United States Department of Health & Human Services Office of the Assistant Secretary for Preparedness and Response Update on U.S. Pandemic Influenza Vaccine Development Rick Bright, PhD Acting Director, Influenza Division Biomedical Advanced Research and Development Authority (BARDA) Office of the Assistant Secretary for Preparedness & Response 2014 National Adult and Influenza Immunization Summit May 15, 2014 Atlanta, GA A Nation Unprepared: US Influenza Vaccines in 2004 • All licensed seasonal vaccines were egg-based (1940s-1950s technology) • Vaccine was produced in a six month production window (January-June each year); no capability outside of that window, no egg supply • Annual immunization was required due to virus drift and limitations of vaccines ─ Vaccine effectiveness estimated at 30-70% • Shortage of seasonal influenza vaccine in fall 2004 due to production failure at one facility highlighted US vulnerability • Limited domestic manufacturing capacity to respond to a pandemic, very limited global capacity as well 1 ASPR: Resilient People. Healthy Communities. A Nation Prepared. 5/15/2014 1 Establishing Pandemic Influenza Vaccine Capabilities: USG Requirements • • The requirements addressed by the BARDA Influenza Portfolio are derived from a number of documents that guide the US Government efforts to prepare for pandemic, include: • Establish and maintaining a dynamic pre-pandemic vaccine stockpile • Establish manufacturing capacity to produce sufficient pandemic vaccine for the entire U.S. population within 6 months of pandemic declaration • Improve, optimize and/or innovate vaccine production technologies Goal: More and better influenza vaccine, faster BARDA’s Mission Enhance national preparedness for CBRN threats, pandemic influenza, and emerging infectious diseases by supporting innovation, developing and acquiring medical countermeasures, and building manufacturing infrastructure. ASPR: Resilient People. Healthy Communities. A Nation Prepared. 5/15/2014 2 BARDA Approach to Making Medical Countermeasures Available Centers for Innovation in Advanced Development & Manufacturing 2012 Regulatory & Technical Expertise Fill Finish Manufacturing Network 2006 2013 Analytic Decision Support Animal Studies Network 2011 2010 Clinical Studies Network 2014 ASPR: Resilient People. Healthy Communities. A Nation Prepared. BARDA is Achieving National Pandemic Influenza Vaccine Goals Universal Vaccines Recombinant Vaccines Cell-based Vaccines Egg-based Vaccines Advanced Development Begins FY15 Flublok® Licensed 01/16/13 FLUCELVAX® Licensed 11/20/12 H5N1 Vaccine Licensed 04/17/07 More, Faster, & Better Vaccines! ASPR: Resilient People. Healthy Communities. A Nation Prepared. 5/15/2014 3 BARDA: Influenza Vaccine Manufacturing Improvement Initiative WT Reassortment 17 days Seed 6 promising donors to improve vaccine yield Faster potency reagents, Alternative assays 7 days faster sterility assay ASPR: Resilient People. Healthy Communities. A Nation Prepared. BARDA: Enhancing Domestic Vaccine Manufacturing Capacity • Expanding Existing Capacity by Retrofitting Vaccine Manufacturing Infrastructure • Changing Flu Vaccine Industry 2013 ISPE Facility of the Year sanofi pasteur – Swiftwater, PA Novartis – Holly Springs, NC 7 ASPR: Resilient People. Healthy Communities. A Nation Prepared. 5/15/2014 4 Centers for Innovation in Advanced Development and Manufacturing 8 ASPR: Resilient People. Healthy Communities. A Nation Prepared. Fill Finish Manufacturing Network Cook Pharmica JHP Pharmaceuticals DSM Pharmaceuticals Nanotherapeutics/Baxter 9 ASPR: Resilient People. Healthy Communities. A Nation Prepared. 5/15/2014 5 Current Geographical Distribution of Influenza Vaccine Production Romania Cantacuzino Institute Kazakhstan RIBSP Serbia Torlak Institute Egypt VASERA Mexico Birmex South Korea Green Cross Vietnam IVAC VABIOTECH PATH India Serum Institute Thailand GPO Brazil Instituto Butantan Indonesia Bio Farma South Africa Biovac Licensed/Active Influenza Vaccine Producers BARDA/WHO Cooperative Agreement Grantees BARDA/WHO Licensed Vaccine for Human Use (as of 2/2014) ASPR: Resilient People. Healthy Communities. A Nation Prepared. 10 Influenza Vaccine Landscape Pre Clinical Egg-based inactivated Split w/ SPA03 Proprietary Adjuvant Phase 1 WIV Split w/ iscomatrix Egg inactivated Phase 2 H5N1, WIV H5N1 WIV w/ Adjuvant Phase 3 Market Approval QIV, High dose, intradermal H5N1 AS03 WIV QIV Split Split Egg, Thailand Pandemic Institutul Cantacuzino Split Adimmune- Taiwan Seasonal HuaLan Seasonal Seasonal MDCK subunit (EU) US 2009/2010 Vero, Influject/ Cevapan(EU) Seasonal WIV Split Cell-culture inactivated EB66 EB66; H5N1 PER.C 6 Monkey Kidney Cell Japan EB66 Vero, Influject/ Cevapan(EU) Mar 2014 Study Start Serum Institute of India Ltd LAIV dNS1 - Vero Egg, Thailand Recombinant (SUV & VLPs) H1N1 Cell; HN-VAC (India) VLP / HA VLP, Insect cells VLP, 293 cells Salmonella, Oral rHA, Plants Yeast, IN - Oral Salmonella, Oral Chimeric VLP + microneedles Egg, H5N2 Egg H5N1/H9N2/H7N9 rHA, Plants QIV, Egg dNS1- Vero H5 Egg, Thailand H1 Egg, Thailand rHA Insect cells VLP, Plants VLP, Insect Cells rHA, Insect cells Split HA, Flagellin, e coli rHA + GLA-SE Egg Egg (Russia) Seasonal rHA Insect Cells Pandemic Molecular HAs Universal NYU / MSSM Vectors/ Adjuvant COBRA HA VLP M2e Liposome Novel peptides NIAID Nanoparticle MVA Based Adenovirus M & NP MVA Based DNA rHA, Plants SynBio LAIV HA stalk; Chimeric Mass Gen Hospital Listeria Adenovirus NP & ISS Tech Egg inactivated Seasonal & Pandemic US License Adenovirus, Oral Pandemic MVA Seasonal ASPR: Resilient People. Healthy Communities. A Nation Prepared. DNA / Vaxfectin 5/15/2014 Peptide based DNA / SnyCon w/ Electroporation 11 20MAR2014 6 Which Flu Vaccine is Right for You? ASPR: Resilient People. Healthy Communities. A Nation Prepared. Influenza Vaccine Challenges: Limitations of Current Vaccines • Vulnerable to antigenic drifts and shifts • Antibodies target highly variable regions of HA and NA • Single site mutations can reduce efficacy • Provide minimal cross-protection within subtypes or against other subtypes of influenza • Short duration of immunity, particularly in at-risk populations (e.g., pediatric, geriatric) • Vaccine efficacy is modest • Requires viral isolate for production • Avian influenza strains will likely require adjuvant There is a need for new, improved influenza vaccines ASPR: Resilient People. Healthy Communities. A Nation Prepared. 5/15/2014 7 Where Do We Go From Here? Safe for all ages Effective Goal: Develop more effective influenza vaccines that provide a long duration of protection against a broad range of influenza viruses Long lasting immunity Broadly Reactive Rapid Response Simple Manufacture Universal? ASPR: Resilient People. Healthy Communities. A Nation Prepared. Universal Influenza Vaccines • What is a “universal vaccine”? ─ Idealized vaccine: single vaccine for any influenza A subtype ─ A vaccine that provides safe, effective and long-lasting immunity against a broad spectrum of influenza viruses • Could be used for several seasons ─ ─ ─ ─ ─ Simplify the vaccine strain selection process Simplify the influenza vaccination process Reduce vaccine mismatches Reduce potential for vaccine shortages Increase global supply of vaccine • Potentially reduce vulnerability to novel influenza viruses ─ Population would be “primed” for newly emerging viruses ASPR: Resilient People. Healthy Communities. A Nation Prepared. 5/15/2014 8 Universal Vaccine Strategies Leveraging Old and New Discoveries • Broaden B cell epitope recognition • Identify broadly reactive epitopes (HA Stalk, M2 extracellular, NP) • Th1 vs Th2 responses • Multi-epitope vaccines • Vector delivered vaccine Vaccine Design Adjuvants • Humoral vs Cell-mediated • Target occluded sites Administration HA1 (variable region) HA2 (conserved region) • Location: Intranasal, intradermal or intramuscular • Timing: Prime/boost • Regimen R. Rappuoli, F1000 Medicine Reports 3 (2011): 16. Source: NIAID http://tinyurl.com/69n9lap ASPR: Resilient People. Healthy Communities. A Nation Prepared. 16 Closing Thoughts • In 2005, the US was in a very vulnerable position to be able to respond to seasonal or pandemic outbreaks of influenza • The USG, through BARDA, NIH, FDA and CDC, has taken bold and significant steps to address these vulnerabilities, particularly in areas of innovation for new technologies in the areas of vaccines, therapeutics and diagnostics for influenza • There has never been a greater global capacity to respond to a pandemic outbreak of influenza, nor a greater global capacity to produce influenza vaccines • There has never been a greater variety of influenza vaccines available to address population variation than there are today • The landscape of new influenza vaccine development is active and rapidly evolving – 94+ products/candidates; continued scientific discoveries will provide greater opportunities for innovation • While the field of influenza vaccine types appear to be moving towards a variety of niche vaccines in the near term, it is apparent from the landscape that the ultimate aim is to develop a single, more effective influenza vaccine that could be used by all populations ASPR: Resilient People. Healthy Communities. A Nation Prepared. 5/15/2014 9 Rick Bright, PhD Acting Director Influenza Division BARDA U.S. Department of Health and Human Services [email protected] 5/15/2014 10