2nd Influenza Research and Development
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Day 1 Day 2 Day 3
Day 1 - Monday, July 08, 2013
Plenary Keynote Session
12:00 Registration
12:55 Welcome & Opening Remarks
1:00

Global Trends in Pandemic Preparedness: Changes After the Last Pandemic?
 
Klaus Stohr
 Vice President, Global Head - Influenza Franchises
 Novartis Vaccines and Diagnostics
  The last influenza pandemic highlighted the existing gaps in vaccine supply: limited global production capacity, owing to biological and technological realities 3-4 months are required before first vaccine doses are available, pandemic peaked before supply fully ramped up. Also, countries with domestic supply or advanced purchase agreements had preferential access to pandemic vaccines. There was no vaccine available in developing countries. As a consequence, an increasing number of concerned governments are now securing first-come-first-serve pandemic vaccine supply agreements. In the not too distant future, the majority of the global supply is likely going to be contractually bound by a few countries. Not surprisingly, there are only a very small number of developing countries that embarked on domestic vaccine manufacturing projects; most of them are in very early stage or have only limited scope.

Although influenza vaccine development is still at high pace, revolutionary new production technologies are not yet in sight although there are a few high promising candidates.

Efforts to accelerate pandemic vaccine investment will have to acknowledge that it is mainly driven from two sources: political commitment to preparedness/public health or opportunities available from seasonal influenza vaccine use/manufacturing.
1:45 A Novel Multi-antigen Vaccine to Prevent Staphylococcus Aureus Infection and Disease. Can We Beat the Bug at Its Own Game?
 
Kathrin Jansen
Senior Vice President, Vaccine Research East & Early Development
Pfizer
  Staphylococcus aureus (SA) causes serious disease in both hospital and community settings and is becoming increasingly resistant to antibiotic treatment. Currently there are no prophylactic vaccines to prevent SA disease, yet the field has already experienced several vaccine failures. Learning from past experiences and taking advantage of a more recent in depth understanding of the pathogenesis mechanisms of the organism, one needs to conclude that for a prophylactic vaccine to be successful, a multi-antigen vaccine approach will be crucial. Furthermore, it is becoming increasingly clear that a vaccine must address multiple bacterial virulence mechanisms and must induce a potent antibody response that results in opsonophagocytic killing of the pathogen. To full-fill these premises, we are developing a multi-antigen vaccine composed of serotype 5 and 8 capsular polysaccharides (CP5 and CP8) conjugated to the protein carrier CRM197 and two recombinant surface-expressed protein antigens, clumping factor A (rmClfA) and manganese transporter C (MntC). The rationale for antigen selection, along with the preclinical and clinical evidence that such a vaccine candidate might be effective, will be discussed.
2:30  
 
Gary Nabel
Senior Vice President, Chief Scientific Officer and Deputy to the President for Global R&D
Sanofi
   
3:15 Networking Break
Joint Session with 11th Vaccines Research & Development:

Adjuvants & Delivery Systems
 Chairperson: John Donnelly, Director, Polio Vaccine Development and Scale-up Project, PATH
3:45 ICMVs Inter-bilayer Cross-linked Multilammellar Vesicles, A System for Co-delivery of Antigen and Adjuvant
  Alan Shaw, President and CEO, Vedantra
  One of the biggest disappointments in modern molecular biology has been the poor immunogenicity of pure soluble protein antigens. We all thought that if you could clone it and express it, you would have a vaccine. Forty years later, we now realize that “pure” is not necessarily a good thing. A good immune response requires antigen plus some type of molecular “schmutz” embodied in one of a variety of Pathogen-Associated molecular Patterns; substances that we mammals don’t’ make such as MPLA, non-methylated CpG, flagellin, naked rNA and so forth. The immune system evolved to recognize antigens in the context of these pathogen patterns, so we now realize that a combination of antigen and pathogen pattern need to go together to the sites and cells that process antigens and trigger an immune response. Co-packaging antigen and pathogen pattern in lipid nanoparticles for targeting lymph nodes offers a potential solution.
4:10 The Use of Novel Toll-like Receptor Agonists and Delivery Systems to Increase the Effectiveness of Vaccines
  Mark A. Tomai, Head of Toll-like Receptor and Microneedle Business Development, 3M Drug Delivery Systems
  3M Drug Delivery Systems has been developing 2 different enabling technologies for the vaccine industry. The first is our small molecule toll-like receptor (TLR)7 and TLR8 agonists for use as vaccine adjuvants. Our lead compound 3M-052 shows potent adjuvant activity in a number of mouse models with limited evidence of systemic exposure, unline many other small molecule TLR agonists. The molecule not only enhances antibody responses but can enhance cell-mediated iimune responses as well. This molecule is currently being evaluated in preclinical toxicology studies.

The second technology 3M is focused on is our solid microneedle system for delivery of vaccines to the epidermis and dermis. Here the antigen is coated onto the microneedle array and delivered into the skin within minutes. The benefits of this system include potential for antigen sparing, reduction in doses, room temperature stability and better compliance.

Attendees will learn about the following:
• The benefit of TLR7/8 agonists for augmenting antibody and cell mediated immune responses
• The importance of formulation in keeping these types of molecules at the application site
• The potential benefits of delivering vaccines to the skin to enhance vaccine efficacy
• The potential for microneedles to generate a more stable vaccine product
4:35 FEATURED PRESENTATION
  The Next Generation of Vaccine Adjuvants
 
Derek O’Hagan
VP, Global Head, Vaccine Delivery and Formulation Research
Novartis Vaccines and Diagnostics
 
  Formulation science is an unappreciated and often overlooked aspect in the field of vaccinology. In this talk I will highlight key attributes necessary to generate well characterized adjuvant formulations. The relationship between the adjuvant and the antigen impacts the immune responses generated by these complex biopharmaceutical formulations. I will use both well established and new generation vaccine adjuvants to illustrate that a vaccine formulation is more than a simple mixture of component A and component B. This talk will identify the challenges and opportunities for new generation adjuvants. As antigen and adjuvant formulations increase in complexity having a well characterized robust formulation will be critical to ensuring robust and reproducible results throughout preclinical and clinical studies.
5:00 FEATURED PRESENTATION
  Adjuvants in Vaccines : What Have We Learned from the Past, How Will This Impact the Future?
 
Nathalie Garcon
Vice President, Head of Global Adjuvant Center for Vaccines
GSK bio
 
5:25 Networking Reception and Poster Session
Day 1 Day 2 Day 3
Day 2 - Tuesday, July 09, 2013
7:00 Continental Breakfast & Registration
7:55 Welcome & Opening Remarks
Virology & Pathogenesis
 Chairperson: Scott Hensley, Assistant Professor, Wistar Institute
8:00 Influenza Genome Packaging “Failure”: It's a Feature, Not a Bug
  Jonathan Yewdell, Chief, Cellular Biology Section, Laboratory of Viral Diseases, NIAID
  Genome segmentation enhances influenza A virus (IAV) evolution by facilitating reassortment and complementation between heterologous viruses.  It currently believed that to maximize viral fitness, virions efficiently package the eight viral genome segments.  We show using a variety of IAV strains that virion packaging is nowhere near perfect, with more than 90% of virions failing to express the gene products of a given segment, likely due to genetically controlled packaging “failure”.  IAV adaptation to guinea pigs reveals that a single amino acid substitution in an internal gene reduces synthesis of vRNA in infected cells in a segment specific manner, decreasing the incorporation the gene segment and its gene products into virions. This represents a novel epistatic mechanism for selectively controlling IAV gene expression based on modulating vRNA segment synthesis to exploit the flexibility offered by a segmented genome combined with in vivo multiplicity complementation.

Influenza Evolution
• Much remains to be learned about basic IAV biology
• This requires having an open mind about the “facts” of IAV virology and immunology
• In vivo complementation may be a critical feature of viral fitness, point to the swarm like nature of IAV populations
• Genome segments packaging is exploited by the virus to adjust viral gene expression and maximize viral fitness
8:25 Recombinant Influenza Proteins Go Viral
  James Stevens, Team Leader, Centers for Disease Control and Prevention
  Recombinant proteins allow researchers in all disciplines to produce of large quantities of material for use in structural and functional studies, mutational analyses, enzymatic studies, antigen production, drug discovery, and vaccine production. Many of these uses can also be applied to the field of influenza research. An overview will be presented of some of the areas to which recombinant expression of the influenza coat proteins, hemagglutinin and neuraminidase can contribute an understanding the virus and help develop improved diagnostics.

The usefulness of recombinant influenza proteins
Effects of mutations on:
 • Hemagglutinin receptor interactions
 • Sensitivity to antivirals (neuraminidase inhibitors)
 • Antigenicity
Serological studies
8:50 The Interplay of Viral Genes in Reassortment During Influenza Vaccine Seed Virus Production
  Joanna Cobbin, Department of Microbiology and Immunology, University of Melbourne
  Yields of egg-grown influenza vaccines are maximised by production of a seed strain using “classical reassortment” of the seasonal isolate with a highly egg-adapted strain. These seed strains are selected based on high-growth phenotype and the presence of the seasonal haemagglutinin (HA) and neuraminidase (NA) surface antigens. Retrospective analysis of H3N2 vaccine seed viruses indicated that, unlike other internal proteins, which were predominantly derived from the high growth parent, the polymerase subunit PB1 could be derived from either parent depending on the seasonal strain. In reassortment between A/Udorn/307/72 (Udorn) and egg-adapted A/Puerto Rico/8/34 (PR8) the seasonal PB1 gene is selected even though its inclusion with the seasonal HA and NA results in a poorer growing virus with less HA per virion. Competitive gene transfections were used to investigate the mechanisms driving selection and showed that the Udorn PB1 gene co-segregated with the genes encoding the surface glycoproteins originating from the seasonal strain. Analysis of chimeric PB1 genes determined that this observed co-segregation was not directed through the previously identified packaging sequences but interactions involving the internal coding region of the seasonal PB1 gene. This study identifies associations between viral genes that can direct selection in classical reassortment.

These findings may provide insight into:
• Improvements to the process of vaccine seed strain selection
• Novel methods to investigate preferential gene co-segregation
• Areas of the influenza genes controlling packaging of gene segments
• A possible mechanism explaining why PB1 may co-segregate with novel surface antigens in pandemic viruses
9:15 Using Ferrets to Assess the Potential for Influenza Virus Transmission via Respirable Aerosols
  Taronna Maines, Microbiologist, Influenza Division, Centers for Disease Control and Prevention
  Emerging influenza viruses that cause epidemics and pandemics represent a constant threat to public health worldwide. Transmission of influenza viruses occur in different ways but the relative predominance of each is not well understood and a role for respirable aerosols continues to be fiercely debated. A number of studies have reported the presence of viral RNA in respirable aerosols exhaled by individuals with influenza virus infections but information remains limited about the amounts of infectious virus present in those aerosols due to challenges in preserving the viability of virus during aerosol collection. Using the ferret model, we recently developed procedures in the laboratory allowing us to measure the amounts of infectious influenza virus in aerosols exhaled from animals infected by highly transmissible, human influenza viruses and to make comparisons with animals infected by avian influenza viruses that do not transmit as readily. Our findings provide support for the potential for influenza virus aerosol transmission.

• Improves the utility of the ferret model for influenza virus research and for the risk assessment of emerging influenza viruses
• Identifies procedures that improve the preservation of infectious influenza virus during aerosol collection
• Provides insight into a potential role for aerosols in influenza virus transmission
The Role of T-Cells
 Chairperson: Jonathan Yewdell, Chief, Cellular Biology Section, Laboratory of Viral Diseases, NIAID
9:40 Multiple CD4 Memory T Cell Subsets Protect via both Help and Cytotoxicity
  Susan Swain, Professor, Department of Pathology, University of Massachusetts Medical School
  The specialty pharmaceuticals industry has had an explosive growth. Analyst project that revenues will exceed $60 billion annually by the end of this decade. However, the issue that arises with these products is that there are not any alternatives to these agents. Payers are now having the challenge to bring specialty pharmaceuticals out of their silo in order to ensure adequate, appropriate and affordable access. A solution that many organizations are adopting is transitioning the management of specialty pharmaceuticals from the medical benefit to pharmacy benefit which is a significant change that is aggravated by high co-pay and co-insurance requirements. This workshop addresses key structure and management challenges, formularies and assesses the impact of managed care in-house specialty pharmacies.

The Evolution of Specialty Pharmaceuticals and the Impact on Formularies:
• What are key strategies that payers are developing to manage specialty pharmaceuticals and services?
• MCO in-house specialty pharmacies – what does this mean and what is the impact on formularies?
• What are the reviews like?
• What are the special handlings?
• What disease states present the most significant challenges
• What are the top five strategies that payers are looking to implement in the next five years?
10:05 Morning Networking Break
10:35 Nucleoprotein of Influenza A Virus is a Major Target of Immunodominant CD8+ T Cell Responses
  Weisan Chen, Professor, Department of Biochemistry, School of Molecular Science, La Trobe University
  To rationally design T cell based vaccines, we need to identify the most immunodominant T cell epitopes. In this study, we have used a systematic approach to identify immunodominant peptides in both HLA-A2 positive and HLA-A2 negative donors. A broad range of CD8+ T cell responses were observed in the 15 donors studied. Most donors had immunodominant responses against the relatively conserved internal nucleoprotein (NP). Dissecting the minimal epitope regions within the immunogenic NP led to the identification of many novel immunodominant epitopes, which include a 14mer and a 8mer peptides. The majority of immunodominant epitopes was clustered within the carboxyl terminal 2/3 of the NP protein and were highly conserved. We also subjected NP to three common computer algorithms for epitope prediction and found that most of the novel epitopes would not have been predicted. Our study emphasizes the importance of using a systematic approach to identify immunodominant CD8+ T cell responses and suggests the epitope-rich regions within NP present a promising target for the T cell-mediated multi-strain influenza vaccine.

Potential importance:
• Help us to understand anti-influenza immunity
• Help us to reveal the major HLA alleles
• Help us to design future T cell-based vaccines
• Important for monitoring T cell vaccine efficacy
11:00 Heterologous Immunity, T Cell Crossreactivity and Influenza
  Liisa Selin, University of Massachusetts Medical School
  Heterologous immunity occurring as a consequence of T cell cross-reactivity (XR) between unrelated pathogens, such as influenza A (IAV), vaccinia (VV), and arenaviruses, has been shown by us with animal models to contribute to reduced (beneficial) or enhanced viral loads, and remarkably altered immunopathology (detrimental). XR T cell expansions can change immunodominance hierarchies and narrow and skew the antigen-specific T cell repertoires. We have demonstrated heterologous immunity in human infections with Epstein-Barr virus (EBV), while other investigators have shown its role in influenza, dengue, and hepatitis C virus (HCV) infections. We have identified networks of cross-reactive (XR) CD8 T cells, which interact with BMLF1280 in HLA-A2+ patients with acute infectious mononucleosis (AIM) and have directly correlated the severity of AIM with the frequency of memory influenza A M158-specific CD8 T cells XR with EBV-epitopes. We have observed in 5 EBV-seronegative (EBV-SN) healthy adults a unique XR between M1-specific T cells and EBV epitopes raising the intriguing possibility that these may be protective. We have found the XR M1/BMLF1 repertoire to be completely different between the AIM patients the EBV-SN middle-aged donors suggestintg that TCR repertoire is determining the outcome of infection. Our recent data suggests that XR responses between EBV lytic antigens and IAV-M1 are being activated in patients with acute IAV infection. Our overall objective is to determine how XR T cells impact T cell selection and function and influence disease outcome, for better or worse, as the host is exposed to subsequent acute or persistent infections such as IAV or EBV. We continue to define new networks of XR T cell epitopes to common human pathogens using the Janus-matrix Platform. Insights on these issues are necessary for the intelligent design of effective modern vaccines without unwanted side effects and to develop therapeutic interventions when virus infection does induce immunopathology.
Antibodies & Vaccination
 Chairperson: Jonathan Yewdell, Chief, Cellular Biology Section, Laboratory of Viral Diseases, NIAID
11:25 Immune History Shapes Specificity of Influenza Antibody Responses
 

Scott Hensley, Assistant Professor, Wistar Institute
  Influenza viruses constantly accumulate mutations in antibody binding sites within the hemagglutinin and neuraminidase proteins, a process termed ‘antigenic drift’. Due to antigenic drift, humans are frequently re-infected with antigenically distinct influenza strains and vaccines must be updated routinely. As early as the 1950’s, it was noted that the human immune system preferentially mounts antibody responses to previously circulating strains, as opposed to new antibody responses that exclusively target newer viral strains. Remarkably, the specificities of antibodies elicited by sequential infections have not been examined in great detail. Here, we show that pre-exposure histories greatly influence the specificities of human influenza antibody responses. Importantly, sera isolated from ferrets recovering from primary influenza infections had similar specificities compared to human pediatric samples, whereas sera isolated from ferrets sequentially infected with antigenically distinct influenza strains had similar specificities compared to adult samples. Influenza vaccine strains are currently selected based on antigenic analyses using sera collected from ferrets recovering from a primary infection. Our studies indicate that these sera might not be fully representative of human population immunity.

• Humans are routinely re-infected with antigenically distinct influenza strains
• Pre-exposure history greatly influences specificity of antibody responses
• Influenza vaccine strains are currently chosen based on anti-sera generated in animals with no pre-exposure history
• This type of sera might not be reflective of human population immunity.
11:50 Influenza Vaccine Immunogenicity, Guidelines and Assays for Evaluation
  Emanuele Montomoli, Professor, Molecular and Developmental Medicine, University of Siena
  Correlates of protection against influenza viruses have not been fully defined, it is widely believed that protection against influenza can be conferred by serum haemagglutinin (HA) antibodies. The immune response to injected influenza vaccine are routinely assessed by titrating serological HA antibodies which can be detected in serum 3-4 weeks after primary infection or vaccination. The most commonly used serological assays used for influenza viruses include hemagglutination inhibition (HI), single radial haemolysis (SRH), microneutralization (MN), ELISA and Western blot. Recently, ELISA tests have been improved, thanks to the clarification of the structure of HA. HI and SRH remain the most commonly applied methods, while the latter is being increasingly replaced by MN. HI has low sensitivity in detecting responses to avian viruses. SRH utilizes a complement-mediated haemolysis reaction to measure the amount of antibody produced and appears to be as sensitive as the MN assay. Improvements in these assays will be a further step in the evaluation of new influenza vaccines. Additional immunological assessments, such as cell-mediated immunity and the role of neuraminidase, need to be explored to give better insight into the overall effects of vaccination. Development of new or improved influenza vaccines will require a definition of novel, and specific correlates of protection. These correlates should associate immune responses with outcomes that are relevant to specific age and risk groups, such as children and hospitalization.

• Improve know-how concerning the assays;
• More assays to choose for vaccines evaluation;
• Comparison of HI / SRH with MN results;
• Role of NA in the influenza vaccination;
• Correlates of protection for specific groups.
12:15 Lunch Provided by GTC
1:15 Rational Design of Influenza Vaccines for Older Adults: An in Vitro Model for Pre-clinical Testing
  Janet McElhaney, Health Sciences North Volunteer Association Research Chair in Geriatrics, Professor of Medicine, Clinical Sciences Division, Northern Ontario School of Medicine, Advanced Medical Research Institute of Canada
  Immune responses to influenza vaccination decline with aging due to changes in both innate and adaptive immune mechanisms. Our studies have shown that the addition of TLR ligands as adjuvants can be combined with seasonal influenza vaccine in older adult PBMC to enhance the response to live influenza virus challenge. Specifically, TLR4 ligand (GLA-SE) was shown to stimulate the production of pro-inflammatory cytokines (TNF-alpha, IL-1, IL-6) by myeloid dendritic cells. PBMC stimulated with vaccine/GLA-SE showed a significant enhancement of the cell-mediated immune response overcoming the age-related decline in the Th1:Th2 cytokine (IFN-gamma-:IL-10 ratio) and cytolytic (granzyme B) response to live influenza virus challenge. Key cytokines produced in response to GLA-SE when combined with seasonal influenza vaccines, enhance the cytolytic T cell response by improving the proliferation and preventing apoptosis of the critical mediators of killing of virus-infected cells. Thus, we predict that GLA-SE combined with seasonal influenza vaccine would enhance the T cell response to influenza and improve protection in older people by mechanisms that cannot be replicated by the simple addition of inflammatory cytokines to the vaccine.
1:40 Update on the Plant-Made Influenza Virus-Like Particles Vaccine Development
  Sonia Trepanier, Director, Preclinical and Clinical Studies, Medicago
  In the last decade it has been recognised that VLPs used as vaccines have the potential to allow for the full exploitation of the immunogenic potential of antigens. Combining a transient plant-based technology offering a rapid and low-cost production system with VLP technology increases the capacity to accelerate development of new vaccines.

Medicago is the most clinically advanced vaccine company using a plant-based production platform with ongoing clinical trials in two countries, which demonstrates the safety of the platform and process as well as the efficacy of influenza VLP vaccine products. This technology can enable the development of a vaccine for testing in approximately one month after the identification and reception of the genetic sequence for a pandemic strain, as was demonstrated at the onset of the 2009 pandemic.

This presentation will focus on the technology used to produce influenza VLP vaccines in plants, on VLP characterization, regulatory pathways and clinical trials data. Safety of VLP vaccines, including the absence of allergenicity from plant glycans will be discussed. Also, the extent of the immune response induced by plant-made influenza VLP vaccines will be shown including both humoral and cell-mediated immunity. Finally, clinical data along with recent preclinical data will illustrate the cross-reactive/protective potential of non-adjuvanted doses of plant-made influenza VLP vaccines.

In conclusion, Medicago’s VLP platform has the capacity to manufacture efficacious vaccines harboring unique intrinsic properties providing optimal humoral and cellular immune responses, long lasting immunity and broad protection against multiple Influenza strains. This platform can provide more potent vaccines with speed and cost advantages over competitive technologies and can allow vaccination of the population before the first wave of a pandemic strike. The plant production system can supply large volumes of vaccinal antigens.
2:05 Safety and Immunogenicity of Plant-produced Recombinant HA Vaccine in Human Volunteers
  Vidadi Yusibov, Executive Director, Fraunhofer USA Center for Molecular Biotechnology
  Novel influenza viruses continue to pose a potential pandemic threat worldwide. In recent years, plants have been used to produce recombinant proteins, including subunit vaccines. A subunit influenza vaccine, HAC1, based on recombinant hemagglutinin from the 2009 pandemic A/California/04/2009 (H1N1) strain of influenza virus, has been manufactured using a plant virus-based transient expression technology in Nicotiana benthamiana plants and demonstrated to be immunogenic and safe in pre-clinical studies. A first-in-human, Phase 1, single-center, randomized, placebo-controlled, single-blind, dose escalation study was conducted to investigate safety, reactogenicity and immunogenicity of an HAC1 formulation at three escalating dose levels (15 µg, 45 µg and 90 µg) with and without Alhydrogel®, in healthy adults 18-50 years of age (inclusive).

The experimental vaccine was safe and well tolerated, and comparable to placebo and the approved monovalent H1N1 vaccine. The HAC1 vaccine was also immunogenic, with the highest seroconversion rates, based on serum hemagglutination-inhibition and virus microneutralization antibody titers, in the 90 µg non-adjuvanted HAC1 vaccine group.
2:30 A Robust Flu Vaccine with Long-lasting, Cross-protective Immunity
 

Pamuk Bilsel, Chief Scientific Officer, Flugen
  Influenza (flu) virus causes a respiratory disease resulting in over 200,000 hospitalizations and ~ 36,000 deaths per year in the US Flu vaccines have remained virtually unchanged for decades. Despite the annual update of the three hemagglutinin (HA) vaccine antigens to match the circulating influenza strain, current vaccine efficacy is estimated to be ~60% across the population as a whole and much less for the elderly. Flu vaccine protection is sub-optimal and substantially lower than for most routinely recommended vaccines The low efficacy rates are due primarily to the relatively poor immune response provided by both inactivated and live vaccines. There is an urgent need for highly protective flu vaccines that provide broad-spectrum immunity across all segments of the population.

FluGen has developed a new vaccine, M2SR (Single Replication), which exploits the best features of both inactivated and live attenuated influenza vaccines. Like the inactivated vaccine, it elicits a strong humoral response against the major neutralizing antigen, the HA. Similar to the live attenuated influenza vaccine, it is administered intranasally to mimic a natural infection and induce broad-spectrum immunity including mucosal and cell-mediated responses. The novelty of M2SR is that the vaccine virus presents multiple antigen targets to the immune system like a wild-type virus and activates the immune system without production of progeny virus. We have shown that the M2SR vaccine provides broad-spectrum, long-lasting cross-protection against multiple influenza subtypes including H5N1 in mice and ferrets.

M2SR, a single replication next generation live flu vaccine
• Broad-spectrum immunity
• Mechanism of cross-protection
• Induction of long-lasting immunity
• Cell-based production
2:55 Afternoon Networking Break
3:25 Not Your Father’s Influenza Vaccine
  Wayne Hachey, Head, Government and Clinical Affairs, Protein Sciences
  A vaccine to prevent influenza was initially developed by the Department of Defense in the 1940’s. Today influenza vaccine production is still based on that decades old technology. One notable exception, Flublok, is FDA approved, does not use eggs or virus, does not require egg attenuated strains or thimerosal. Flublok was recently cited by The ACIP for use in individuals with severe egg allergy. It is pure, safe and effective. Flublok is the first recombinant influenza vaccine. Using a cell line from the ovaries of the Army Caterpillar Worm, this platform leverages the natural infection process of insect cells by baculoviruses. The baculoviruses is re-engineered such that it programs the infected insect cells to generate large quantities of desired recombinant protein(s). Our proprietary expressSF+ cell line has been optimized for this purpose. The end result is the production of large amounts of pure protein, generated more quickly and less expensively than other production system. In non-inferiority trials Flublok is comparable or in some cases better than egg based vaccine. This technology permits the rapid production of large amount of vaccine shortly after the appearance of novel strains of Influenza.

• Introduction to a new vaccine production platform.
• Universal acceptance of an influenza vaccine is partially dependant on overcoming public concern regarding purity, mercury, egg protein and antibiotic exposure.
• To counter the next pandemic, a platform that permits rapid vaccine production without reliance on egg based production methods is imperative.
• Awareness of a vaccine production platform that can be modified to address current and future biological threats.
Antivirals & Therapeutics
 Chairperson: Larisa Gubareva, Team Leader, Influenza Division, Centers for Disease Control and Prevention
3:50 New Viruses, New Antivirals: Old and New Challenges for Public Health
  Larisa Gubareva, Team Leader, Influenza Division, Centers for Disease Control and Prevention
  A number of factors make influenza a challenging target for antiviral development. Recent human infections with H3N2v, H7N9, and other zoonotic viruses reinforce the existing concerns of an impending pandemic. Current therapeutic options available for managing influenza infections are limited to the two FDA-approved neuraminidase inhibitors, oseltamivir (oral) and zanamivir (inhalation), due to the widespread resistance to M2-blockers. A potential for rapid emergence of viruses resistant to neuraminidase inhibitors necessitates the development of drugs with alternative mechanisms of action, as well as drugs with broad-spectrum activity. Regardless of the antiviral drugs used, emergence and transmission of resistant variants must be monitored. Presently, drug-resistance testing in the clinical settings is very limited and monitoring is mainly conducted by CDC and public health laboratories. Detection of resistance using genotypic assays, such as pyrosequencing, requires knowledge of molecular markers of resistance, which may not be available for newly emerged viruses. CDC conducts research to identify potential resistant markers of novel viruses, such as H7N9/2013, as well as carries out susceptibility assessment to FDA-approved and investigational drugs. To assist with the development of new antiviral drugs and detection methods, CDC provides an array of reference viruses and other materials.

• Emerging and re-emerging influenza viruses pose a threat to human health
• Only two FDA-approved drugs are available for control of influenza infections
• Broad-spectrum antiviral drugs and drugs with alternative mechanisms are needed
• Antiviral testing in the clinical setting is very limited
• Reference materials are available, although sparse
4:15 Exploring Host Targets for New Influenza Antivirals
  Megan Shaw, Associate Professor, Department of Microbiology, Icahn School of Medicine at Mount Sinai
  The vast majority of antiviral drugs available today are directed at the function of a viral protein and consequently, resistance is a common problem. Of the two classes of FDA-approved influenza antivirals, only the neuraminidase inhibitors are currently recommended for clinical use due to widespread resistance to the adamantanes. This leaves us with few therapeutic options. An alternative strategy, and one that should reduce the chance of resistance, is to target a host factor that is required by the virus for efficient replication. As a small RNA virus, influenza virus relies heavily on host cellular functions and several RNA interference (RNAi) screens have been performed to identify these required host factors. In total these screens have implicated over 1000 human proteins but there is minimal overlap between the screens and greater evidence for the vital role of a particular host factor is required to support its selection as a drug target. To this end we have employed an integrated “OMIC” approach to prioritize host factors with the most support for a role during influenza virus infection. Moreover, we have incorporated data on respiratory syncytial virus (RSV). Although these two viruses have distinct genetic structures, they encounter a similar host factor repertoire in the human respiratory tract and therefore they likely share dependency on many cellular functions. We believe that this strategy greatly facilitates the identification of host factors to explore as targets for broad-spectrum antiviral drugs.

• Current influenza drugs target viral proteins
• Resistance to current influenza drugs is a growing problem
• Host factors required by influenza virus are potential targets for new drugs
• The benefits of targeting host factors are reduced chances of resistance and potential for achieving broad-spectrum antiviral activity.
4:40 Influenza Viruses and Host Cell Signaling – Identification and Preclinical Evaluation of Novel Targets for Antiviral Therapy
  Oliver Planz, Professor, Immunology and Cell Biology, University of Tubingen
  Influenza virus exploits a number of cellular signaling pathways during the course of its replication, rendering them potential targets for new therapeutic interventions. Several preclinical approaches are now focusing on cellular factors or pathways as a means of treating influenza. By targeting host factors, rather than viral mechanisms, these novel therapies may be effective against multiple virus strains and subtypes, and are less likely to elicit viral drug resistance. The most promising candidates are inhibitors of intracellular signaling cascades that are essential for virus replication. This presentation reviews novel approaches and compounds that target the Raf/MEK/ERK signaling pathway and the NF-kappa B signaling cascade. Although these new antiviral strategies are still in an early phase of preclinical development, results to date suggest they offer a new approach to the treatment of influenza, supplementing direct-acting antiviral drugs.

Influenza viruses and host signaling – novel targets for antiviral therapy:
• What is the mode of action of intracellular signaling inhibitors as antivirals against influenza?
• What are the most promising targets?
• What are the most promising compounds?
• Are antiviral drugs against influenza targeting cell signaling pathways inherently toxic?
• Are clinical trials in progress?
5:10 [Oral Presentations from Exemplary Submitted Abstracts]
  To be considered for an oral presentation, please submit an abstract here by June 10, 2013. Selected presentations will be based on quality of abstract and availability. Presentation slots fill up fast so please submit your abstract ASAP.
5:35 End of Day 2
Day 1 Day 2 Day 3
Day 3 - Wednesday, July 10, 2013
7:00 Continental Breakfast & Registration
8:00 Chairperson's Opening Remarks
Influenza Pandemic Preparedness
 Chairperson: Klaus Stohr, Vice President, Global Head - Influenza Franchises, Novartis Vaccines and Diagnostics
  FEATURED PRESENTATION
8:15 Pandemic Responses: Past, Present, and Future
 
Robin Robinson
Director, Biomedical Advanced Research and Development Authority
U.S. Department of Health & Human Services
 
9:00 Lessons Learned from the 2009 H1N1 Pandemic Influenza Virus and Vaccine
  Hong Jin, Senior Fellow, Infectious Disease/Vaccine Research, MedImmune
  The issues that were encountered in the rapid delivery of the 2009 H1N1 pandemic vaccine included low vaccine yield, resistance to bromelain cleavage for HA antigen production and lower vaccine thermal stability. We have since solved these problems. We identified several key amino acids (119, 125, 127, 186) in the HA and one residue in the NA (369) that could improve vaccine virus yield without affecting antigenicity. We found that the E374 (HA2 #47) residue in the stalk region rendered the HA insensitive to the bromelain cleavage and also contributed to a higher pH (5.4) fusion threshold compared to the viruses with K374. We proved that the inter-monomer polar interaction between the highly conserved E21 and K374 residues lowered pH (5.0) fusion threshold and conferred higher structural and thermal stability.

Next, we evaluated the contribution of H1N1pdm-specific antibodies from natural infection or acquired maternally in preventing subsequent virus infection and on vaccine mediated immune responses in ferrets. In addition, using newly developed ferret cellular immune reagents and assays, we showed that the live attenuated influenza vaccine containing the H1N1pdm vaccine component not only elicited stronger influenza-specific serum antibody responses but also T cell responses than the inactivated vaccine, in both naïve and influenza-seropositive animals. The H1N1pdm vaccine also offered significant protection against a heterologous seasonal H1N1 virus challenge infection in the upper respiratory tract of ferrets. The lessons learned from the 2009 influenza pandemic will enable better response to the next influenza pandemics.
9:25 Stockpiling to Meet a Pandemic Threat - Exploring the Potential of Adjuvanted Influenza Vaccine
  Steve Rockman, Associate Director, Influenza R&D, BioCSL Ltd Australia
  A pressing public health challenge in the event of an emerging pandemic is the hiatus between disease outbreak and the production and distribution of a strain-matched vaccine. In an attempt to address this need, we investigated the use of stockpiled antigen (H5N1 and seasonal) with a potent adjuvant to assess its ability to invoke a broadly protective response.

ISCOMATRIX™ adjuvant is a potent, saponin-based adjuvant that evokes broad, high-titre, long lasting antibodies and cellular immune responses (CD4 & CD8). ISCOMATRIX™ adjuvant combined with H5N1 antigen has been evaluated in a ferret model of human influenza disease and has been shown to provide single-dose protection against death after lethal H5N1 virus challenge. The H5N1 influenza ISCOMATRIX™ adjuvant vaccine reduced morbidity, decreased viral shedding, was dose sparing and displayed cross clade protection.

As some degree of cross-reactivity between seasonal influenza vaccines and H5N1 virus has been reported, we sought to explore this further in the ferret model. Ferrets given two doses (Day 0 and 21) of an adjuvanted seasonal influenza vaccine (Afluria® with ISCOMATRIX™ adjuvant) survived a lethal H5N1 challenge with minimal morbidity or weight loss compared to Afluria® alone.

Further exploration of the specific components of the seasonal vaccine (H1N1, H1 or N1) demonstrated that, in the presence of ISCOMATRIX™ adjuvant, either of these components could fully protect against a lethal pandemic challenge whereas a H3N2 ISCOMATRIX™ vaccine could not. These data suggest that formulating stockpiled H5N1 antigen with ISCOMATRIX™ adjuvant may provide interim coverage in the early stages of a pandemic while homologous vaccine is developed.
9:50 Synergy Between M-001 and H5N1 Vaccines: A New Approach to Pandemic Preparedness
  Tanya Gottlieb, Business Development, BiondVax
  M-001 is a recombinant universal influenza vaccine candidate comprising conserved T- and B-cell epitopes from 3 influenza proteins that has been designed to elicit both cellular and humoral influenza-specific immunity and protect against a broad array of A and B, seasonal and pandemic, present and future influenza strains. M-001’s positive safety profile and broad anti-influenza immunogenicity has been demonstrated in numerous pre-clinical studies and 4 human trials (two Phase 1/2 and two Phase 2) in adults and elderly involving 440 participants. M-001 has also demonstrated synergy with existing strain-specific influenza vaccines when administered in a prime-boost regimen. This synergy endows M-001 with the capability to transform pandemic influenza preparedness, as envisioned theoretically by Dr Robin Robinson, Director of BARDA, in 2012. Indeed, in a Phase 2 study performed by the Company, priming with M-001 three weeks before the 2011/12 TIV resulted in significantly more elderly (aged 65+) seroconverted towards the constituent H1N1 pandemic swine influenza strain (A/California/7/09), as compared to elderly persons administered the TIV alone. This is the first-in-man demonstration of a universal influenza vaccine candidate serving as a primer for a pandemic influenza strain. Further, in a mouse model, priming with M-001 was shown to result in higher GMT HAI antibody titers and 100% seroconversion after only one H5N1 administration; proof-of-concept for the immunological and dose sparing benefits of M-001 priming of a poorly immunogenic H5N1 vaccine. We propose the universal flu vaccine M-001 is a new paradigm for pandemic preparedness - a pandemic primer that could be stockpiled and administered upon pandemic alert, during the period that a pandemic strain-specific vaccine is being manufactured.

New Paradigm for Influenza Pandemic Preparedness: Synergy between M-001 and H5N1 vaccines
• Stockpiling of pre-pandemic influenza vaccines is expensive and the strain is likely to be a mismatch
• M-001 vaccine comprises a recombinant protein manufactured economically via fermentation that can serve as a priming vaccine for all pandemic strain-specific vaccines

M-001 priming would potentially enable:
• Superior HAI immune responses to pandemic vaccine
• Dose sparing of pandemic vaccine (one instead of two administrations per person)
• More economical and relevant stockpile maintained in preparation for influenza pandemic
10:15 Morning Networking Break
Joint Session with 11th Vaccines Research & Development:

Development of a Broadly Reactive / Universal Influenza Vaccine
 Chairperson: Jonathan Yewdell, Chief, Cellular Biology Section, Laboratory of Viral Diseases, NIAID
 10:45 FEATURED PRESENTATION
  Human Monoclonal Antibodies to Prevent and Treat Influenza A Including Infections by H5N1 and H7N7
 
Jaap Goudsmit
Director and Chief Scientist, Crucell Vaccine Institute
Janssen Center of Excellence for Immunoprophylaxis
  Recently we described a series of human monoclonal antibodies against the stem region of hemagglutinin of the influenza A virus. These antibodies protect mice from either infection by H1N1 and H5N1, like the antibody CR6261 or infection by H3N2 and H7N7, like the antibody CR8020. Relatively low dosages of CR 6261 protect against H1N1 and H5N1 infection while higher dosages protect against disease when administered up to 5 days after challenge. The mutations in H5N1 that are needed for human-to-human transmission, as described by Kawaoka and Fouchier have no impact on the binding of CR6261.

Similarly relatively low dosages of CR8020 protect against H3N2 and H7N7 infection while higher dosages protect against disease when administered up to three days after infection. CR8020 recognizes an epitope that is completely conserved between the H7N7 strain (A/chicken/Netherlands/621557/03), used for our challenge experiments and the H7N9 strain (A/Hangzhou/1/2013) infecting humans in China.

Most recent data on the mechanism of action of CR6261 and CR8020 will be discussed as well as the progress towards proof of concept in humans for both prevention and treatment of infections by either seasonal or pandemic influenza A viruses.
11:10 Broad Neutralization of Influenza Virus and Implications for a Universal Vaccine
  Ian Wilson, Chair and Professor, Department of Integrative Structural and Computational Biology, The Scripps Research Institute
  The major surface antigen, the hemagglutinin (HA), of influenza virus is the main target of neutralizing antibodies. However, most antibodies are strain-specific and protect only against highly related strains within the same subtype. Recently, a number of antibodies have been found that are much broader and neutralize across subtypes and groups of influenza A, as well as influenza B, viruses through binding to functionally conserved sites. We have determined co-crystal structures of broadly neutralizing antibodies with the HA and have identified highly conserved sites in the HA fusion domain (stem) in influenza A (1,2) as well as influenza B (3.) We have also structurally characterized antibodies that bind to the conserved receptor binding site and protect against different strains and subtypes (e.g. Ekiert Nature(4), Xu NSMB(5)) The identification and characterization of these exciting new antibodies provide new opportunities for structure-assisted vaccine design as well as potential therapeutics that afford greater protection against influenza viruses.

Advances in Influenza Research:
• Identification of broadly neutralizing epitopes
• Mechanisms of antibody neutralization
• Structure-assisted vaccine design
11:35 Development of Broadly Reactive Influenza Vaccine
  Ted Ross, Professor, Vaccines and Infectious Disease, Vaccine and Gene Therapy Institute of Florida
  Background: Pandemic outbreaks of influenza are caused by the emergence of a pathogenic and transmissible virus to which the human population is immunologically naïve. Recent outbreaks of highly pathogenic avian influenza (HPAI) of the H5N1 subtype are of particular concern because of the high mortality rate (60% case fatality rate) and novel subtype. In this study, we have engineered an influenza virus-like particle (VLP) that contains a synthetic, consensus-based HA molecule based upon a new methodology, computationally optimized broadly reactive antigen (COBRA). The first COBRA designed HA antigen was designed using H5N1 clade 2 human isolates as input sequences. Subsequent COBRA HA proteins have been generated to include all H5N1 clades and also novel/seasonal (H1N1) influenza.

Results: The COBRA clade 2 HA protein retained the ability to bind the appropriate receptors, as well as mediate particle fusion. We then generated a non-infectious recombinant VLP vaccine using the COBRA clade 2 HA from a mammalian expression system. COBRA clade 2 HA H5N1 VLP vaccines were administered to mice, ferrets, and cynomolgus macaques and the humoral immune responses were compared to those induced by VLPs containing an HA derived from a primary viral isolate or a mixture of primaray isolates. All animals vaccinated with COBRA clade 2 HA H5N1 VLPs had protective levels of HAI antibodies to a representative isolate from each subclade of clade 2, as well as divergent clades 1, 4, and 7. Furthermore, all vaccinated animals were completely protected from challenge with the highly pathogenic clade 2.2 H5N1 virus.

Conclusion: This is the first report describing the use of a H5N1 VLP vaccine containing a synthetic HA antigen. The results show that the COBRA clade 2 HA H5N1 VLP elicits broad humoral immunity and is an effective influenza vaccine against HPAI virus in multiple animal models.
12:00 Role of Mucosal Immune Responses in a Universal Influenza DNA Vaccine
  Deborah Fuller, Associate Professor of Microbiology, University of Washington
  Recent avian and swine-origin influenza virus outbreaks illustrate the ongoing threat of another influenza pandemic. New vaccines that offer accelerated production and broader, more universal protection against drifted and shifted strains are therefore urgently needed. We previously showed that a particle-mediated epidermal delivered (PMED) influenza DNA vaccine expressing a single hemagglutinin antigen (HA) induced protective levels of antibody in humans. In mice and monkeys, we now show that co-formulating PMED DNA vaccines with genetic adjuvants further increases the breadth in specificity and magnitude of antibody and T cell responses offering new promise for use of DNA vaccines alone to address the need for an effective universal influenza DNA vaccine. Adjuvant co-delivery also significantly increases mucosal immunogenicity of PMED-delivered influenza DNA vaccines, an effect that correlates with improved protection from heterosubtypic challenges and suppression of acute viral replication in the lungs of mice. In mice and monkeys, we are investigating immunogenicity and efficacy of a candidate multivalent universal influenza DNA vaccine expressing avian, human, and swine-origin HA, an optimized nucleoprotein and the ectodomain of M2 (M2e) fused to a highly immunogenic carrier genes. The effects of 2 lead genetic adjuvants, GM-CSF and E.Coli heat-labile enterotoxin (LT) on mucosal immunognenicity, protection, and the role of mucosal responses induced by this vaccine in protection in mice and a nonhuman primate model for influenza will be presented.

• Relative immunogenicity of a candidate influenza DNA vaccine in mice, monkeys, swine, and humans. How well do preclinical animal studies predict outcomes of DNA vaccines in the clinic?
• What are the effects of lead adjuvants on mucosal immunogenicity of influenza DNA vaccines?
• What is the role of mucosal vs. systemic responses in protection from influenza in mice and a nonhuman primate model for influenza?
12:25 Conference Concludes
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