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CDC Presentation 7/14/2014 Seasonal Influenza: Ongoing Public Health Threat • Current influenza vaccines are moderately effective (approx. What Are We Expecting From Broadly 60% effective in seasons with a good antigenic match) Protective Influenza Vaccines? • Impacts millions of people globally – 10-20% population; 250,000-500,000 deaths • $80 B / yr. loss attributed to influenza disease in the USA Nancy Cox Director, Influenza Division • Unpredictable changes in HA and NA lead to epidemics and Director, WHO Collaborating Center for Influenza global pandemics Centers for Disease Control and Prevention – Due to antigenic shift and antigenic drift • Two types of influenza that affect humans: Type A and Type B – Type A : H1N1 and H3N2 Second WHO Integrated Meeting on development and clinical trials of influenza vaccines that induce broadly protective and long-lasting immune responses – Type B: Victoria and Yamagata lineages May 5th – 7th , 2014 • Emerging strains present pandemic risk to humans – E.g., H5N1, H7N9, H9N2, H6N1, & H10N8 National Center for Immunization & Respiratory Diseases Influenza Division 1 2 Universal Influenza Vaccines What Is A Broadly Protective Influenza Vaccine? The Ideal situation: Immunity from natural viral infection does not protect . A single vaccine that would provide lifelong against distant antigenic variants protection against any subtype of influenza A and both lineages of influenza B Vaccine-mediated immunity must afford greater Is it achievable? Not immediately. protection across antigenic variants within a subtype and across subtypes than natural immunity A practical outcome: A vaccine that will provide protection for several “Universal “Influenza Vaccine - would induce protection seasons before reformulation against antigenic drift and (ideally) antigenic shift . Surveillance would remain important . Extend protection of each vaccine to 5-10 years (drift/seasonal) . No need to re-formulate annually . Extend protection to several subtypes (shift/pandemic) . Reduce vaccine “mismatches” . Truly “universal”: One vaccine for all influenza viruses . Potential to reduce production and administration costs . Potential surge capacity for rapid scale up/change over . Reduce the potential for vaccine shortages • Year around production increase global vaccine supply 3 4 1 7/14/2014 Global Influenza Vaccine Market Leaders What Do We Expect? Development and licensure of a broadly protective vaccine would be a paradigm shift for seasonal influenza control and pandemic preparedness . Goal: replace current seasonal vaccine approach • Must be at least as effective as current seasonal vaccine • Must be safe; current vaccines have a very good safety profile • Must be an effective approach against a newly emerging pandemic threat . Induction of durable immunity is key to success . Paradigm shift for both industry and for public health . Developing a broadly protective vaccine will be an enormous scientific and programmatic challenge • Will require substantial resources and public-private partnerships • May require adjuvants for breadth and durability of protection Estimated $2.6 billion industry National Center for Immunization & Respiratory Diseases 5 6 Examples of Current Efforts to Develop Broadly Protective Potential Vaccine Targets to Conserved Regions Influenza Vaccines of the Influenza Virus BiondVax Pharmaceuticals Ltd. Proprietary conserved/common epitopes HA - surface, immunogenic Matrix: internal, highly Codagenix Inc. but highly variable conserved, induces CMI . LAIV using Synthetic Attenuated Virus Engineering (SAVE) (Drift/Shift) Dynavax . TLR-based Generex and Immune Targeting M2e: surface, . Peptide/T-cell vaccines immunogenic, more conserved, Inovio Ab-mediated . DNA vaccine protection Molecular Express Inc. Lipid vesicle conjugatable adjuvant NIAID Intramural . Ferritin nanoparticles . DNA prime-boost MSSM HA stalk, highly . Chimeric HAs conserved, NA: surface, NP: internal, highly Sanofi/UPMC platform/format immunogenic, variable conserved, induces CMI, TechnoVax unknown (Drift/Shift) reduce disease severity? . VLP 7 8 2 7/14/2014 Chimeric HA Vaccines: New Heads on Old Stalks Antibodies Against the HA Stalk are Boosted (MSSM, NY) Following Natural Infection, MSSM Approach: To enhance immune response to the J Virol 2013; 87(8):4728 conserved cross-reactive stalk regions of HA . HA chimeras • Reduce chance of cross reactivity from: o Head-specific antibodies • Expand long lived memory B cells Avian Human o Stalk-specific antibodies . Results show successful protection studies in mice and ferrets . Antibodies to stalk originate from highly polymorphic Ig VH1-69 gene segment PNAS 2012; 109(7):2573 • Have identified cross-reactive Abs to group 1 or 2, and 1+2 subtypes • Questions remain o Extensive somatic mutations in VH1-69 genes o VH1-69 implicated in autoimmune diseases 9 10 Chimeric HA Vaccine (MSSM, NY) Chimeric HA Summary . Current versions require virus production in eggs Can sufficiently high titers of antibodies be induced in . Virus like particles (VLPs) also proposed humans to be protective vs. Group 1 and Group 2 • Product yield and stability to be assessed viruses? • VLPs need pre-clinical testing prior to human trials How durable is antibody against the stalk? . Optimal regimen also needs to be determined Are there safety issues associated with antibodies • 1 or 2 dose and amount against the stalk? • +/- LAIV prime (alternative primer: DNA) • +/- adjuvant . What would be the metric for success? . What would be the readout for duration of immunity? Fits profile for a universal vaccine Needs an influenza B component 11 12 3 7/14/2014 Centralized Antigen Approach to More Broadly Cross Reactive or Universal Influenza Vaccine Strategies to Broaden Vaccine Protection Could centralized antigen elicit Abs cross-reactive with all HA Subtypes? Traditional (Standard) New generation/universal . Polyvalent . Centralized antigen Mixed multiple antigens Based on sequencing data into a single formulation Capture multiple antigenic Seasonal TIV and QIV, HPV, features in single molecule Pneumococcal, polio Not naturally-occurring Breadth limited to that of components. 13 14 Vaccine 29 (2011) 3043–3054 Antigen Design Computationally Optimized Broadly Reactive Antigen (COBRA) Align amino acid sequences of human isolates from HPAI H5N1 - clades 2.1, 2.2, and 2.3 Assemble ‘Layered’ Consensus Limit sampling bias Confirm presence of conserved linear epitopes (Immune epitope database; www.immuneepitope.org) Consensus H5 clade 2 COBRA HA VLP vaccine COBRA HA Compared to monovalent VLP vaccine In vitro and in vivo endpoints 15 16 4 7/14/2014 COBRA Summary COBRA Can COBRA approach provide heterologous protection COBRA sequence is a functional HA protein that uses to new divergent H5N1 clades? immune refocusing to increase breadth of protection . Designed to protect against viruses circulating in the past; will it work for future antigenic variants? COBRA vaccine is immunogenic; antibody measured by HAI or neutralization assays Can COBRA provide broad protection in humans against drifted seasonal influenza A and B viruses? COBRA vaccine protects ferrets and mice from H5N1 viral challenge Can COBRA approach provide durable immunity? Are adjuvants needed for the COBRA approach to be successful? Designed as a subtype specific vaccine and fits profile of a broadly cross-reactive influenza vaccine 17 18 A DNA plasmid expressing influenza nucleoprotein induced CD8 T cells, antibodies and conferred protection against viral challenge. National Center for Immunization & Respiratory Diseases National Center for Immunization & Respiratory Diseases 19 20 5 7/14/2014 Licensed DNA Vaccines for Animals Issues with DNA Prime and Protein Boost • Regulatory issues : Toxicity, characterization, plasmid integration, safety issues • DNA prime/protein boost uses an unlicensed approach for humans No DNA vaccine for human use was licensed so far National Center for Immunization & Respiratory Diseases National Center for Immunization & Respiratory Diseases 21 22 DNA Prime/Protein Boost Approach(VRC/NIAID) String of pearls – Synthetic Fusion of Conserved Peptides (Biondvax) Approach: Recombinant protein containing nine Concept: DNA prime vaccination to induce cell‐mediated immunity with a subsequent protein (e.g. TIV) boost to elicit protective, conserved regions of the influenza proteome neutralizing antibodies (nAbs) (influenza A and B epitopes) H5N1 phase 1 clinical trials published . Produced within 6-8 weeks . Results found vaccine to be safe . Best response was with boosts 24-weeks (3 months) post-DNA prime Product: Flu Vaccine M-001X . Note: production of nAbs to the HA stalk region was identified in several individuals but not all Summary Fits the profile of a next generation vaccine platform . Has progressed to human trials Summary . Fits the profile of priming dose to increase antibody and T-Cell . Can adjuvanted protein boost improve antibody breadth and durability of immune responses rather than a stand alone universal vaccine responses? . Can antibody responses to stalk be improved? . Can T cell responses be improved? Hemagglutinin . Can utility be enhanced in combination with another approach? Matrix Nucleoprotein 23 24 6 7/14/2014 BiondVax Vaccine Strategy Biondvax Summary • Multi epitope peptide • Safe in small numbers of human volunteers vaccine • Adjuvanted, two dose regimen gave best results • Montanide ISA 51 VG • Weakly immunogenic – Multi-strain protection adjuvant
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