11th Vaccines Research and Development: All Things Considered 11th Vaccines Research and Development: All Things Considered 11th Vaccines Research and Development: All Things Considered 11th Vaccines Research and Development: All Things Considered 11th Vaccines Research and Development: All Things Considered 11th Vaccines Research and Development: All Things Considered 11th Vaccines Research and Development: All Things Considered 11th Vaccines Research and Development: All Things Considered
Register by June 8th, 2013 for a 10% discount. Or register for 2, the 3rd goes FREE the coupon code RCDVB!
Day 1 Day 2 Day 3
Day 1 - Monday, July 08, 2013
Plenary Keynote Session
Chairperson: Nathalie Garcon, Vice President, Head of Global Adjuvant Center for Vaccines, GSK bio
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 2nd Influenza 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
  FEATURED PRESENTATION
4:35 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.
   FEATURED PRESENTATION
5:00 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
Vaccines for the Developing World
Chairperson: Joseph Joyce, Director, Vaccines Research, Merck Research Laboratories
8:00 The Critical Role of Vaccines in Global Health
  Kim Bush, Director, Life Sciences Partnerships, Bill & Melinda Gates Foundation
  Vaccines are one of the most cost-effective investments that can be made in Global Health. They are the primary reason that the number of children dying worldwide has dropped by 65% in the last 50 years. Yet today, over 1,500 people per hour still die of infectious disease, most are in the developing countries and most are children under the age of five.

The science and resources needed to address vaccine development and product delivery challenges are unique and complex for global health. As such, innovative technologies, partnerships, and funding mechanisms are needed to deliver the best possible solutions.

This discussion will provide visibility and insight into the ways that industry can engage with global stakeholders to help improve the lives of millions of people around the world under sustainable business constructs that leverage the power of diverse partnerships

Industry Engagement in Global Health Partnerships
• What progress has been made in global health through the benefit of vaccines
• How do industry, government, academia, NGOs, and donors collaborate to address global health challenges
• How is innovation and science used to the address the needs of people in poorly resourced countries
• What types of program related investments are available to industry to advance vaccine programmatic work across the full breadth of the development cycle
• What are the benefits to industry for participating in global health partnering
8:25 Roles for Nongovernment Organizations (NGOs), Private Voluntary Organizations (PVOs), and Private Sponsors in New Vaccines for the Developing World
  John Donnelly, Director, Polio Vaccine Development and Scale-up Project, PATH
  Until comparatively recently, new vaccines for public markets in developing countries came from multinational vaccine manufacturers. Contributions by multinationals to immunization in public markets were limited by high production costs and expectations of high markups.

GAVI (NGO) sponsors UNICEF (NGO) to purchase vaccines by tender, allowing for price competition in public markets and creating opportunities for developing country vaccine manufacturers (DCVMs). DCVMs initially developed capacity to produce DTP and BCG vaccines for local use and reinvested to build modern production facilities and add process development capacity. Adding new vaccines to the UNICEF tender program drives uptake in developing countries and expands markets for DCVMs.

Because of their narrow profit margins few DCVMs are able to sustain significant R&D. Therefore few new vaccines have been specifically tailored for the developing world. With the help of donors such as the Bill & Melinda Gates Foundation this situation has improved. New vaccines specifically aimed at developing world markets have been introduced for meningitis A, and are under development for rotavirus, influenza, meningitis ACWYX, polio, and pediatric combinations.

PVOs such as PATH help DCVMs to obtain R&D expertise from universities, vaccine companies and independent consultants, and guides them through preclinical and clinical development of new vaccines, based on existing technologies, but with process improvements to reduce costs and maximize effectiveness in developing world settings.
 
Continued investment in NGOs and PVOs by governments and donors can ensure continued innovation to improve the availability of new vaccines in developing countries.
8:50 Developing Novel Vaccines to Address Unmet Needs in Emerging Economies
  Dan Stinchcomb, Cofounder and CEO, Inviragen
  Future vaccine industry growth is predicted to be driven outside the traditional markets of the U.S. and the EU. The continued emergence of devastating infectious diseases in developing world countries further accentuates the need for novel vaccines. Inviragen has translated two such vaccines from the research bench to the clinic. Inviragen’s lead vaccine, DENVax, is designed to protect against dengue fever, a mosquito-borne disease that threatens 3.6 billion people who live in tropical and sub-tropical regions around the globe. Inviragen has completed two phase 1 clinical trials and has five studies ongoing in three continents worldwide. Clinical development requires early phase testing of multiple formulations, different administration routes and alternative dosing schedules. Ultimately, safety and immunogenicity must be demonstrated in multiple age groups and in both dengue endemic and dengue non-endemic countries. Inviragen’s second vaccine is designed to protect against hand, foot and mouth disease (HFMD) caused by enterovirus EV-71. Large epidemics of HFMD have plagues children in Asia for the last twenty years. Inviragen had completed a phase1 clinical trial and will be initiating a phase 2 study of it’s EV71 vaccine this year. Clinical development of an EV-71 vaccine entails demonstrating safety and immunogenicity in children as well as the ability to protect against HFMD caused by EV71. Each vaccine represents unique development and regulatory challenges yet each also could greatly improve public health in endemic countries.

• Which unmet disease needs represent attractive vaccine market opportunities?
• What role can vaccine biotechnology companies play in developing such vaccines?
• Which vaccine technologies should be used to address such diseases?
• What are the clinical issues that are unique to these diseases?
• What are the regulatory challenges in developing these vaccine for markets outside the US and Europe?
9:15 Novel TB Vaccines: Progress and Challenges
  Ann Ginsberg, Vice Presdent, Scientific Affairs and Acting Chief Medical Officer, Aeras Foundation
  Over the past decade, Aeras, its partners, and others have for the first time in history built a portfolio of clinical TB vaccine candidates. The need for improved TB vaccines will be reviewed and a recent assessment of both potential public health impact and market size will be provided. There are at least 15 candidates that have been or currently are in clinical trials. The portfolio will be presented, and implications of recent clinical trial results for the clinical portfolio and discovery/preclinical research will be discussed. Key challenges in R&D and current thinking about how to overcome these hurdles will also be discussed.

Attendees will learn about the following:
• Why do we need better TB vaccines than BCG? What is the potential public health impact?
• What are the global priorities for improved TB vaccines?
• What candidates are currently in the global clinical portfolio of novel TB vaccines?
• What are the major challenges to success in this field and what are the approaches being taken to overcome them?
• What does the potential market for a preventive TB vaccine look like?
9:40 The Development of Vaccines to Support Malaria Elimination and Eradication
  Ashley Birkett, Director, Research & Development , PATH
  According to WHO estimates, 3.3 billion people are at risk of malaria and there are more than 200 million cases and 650,000 deaths each year. The vast majority of clinical cases (~80%) and deaths (~90%) occur in sub-Saharan Africa, with children under five years of age and primigravid pregnant women most affected. Between 2000 and 2010, the estimated incidence of malaria declined by 17% and malaria-specific mortality rates by 26%. Despite these encouraging gains, associated with the scale-up of preventive, diagnostic, and treatment measures, new interventions are urgently needed. To accelerate elimination and eventual eradication of malaria, interventions that interrupt the cycle of transmission between humans and mosquitoes, and can be implemented safely and effectively, even in the most challenging environments, are required.

Vaccines have been used successfully to eradicate two infectious diseases (smallpox and rinderpest). There is compelling biological evidence that vaccines can induce immunity to block the cycle of malaria transmission from humans to mosquitoes and from mosquitoes to humans. Efforts are underway to translate these findings into highly effective vaccines that can be implemented along with other interventions to accelerate malaria eradication.

Key questions underlying the development of vaccines for malaria elimination and eradication include:
• What is the target product profile (TPP) of a malaria vaccine for elimination/eradication?
• What are the key challenges in the development and licensure of vaccines to break the cycle of transmission, compared to those intended to prevent clinical disease and death? How are these challenges being addressed?
• What are the leading strategies for development of vaccines to support elimination and eradication?
10:05 Morning Networking Break
10:35 New Approaches to HIV Vaccine Design
  Rick King, Vice President of Vaccine Design, AIDS Vaccine Design & Development Laboratory, IAVI
  Generation of a broadly effective HIV vaccine will require a solution to the problem of HIV diversity. Recent results of the RV144 trial suggest that a vaccine is possible and that the elicitation of antibody responses may be critical for activity. Unfortunately, the generation of broadly neutralizing antibodies by vaccination has so far proved unsuccessful. New approaches are emerging that may overcome this hurdle. These include developing highly specific immunogens that mimic the antigenic determinants recognized by broadly neutralizing antibodies found in infected people. Another is to deliver mimics of the native functional Envelope spike that is the target of all broadly neutralizing antibodies identified so far. Developing vaccines to deliver native Envelope spikes has proved to be challenging and the immunogens tested to date do not assume a fully native conformation. We have generated replication competent virus vectors that express Envelope in a native configuration in transduced cells and on the virus particle surface. These new immunogens are currently being tested in animal systems.

• Introduction to the requirements of a broadly effective HIV Vaccine.
• Use of new technologies to define the targets of broadly neutralizing antibodies.
• Use of new technologies to display immunogens.
• New ways to analyze immunogenicity results.
11:00 Molecular Approaches to HIV-1 Envelope Glycoprotein Vaccine Research
  Michael Zwick, Associate Professor, Department of Immunology and Microbial Science, The Scripps Research Institute
  A vaccine is desired to prevent HIV/AIDS but eliciting neutralizing antibodies to primary isolates is a major stumbling block. HIV-1 neutralizing antibodies target envelope glycoprotein (Env) trimeric spikes on the virus. However, because native Env trimers can dissociate and coexist with non-fusogenic forms of Env interpreting these results is difficult. In one study, antibodies were elicited in rabbits against Env subunit gp120 that showed extremely high potency to a single primary isolate. The epitopes targeted overlap with conserved receptor binding sites and the glycan shield of gp120. We have more recently been focusing on stabilizing the native Env trimer to facilitate its analysis as an immunogen at the molecular level and to mitigate confounding effects of its decay. We used directed evolution to select for HIV-1 virions that display native Env with increased stability and homogeneity. In an alternative strategy, we have been using chemical crosslinking to stabilize and purify native Env. With both subunit and trimeric Env approaches, issues surrounding Env presentation to the immune system and immunodominance may need to be overcome to deal with this difficult but important vaccine target.

Benefits:
• overview of the classic neutralizing antibody problem with HIV-1
• example of a potent antibody response to HIV-1 in animals
• examples of how instability of HIV-1 spikes can be overcome
• summary of additional obstacles to be faced in HIV-1 Env vaccine design
11:25 Novel HIV Vaccine Strategies
  Dan Barouch, Professor, Medicine, Harvard Medical School; Director, Center for Virology and Vaccine Research, Beth Israel Deaconess Medical Center
  Alternative serotype adenovirus (Ad) vectors such as Ad26 and Ad35 are biologically substantially different than Ad5 vectors. We have previously shown that Ad26/MVA and Ad35/Ad26 regimens expressing SIVsmE543 antigens afforded partial protection against both acquisition of infection as well as virologic control following fully heterologous, neutralization-resistant, intrarectal SIVmac251 challenges in rhesus monkeys. We have now extended these findings with the observation that Ad/MVA and Ad/Ad vector regimens expressing HIV-1 mosaic antigens afforded partial protection against acquisition of infection following fully heterologous, neutralization-resistant, intrarectal SHIV-SF162P3 challenges in rhesus monkeys. We have also produced stable Env gp140 trimers and have observed that the inclusion of a protein boost augments protective efficacy against both SIV and SHIV challenges. Clinical development strategies for Ad26/MVA vectors expressing HIV-1 mosaic antigens with and without an Env gp140 trimer protein boost will be discussed.
11:50 The Role of USAID in this Decade of Vaccines
  Angela Shen, CAPT, US Public Health Service, USAID - Global Health Bureau
  In an era coined as the Decade of Vaccines the global immunization community is committed to the vision of a world in which all individuals and communities enjoy lives free from vaccine-preventable diseases. A global health priority for USAID is Ending Preventable Child and Maternal Deaths by 2035. Immunization is central to achieving accelerated declines in under five mortality toward this priority, particularly in 24 USAID priority countries which compromise over 75% of maternal and child deaths globally. This talk provides an overview of USAIDs investments in global immunizations including USAIDs role in GAVI and the role and work of USAID and its implementing partners at the country level.
12:15 Lunch Provided by GTC
Government & Biodefense Programs
Chairperson: David Weiner, Professor, Department of Pathology and Laboratory Medicine; Chair, Gene Therapy and Vaccine Program, CAMB, University of Pennsylvania Perelman School of Medicine
1:15 Current Biodefense Vaccine Programs and Challenges
  William C. Florence, Acting Branch Chief, Medical S&T Division, Vaccines, DTRA - JSTO
  The Defense Threat Reduction Agency’s Joint Science and Technology Office manages the Chemical and Biological Defense Program’s Science and Technology portfolio. The Joint Science and Technology Office’s mission is to invest in transformational ideas, innovative people, and actionable technology development for Chemical and Biological Defense solutions, with the primary goal to deliver Science and Technology products and capabilities to the warfighter and civilian population that outpace the threat. This commentary focuses on one thrust area within this mission: the Vaccine program of the Joint Science and Technology Office’s Translational Medical Division. Here, we will describe candidate vaccines currently in the S&T pipeline, enabling technologies that should facilitate advanced development of these candidates into FDA licensed vaccines, and how the ever-changing biological threat landscape impacts the future of biodefense vaccines.
1:40 [Tentative]: Connie Schmaljohn, Chief Scientist, USAMRIID
New Vaccines & Future Trends in Vaccine Development
Chairperson: David Weiner, Professor, Department of Pathology and Laboratory Medicine; Chair, Gene Therapy and Vaccine Program, CAMB, University of Pennsylvania Perelman School of Medicine
2:05 Technologies for New and Improved Vaccines
  Jeffrey Ulmer, Global Head, External Research, Novartis Vaccines & Diagnostics
  Vaccines are without a doubt the most successful of mankind’s medical interventions. However, despite more than two centuries of effective use of vaccines, many substantial challenges remain. These include: 1) improvement of existing but suboptimal vaccines (e.g., tuberculosis, influenza), 2) discovery and development of new vaccines against targets to address large unmet medical needs (e.g., HIV, malaria, cancer), and 3) rapidly responding to new pathogens (e.g., newly emerging microbes, bioweapons). Advances in these areas will require the application of new technologies and paradigms in the areas of antigen identification and optimization, novel potent and safe adjuvants, and enhanced vaccine delivery systems.
2:30 LEAPS Technology Vaccines That Promote Dendritic and T cell Responses Including Anti-HER-2/neu in a Mouse Model of Breast Cancer
  Ken Rosenthal, Professor, Microbiology, Immunology and Biochemistry, Northeastern Ohio Medical University
  The Ligand Epitope Antigen Presentation System (LEAPSTM) converts a peptide containing a T cell epitope as small as 8 amino acids into an immunogen and directs the nature of the subsequent response. The J-HER vaccine was produced by tandem synthesis of the J peptide (a peptide from the beta-2-microglobulin), a triglycine linker, and a CD8 T cell epitope from HER-2/neu. J-HER elicited responses that prevent and block the progression of tumor growth of HER-2/neu expressing TUBO cells in mice, a breast cancer model. A similar LEAPS vaccine against HSV-1 (JgD) elicited protection by promoting maturation of dendritic cell precursors and then stimulating T cell but not antibody protections against lethal viral challenge. JgD also stimulated human monocyte differentiation into dendritic cells. Mice immunized with J-HER twice at 2 week intervals one week prior to tumor challenge had significantly smaller tumors compared to unimmunized mice. Immunization of mice one week after tumor implantation reduced or blocked tumor growth. Unlike other protein vaccines, J-LEAPS vaccines act as both adjuvant and immunogen to promote the maturation of dendritic cell precursors into cells which initiate and direct T cell immune responses to the incorporated epitope. The J-HER vaccine is the prototype for other anti-cancer LEAPS vaccines with potential for translation to human tumor therapy.

• Overview of LEAPS vaccine platform technology
• J-LEAPS vaccine activation of dendritic cells and T cell responses
• J-HER incorporates a minimal T cell epitope from HER-2/neu and confers protection and treatment of breast tumors in a mouse model
• J-HER as a prototype for other tumor vaccines
2:55 Afternoon Networking Break
3:25 Crystal Structures of HIV-1 gp41 Peptide and Small Molecule Mimetics Bound to Neutralizing Antibody D5
  Joseph Joyce, Director, Vaccines Research, Merck Research Laboratories
  The N-heptad repeat (NHR) region of HIV-1 gp41 has been validated as a potential vaccine target by the identification of a number of neutralizing monoclonal antibodies including D5, 8K8, HK20, and DN9, which bind in or near a highly conserved hydrophobic pocket within the pre-hairpin fusion intermediate (PHI). Recently, we reported that a peptide mimetic of the PHI, (CCIZN36)3, elicits a polyclonal neutralizing antibody response in animals. Separately, we have shown that a benzyl piperidine hapten selected to bind with high affinity to D5 exhibits mimicry of the gp41 hydrophobic pocket.

We present here crystal structures of (CCIZN36)3, and hapten bound to D5, which allow for a detailed molecular understanding of how the same antibody can bind with high affinity to dramatically different chemical entities. The hapten binds to the same hydrophobic pocket on D5 as (CCIZN36)3, and exploits many of the same interactions observed in the peptide-D5 complex. Importantly, we compare these structures with the previously reported structure of D5 bound to the PHI mimetic, 5-helix. Our data shows that (CCIZN36)3 presents three identical epitopes that are simultaneously recognized by three D5 Fab molecules. The epitopes are presented in a manner that changes the relative orientation of the Fab when compared to the D5- 5- helix structure. Comparative immunogenicity studies in Guinea pigs demonstrate that (CCIZN36)3 elicits more potent functional neutralizing antibody titers relative to 5-helix. Together, these observations suggest that (CCIZN36)3 is a more accurate mimetic of the PHI as present on the native gp41 core structure.

Our results have implications for the design of improved vaccine candidates based on structured NHR peptides and small molecule gp41 mimetics. The findings presented here help to lay the groundwork for improved understanding of the mechanisms by which antibody recognition occurs and for how haptens function to disrupt protein-protein interactions.

Key Points and Benefits:
• Increased understanding of structural characteristics of HIV-1 envelope glycoprotein complex
• Informs immunogen design of more accurate peptide mimetics of the HIV-1 NHR fusion intermediate
• Investigate link between structure and functional immune response to NHR mimetics
3:50 The Human Nasopharynx and Vaccines against Respiratory Infections: A two Way Relationship
  Adam Finn, Professor, Paediatrics, University of Bristol; Honorary Consultant Paediatrician, Bristol Royal Hospital for Children
  The effectiveness of existing human vaccines against respiratory viral and bacterial infections depends heavily on mucosal immune responses which alter rates of transmission, but most existing tools for assessing and comparing vaccine effectiveness are serum antibody assays which measure direct protection against invasive disease. Establishing reliable correlates of mucosal efficacy depends upon an understanding of mucosal immune mechanisms, host-pathogen interactions and the ecology of the upper airway. In a series of studies we have examined B and T cell responses to a variety of pneumococcal protein antigens using adenoidal mononuclear primary cell cultures obtained from children undergoing adenotonsillectomy. We have also examined trends in nasopharyngeal colonisation in healthy pre-school children and children with respiratory infections, examining the impact of pneumococcal conjugate vaccine use and the interaction of pneumococcal serotypes and other bacterial and viral species.

• What do human upper respiratory specific immune responses look like and how do they change with age?
• How could this information translate into measures which could be used in human vaccine trials to predict impact on transmission?
• What could be the result of ecological changes in nasopharyngeal bacterial colonisation driven by mass vaccination programmes?
• How do respiratory viruses affect bacterial colonisation and what does this mean for vaccine development?
• What are the future directions that research into prevention of respiratory infections may take?
4:15 Making the Next (and possibly final) Generation Pneumococcal Vaccine
  Richard Malley, Kenneth McIntosh Chair in Pediatric Infectious Diseases, Division of Infectious Diseases, Boston Children’s Hospital, Harvard Medical School
  There is ample evidence that anticapsular antibodies confer serotype-specific immunity to pneumococci. From both murine and human studies, it is very clear that anticapsular antibodies provide protection against invasive disease. For mucosal colonization or disease, there is compelling evidence that higher levels of antibodies directed against the capsule will provide significant protection as well. Similarly, it has also been shown that antibodies directed against non-capsular antibodies may also confer protection against pneumococcal infections.

At the same time, there are some clues that antibodies may not be the only component of acquired immunity to this mucosal organism. First of all, children show reduced risk of invasive disease well before these anticapsular antibodies appear, suggesting the involvement of other mechanisms. HIV-infected adults are at significantly higher risk of pneumococcal disease. Recently, in elderly patients with chronic obstructive pulmonary disease, higher levels of anticapsular or noncapsular antibodies directed against pneumococcus do not appear to provide increased protection against acquisition of a new strain of pneumococcus.

So what could some other protective factors be? Our laboratory has reported that immunization of mice with whole pneumococci confers CD4+ TH17 cell-dependent, antibody- and serotype-independent protection against colonization. A critical role of interleukin (IL)-17A is shown by experiments using mice lacking the IL-17A receptor and correlative studies. These pneumococcus-specific T cell responses are readily detectable in children and adults and rise following recent pneumococcal infection or exposure.

This line of investigation has major implications for the development of novel vaccine strategies against pneumococcus. While the conjugate pneumococcal vaccines currently licensed have had a major impact on disease, it has become clear that additional or alternative strategies are needed. The phenomenon of serotype replacement, whereby strains carrying capsular polysaccharides not covered by the vaccines emerge and become more important causes of disease, has been seen in most settings where these vaccines have been introduced.

As will be described in this presentation, the goal is to develop a vaccine that can provide T-cell mediated protection against nasopharyngeal colonization and B-cell mediated protection against pneumonia and invasive disease. Various approaches will be described, with a discussion of the advantages and potential disadvantages of each.
4:40 A New Fight against an Old Bug: Toxin RBD-based DNA Vaccines for Prevention of Clostridium Difficile-associated Disease
  Michele A. Kutzler, Assistant Professor of Medicine; Assistant Professor of Microbiology and Immunology, Division of Infectious Disease & HIV Medicine, Drexel University College of Medicine
  Colonic infection with Clostridium difficile (CDI) can result in a spectrum of conditions that range from mild diarrhea to severe colitis with potentially life-threatening complications and costs the United States healthcare system approximately $1.1 billion/year. Hospitals and LTCF are experiencing a 23% annual increased CDI rate since 2000, and mortality has doubled with greater than 90% of these deaths in individuals who are >85yrs. Protection against severe CDI is mediated by host antibody responses against the toxins of C. difficile and IgG and IgM neutralizing antibodies are independently associated with protection against recurrent CDI. We created highly optimized plasmids encoding the receptor binding domain (RBD) from TcdA and TcdB where any putative N-linked glycosylation sites were altered. C57BL/6 mice and rhesus macaques were immunized intramuscularly 3 times with both plasmids, 2 weeks apart, followed by in vivo electroporation (Inovio Pharmaceuticals Cellectra). Vaccination induced significant levels of anti-RBD antibodies as well as frequencies of RBD-specific antibody secreting cells. Peripheral titers of antigen-specific IgG were higher than IgA. Moreover, humoral responses to TcdA RBD were more robust than for TcdB RBD. Sera from immunized mice and NHP neutralized purified toxins in an in vitro cytotoxicity assay. Mice that received active immunization or passive transferred NHP serum antibodies were protected from a lethal intraperitoneal challenge of purified TcdA and/or TcdB. These data demonstrate the robust immunogenicity and efficacy of a TcdA/B RBD-based DNA vaccine in preclinical models of acute infection.

• Overview of current epidemiology, risk factors of and treatment options for Clostridium difficile infection
• Overview of the pathogenesis of Clostridium difficile infection mediated by two enterotoxins, A and B
• Discussion of the required host immune responses necessary for successful defense against infection and recurrence of disease
• Presentation of current pipeline immunotherapies for prevention of Clostridium difficile associated disease
• Highlight of the design and preclinical immunogenicity and efficacy testing of a novel highly optimized DNA-based vaccine encoding the RBD of Clostridium difficile toxins A and B
5:05 [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
DNA & RNA Vaccines
 Chairperson: Ken Rosenthal, Professor, Microbiology, Immunology and Biochemistry, Northeastern Ohio Medical University
8:10 Synthetic Vaccines for Difficult Targets
  David Weiner, Professor, Department of Pathology and Laboratory Medicine; Chair, Gene Therapy and Vaccine Program, CAMB, University of Pennsylvania Perelman School of Medicine
  DNA vaccines represent an important vaccine technology, which has many conceptual advantages over traditional vaccine platforms. However, in humans the immune potency of this approach has been poor. We have developed a combination of technologies for plasmid optimization, adjuvant technology which when combined with enhanced EP delivery results in dramatically improved immune potency of this platform in primates and humans. These combined DNA approaches drive immune response similar or superior to live viral vector protocols in important model systems including HIV, HPV therapy, Influenza among others. We will present data in animal models and in human studies that illuminate specific features of these improved DNA vaccine and benchmark their development against other important vaccine technologies. These studies have critical implications for the treatment or prevention of infection by difficult pathogens and in the expanding theater of immune therapy.

• New approaches to development of CTL in humans
• Details of the Synthetic DNA platform
• Novel Vaccine strategies for diverse pathogens
• Clinical performance in immune therapy setting
8:35 Re-emergence of DNA Vaccination – A Promising Technology with New Potential
  Shan Lu, Professor, Medicine, University of Massachusetts Medical School
  While the DNA vaccination concept was formally accepted, scientifically, 20 years ago, its human application has been questioned due to its low immunogenicity as learned from early clinical studies. Recently, improvements in delivery systems and the use of a prime-boost approach have generated impressive results, not only in animal models but also in human studies. Furthermore, it was discovered that DNA immunization is effective in eliciting high quality antibody responses, in addition to previously recognized benefits of inducing T cell immunity, further confirming the value of DNA vaccines for broad applications against infectious diseases.
9:00 RNActive Vaccines – A Disruptive Technology for Vaccination Now in Clinical Development
  Kajo Kallen, Principal Scientific Fellow, CureVac GmbH
  Nucleotide based vaccines represent an enticing, novel approach to vaccination. We have developed a novel immunization technology, RNActive® vaccines, that has two important characteristics: mRNA molecules with strongly enhanced protein expression capacity (around 5 orders of magnitude) are engineered by modifications of the mRNA nucleotide sequence only with the naturally occuring nucleotides A (adenosine), G (guanosine), C (cytosine), U (uridine). The primary amino acid sequence of the expressed antigens remains unaltered. Secondly, these modified mRNA molecules are complexed with protamine. This is important for activation of the immune system by involvement of toll-like receptor (TLR) 7 and bestows self-adjuvanting activity on RNActive® vaccines. RNActive® vaccines are characterised by the induction of strong, balanced immune responses comprising humoral and cellular responses, effector and memory responses as well as important subpopulations of immune cells, such as Th1 and Th2 cells. In human patients, pre-germinal center and germinal center B cells were detected upon vaccination. RNActive® vaccines successfully protect against lethal challenges with a variety of different influenza strains in preclinical models. Anti-tumor activity was observed preclinically under therapeutic as well as prophylactic conditions. Initial clinical experiences suggest that the preclinical immunogenicity of RNActive® could be successfully translated to humans.
9:25 Non-viral Delivery of Self-amplifying RNA Vaccines
  Andrew Geall, RNA Vaccine Platform Technology Leader, Vaccines Delivery and Formulation Research, Novartis Vaccines and Diagnostics
  At Novartis we have reinvented the gene vaccine by creating a synthetic self-replicating RNA vaccine platform capable of providing a rapid immune response to prevent and treat current and emerging infectious threats. We have achieved proof of concept for 1st generation self-replicating RNA vaccines in small and large animal models. The vaccine RNA is produced by an enzymatic transcription reaction and formulated with a synthetic lipid nanoparticle delivery system, thereby avoiding the limitations of cell culture production that complicate production of other vectored delivery systems. Given the many positive attributes of nucleic acid vaccines, our results suggest that a comprehensive evaluation of non-viral technologies to deliver self-amplifying RNA vaccines is warranted.

Reinventing the nucleic acid vaccine
• Novartis has developed the SAM® vaccine platform
• The Platform takes advantage of cell-free RNA production from a transcription reaction and delivery with a synthetic delivery system
• The broad utility of this novel vaccine technology has been demonstrated with genes encoding antigens from several pathogens and found to elicit broad and potent protective immune responses
• Responses are comparable to a viral delivery technology, but without the inherent limitations of viral vectors
9:50 Comparison of The Live Attenuated Yellow Fever Vaccine 17D-204 to its Virulent Parental Strain Asibi by Deep Sequencing: Lack of Quasi-species in the 17D Vaccine
  Alan Barrett, Director, Sealy Center for Vaccine Development, University of Texas Medical Branch
  Deep sequencing has attracted great interest for the study of genomes, including its application to vaccine development. To date, very few studies have used deep sequencing for vaccine development, and this has been restricted to DNA viruses. Viral population structure is hypothesized to affect virulence and pathogenicity in the host; however the specific determinants of these processes are unknown. This is the first study to perform a direct comparison of population structures for a live RNA virus vaccine with the virulent parental virus from which the vaccine was derived. As a model system, the yellow fever virus (YFV) vaccine strain 17D-204 and the virulent parental strain Asibi were sequenced by massively parallel methods. We found several aspects of variant structure that may contribute to differences in virulence between YFV vaccine and parent viruses. In particular, the lack of quasi-species diversity in the 17D-204 vaccine virus is very important for vaccine development and quality control.

• There has been little application of New Generation Sequencing/deep sequencing to vaccine development
• Quasi species are thought to be a problem for live attenuated RNA virus vaccines. Our data for the yellow fever 17D vaccine indicates that quasi-species may not be present.
• Lack of quasi-species is important for consideration of safety of live attenuated vaccines and vaccine lot-to-lot consistency.
• Deep sequencing can be very useful to the investigation of mechanisms of attenuation of live vaccines.
10:15 Morning Networking Break
Joint Session with 2nd Influenza 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
Day 1 Day 2 Day 3
Attend ALL GTC Conferences for One Year for only $3995 ($1990 for acad/govt)
Click here to sign up!