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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

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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

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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

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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

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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.

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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

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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

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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

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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

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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 (Seppic, – Generates both humoral and cellular responses France) • Quite easy to produce – 6-8 weeks production • Manufactured in – linear epitopes bacteria and purified • Could be stockpiled (+/- adjuvant) by ion exchange and • Vaccination and production any time of the year • Primes for administration of seasonal/pandemic chromatography vaccine

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Biondvax What Do We Expect? • Development and licensure of a truly “universal” flu vaccine is an enormous scientific and regulatory challenge • How durable is immunity to these conserved • We must do better than nature can do with respect to epitopes? protection from influenza disease • How can responses be improved even more? – Individuals over 57 years of age have been exposed to H1N1, H2N2, H3N2 and B viruses over a lifetime but death • Could this approach be combined with and hospitalization are highest in older age groups another next generation influenza vaccine • Incremental advances in breadth and durability of protection approach? are desirable in the interim • Combinations of approaches may be required for success • Understanding correlates of protection essential for success

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Acknowledgements

• Ruben Donis (ID/OD) • James Stevens (ID/VSDB) • Jackie Katz (ID/IPB) • Prakash Sambhara (ID/IPB) • Joe Miller (ID/OD)

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