts - PA, RFA, RFP, IAA, BAA Allows support for diverse research projects Academia and Industry http://www.niaid.nih.gov/researchfunding/Pages/default.aspx

20. DMID Resources for Researchers http://www.niaid.nih.gov/LabsAndResources/resources/dmid/

21. Animal Models of Infectious Diseases • Provision of a broad range of in vivo models (small animal, non-human primate, and non-traditional models) • Development of novel models • Refinement of existing models • Screening of products and efficacy testing to support FDA submissions

22. Vaccine Manufacturing Services • Training and Workshops • Feasibility, Gap Analysis, and Product Development Plan Support • Process Development Including Assay Development for • Product Release • Pilot/GLP and cGMP Manufacture • Audits Includes vaccines, other biologics, challenge material, antigen enhancing substances, and delivery systems.

23. Assay Development: Examples Flow Cytometry T-Cell proliferation Cell viability Additional Memory B cell ELISpot Affymetrix Gene Chip Immunohistochemistry Viral plaque assay TCID50 • ELISA • Serum responses • IgG subclass • Avidity/ELISA • Cytokine • mRNA levels (qRT-PCR) • ELISAs • Intracellular staining • Quantitation Luminex • Functional • Toxin neutralizing • Microneutralization • Opsonophagocytic / bactericidal

24. Evaluation and Testing Services • Assay Development • Measure humoral and cell mediated responses • Broad range of assays • Immunogenicity and efficacy testing • GLP and non-GLP studies • Pivotal efficacy studies under the animal rule • Clinical and Non-clinical sample testing • Support phase I-III • Safety and toxicology studies • Tissue cross-reactivity • Biodistribution

25. Provide reagents and resources for biodefense and emerging infections agents to the scientific community for use in basic and applied research Academic, industry scientists Global access “Free” (shipping costs) Reagent Repository: BEI Research Resources www.beiresources.org

26. NIAID Resources for Researchers http://www.niaid.nih.gov • Preclinical Research • Animal Models of Infectious Disease • Bioinformatics Resource Centers • Cell, Tissue, and Organism Repositories • Clinical Laboratory Diagnostics for Invasive Aspergillosis • Clinical Proteomics Centers • DAIDS HIV Research Counseling and Testing (HRCT) Curriculum in Biomedical HIV Prevention and Treatment Research • Division of AIDS Anti-HIV/OI/TB Therapeutics Database • Genomic Sequencing Centers • HIV-1 Vaccine Development Resources (VDR) • In Vitro Assessment • Malaria Vaccine Production and Support Services • Preclinical Development Services for Diagnostics • Preclinical Development Services for Therapeutics • Preclinical Development Services for Vaccines • Preclinical Master Contract (HIV/AIDS) • Reagents • Structural Genomics Centers • Systems Biology • TB Clinical Diagnostics • Therapeutic Development Services • Topical Microbicide Safety and Efficacy Evaluation in Non-Human Primates • Vaccine Development Services • Vaccine Reagent Resource (HIV/AIDS)

27. NIAID Resources for Researchers http://www.niaid.nih.gov/labsandresources/resources/

28. NIH’s Network of Vaccine and Treatment Evaluation Units (VTEUs) • Established in 1962 • Clinical trials to evaluate vaccines, diagnostics and therapeutics • Epidemiologic studies • Access to healthy and sick populations • Pediatric • Adult • Elderly • Domestic and international capabilities

29. Summary • NIAID/DMID/EHDB is assisting many investigators through grants and preclinical services • EHDB has conducted preclinical services and multiple clinical trials for multiple investigators • Program Officers are subject matter experts and entry point for services • Get to know your program officer (funded or not) • Website: www.niaid.nih.gov • Contact: rodolfo.alarcon@nih.gov • Rodolfo.alarcon@nih.gov

30. Direct NIAID Contributions to Selected FDA-Licensed Vaccines, 1994 - 2015 Credit: AS Fauci

31. Selected Infectious Diseases of Global Public Health Importance Credit: AS Fauci

32. DMID Partnerships: Two Mechanisms R21/R33 R01

33. NIAID Small Business Innovation Research/Small Business Technology Transfer Programs • Standard SBIR and STTR solicitations (PA-11-096; PA-11-097), US companies • NIAID Advanced Technology Programs (PA-10-123; PA-10-124) • Phase II Competing Continuation

34. NIAID Small Business Innovation Research/Small Business Technology Transfer Programs • Vaccine development for tuberculosis, STIs, hepatitis B and C, and malaria and other high-impact global parasitic diseases. • Therapeutics for tuberculosis, hepatitis B and C, and malaria and other high-impact global parasitic diseases. • Therapeutic enhancement and formulation technologies with the goal of improving drug development timeframes, productivity, efficacy, specificity, safety, stability, and delivery. http://www.niaid.nih.gov/researchfunding/sb/Pages/default.aspx

35. Phase IV Rotavirus Vaccine Trial (VTEU) ClinicalTrials.gov A service of the U.S. National Institutes of Health NCT 01266850

36. Phase IV RV Vaccine Trial Enrollment Twelve VTEU sites and subsites involved and reporting 100% enrolled (04/08/13), 2 year completion