Day 1 - Monday, November 9, 2009

7:00

Registration & Breakfast

7:55

Welcome and Opening Remarks

Daniel Zimmerman, Ph.D., Senior Vice President Research and Development, Cellular Immunology, CEL-SCI Corporation

KEYNOTE PRESENTATION

  8:00

A Novel Replication-Defective Virus Based Platform for 3rd Generation Flavivirus Vaccines

Konstantin Pugachev, Ph.D.
Director, Head of the Virology Dept.
Sanofi Pasteur

The Flaviviridae family of small plus-strand RNA viruses includes a number of major human and veterinary pathogens, such as yellow fever (YF), dengue, Japanese encephalitis (JE), tick-borne encephalitis (TBE), West Nile (WN), hepatitis C, etc., viruses. The 1st generation vaccines that are currently commercially available for YF, JE and TBE are killed or empirically attenuated virus vaccines. The introduction of infectious clone technology allowed for development of 2nd generation vaccines such as the sanofi pasteur live chimeric vaccines ChimeriVax® against JE, dengue and WN. We are developing a 3rd generation flavivirus vaccine platform, RepliVax®, which is based on replication-defective virus attenuated by a specifically engineered deletion(s). The replication-defective viruses can be also used as vectors for delivery of non-flavivirus immunogens.

• Flavivirus vaccines
? Flavivirus pathogens
? Overview of existing vaccines, and new chimeric vaccines from sanofi pasteur
? Anticipated features of RepliVax® based vaccines:
o As safe as killed vaccines, no adjuvants
o As efficacious as live vaccines, providing durable immunity
o Potential for cocktail and dual vaccines against flavivirus and non-flavivirus pathogens
o Manufactured to high yield in cell culture

Session I - New Technologies in Vaccine Development
Moderator: Daniel Zimmerman, Ph.D., Senior Vice President Research and Development, Cellular Immunology, CEL-SCI Corporation

  8:45

In Vitro Biomimetic Models Reflecting Human Immunophysiology

William Warren, Ph.D., President, VaxDesign

While the duration and size of human clinical trials may be difficult to reduce, there are several parameters in pre-clinical vaccine development that may be possible to further optimize. By increasing the accuracy of the models used for pre-clinical vaccine testing, it should be possible to increase the probability that any particular vaccine candidate will be successful in human trials. In addition, an improved model will allow for collection of increasingly more informative data in pre-clinical tests thus aiding in the rational design and formulation of candidates entered into clinical evaluation. We discuss the development of an in vitro human immune system (MIMIC system) and provide datasets where the MIMIC model has been found to reflect in vivo immunophysiology in the following ways:
1. Similar time kinetics for both recall and naïve immune responses
2. Induction of naïve multifunctional yellow fever-specific CD4 T helper cells;
3. Correlations between donor-to-donor variability
4. Stimulation of mixed Th1/Th2 cytokine responses
5. Induction of naïve YF-specific CD8+ T cell responses
6. Activation of similar transcription factors and target genes to YF vaccination
7. Rapid T-independent IgM generation
8. Immunotoxicological responses to immunopotentiators and biologics

  9:10

The Non-clinical Safety Assessment of Vaccines

Jayanthi Wolf, Ph.D., Associate Director, Biologics Safety Assessment, Merck

The safety assessment of vaccines is an important part of product development for new vaccines. The purpose of non-clinical safety assessment is to provide evidence for vaccine safety in animal models in order to support entry into clinical trials. This presentation will provide considerations for developing non-clinical safety assessment programs for novel vaccines. Regulatory guidelines from the EMEA, WHO, and U.S. FDA will be outlined, which address the non-clinical safety assessment of vaccines. The choice of a relevant animal model, types of toxicology studies, design of the treatment schedule, and the ante-mortem and post-mortem parameters investigated will be introduced and described. Finally, case studies will be presented to discuss how these concepts can be applied to prophylactic and therapeutic vaccine programs using new technologies.

  9:35

Enhancing the Immunogenicity of Peptides and Modulating Immune Responses by LEAPS Immunogens

Ken S. Rosenthal, Ph.D., Professor, Microbiology, Immunology and Biochemistry, NEOUCOM Northeastern Ohio Universities College of Medicine

The Ligand Epitope Antigen Presentation System (L.E.A.P.S.^TM) 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.  Tandem synthesis of the J peptide (a peptide from beta-2-microglobulin) with peptides of 8-32 amino acids from HSV-1 or HIV made them immunogenic and promoted Th1 immune responses. The HSV peptides were capable of inducing protection from lethal infectious challenge.  Immunization of mice with JgD, with a peptide from HSV-1 glycoprotein D, or JH, with a peptide from the HIV p17gag protein, induced production of IL12p70, and later interferon gamma but without TNFalpha or IL1.  Addition of these peptides to mouse bone marrow cells, purified mouse pre-dendritic cells or human monocytes was sufficient to promote their differentiation into IL12p70 producing dendritic cells capable of activating splenic T cells to make interferon gamma in an antigen specific manner. We hypothesize that the activated dendritic cells present the antigenic peptide to T cells with IL12p70 to steer a naïve immune response to a Th1 response. A J-L.E.A.P.S. conjugate with a peptide from bovine collagen induced a combination of IL12p70 and IL10 from bone marrow cells and was capable of restricting the progression of rheumatoid arthritis in a mouse model.  We hypothesize that the cytokines produced in response to the L.E.A.P.S. immunogen modulated ongoing immune responses to specifically curtail the immunopathogenesis. J- L.E.A.P.S. vaccines appear to promote the development of dendritic cells which direct the subsequent immune response through cytokine production and antigen presentation. 

  10:00

Refreshment Break and Networking

  10:30

Harmonized Monitoring and Reporting of Immune Responses: Powerful Early Evaluation Methods of Immunotherapeutic Vaccine Efficacy

Sylvia Janetzki, Ph.D., President, Zellnet Consulting

Monitoring of early immune responses in immunotherapeutic vaccine trials can provide important information on vaccine take and action. Immune responses can be assessed with a number of established bioassays. However, an abundance of different protocols and procedures exists for these bioassays, interfering with data reproducibility and comparison, as demonstrated in recent large international proficiency panels conducted by the Cancer Vaccine Consortium (CVC). The CVC panel program was utilized for the identification of crucial protocol variables which were used to initialize a harmonization process of bioassays. Monitoring approaches could be optimized across panelists without imposing strict standardization on individual laboratories, and the inter-laboratory variability was decreased dramatically. Panel results demonstrate that harmonization of assays leads to improved and reproducible assay performance. Further, a program has been initiated to provide a reporting framework for immune monitoring data. With this program, Minimal Information About T-Cell Assays (MIATA), immune monitoring practices and quality measures taken are made transparent, and with that an objective and thorough interpretation of results from immunological T-cell assays is granted. Both, assay harmonization and the MIATA reporting framework, are important milestones for the immunomonitoring field in the quest to define early biomarkers and establish surrogate endpoints in immunotherapeutic vaccine trials.

  10:55

DepoVax(TM): A Delivery Platform for Active Cancer Immunotherapy and Enhanced Infectious Disease Vaccine

Marc Mansour, Ph.D., VP Research & Development, ImmunoVaccine Technologies Inc.

Vaccines being developed today for cancer therapy and infectious disease applications are in need of significant enhancement. Adjuvanting technologies that can boost the immune response are therefore of particular interest to vaccinologists. ImmunoVaccine Technologies has developed a liposome/oil vaccine delivery formulation (DepoVax™) with the potential to overcome these limitations. In the context of Immunotherapy of cancer, we have shown that the therapeutic use of DepoVax™ is highly effective in eliminating established tumors in a preclinical challenge model. Unlike other cancer vaccines, DepoVax does not induce regulatory T cell (T reg) activation, allowing for a long term cellular response. DepoVax is being combined with carefully selected peptide antigens in preparation for an upcoming clinical trial in cancer therapy. In the context of infectious diseases, the DepoVax platform provides single dose capability with rapid and long-lasting humoral responses. A pandemic influenza vaccine formulation was capable of producing strong immune responses as early as 2 weeks, without the need for boosting. Similarly, a single dose of a hepatitis B vaccine in IVT’s technology was vastly superior to a control vaccine, producing the efficacy expected with 3 doses of the alum-adjuvanted control vaccine. The DepoVax technology, an optimized “depot” platform capable of enhancing cellular and humoral responses, is an easy to use vaccine delivery platform with the potential for commercial scale production and a proven safety/ efficacy record in a variety of pre-clinical models.

  11:20

A Targeted / Adjuvanted Nanoparticle-Based Platform for “Genetic Vaccination” and “Immunomonitoring”

Pirouz Daftarian, Ph.D., Head, Biological Modifiers Laboratory, University of Miami

Current approaches to vaccine design have shown that vaccines which mimic natural antigens to be produced in their native conformations are most effective in generation of functionally relevant immune response. For instance, vaccination with attenuated virus, which allows expression and processing of viral antigens using the standard infection mechanism, generally provides much stronger immune protection than obtained with killed virus or subunit vaccine. Since use of live virus as vaccine is not practical for many applications, recent approaches to vaccine design have focused on the use of DNA vaccines. These vaccines present a broader repertoire of epitopes in a more physiologically relevant form which more closely resemble that seen in active infection, and are expected to induce stronger and more lasting humoral and cellular immunity, and presumably afford a greater degree of protection to subsequent infection. Unfortunately, in vivo delivery of DNA by current methods has poor in vivo transfection frequency, targets all cells including non-professional antigen presenting cells, and does not induce robust immune responses, therefore limiting the usefulness of genetic immunization. We describe a novel (proprietary) “targeted nanoparticle-DNA delivery platform for genetic vaccination” that resulted in i) high levels of expression of protein in skin and/or lymph nodes and ii) robust immune responses. The targeted nanoparticle/DNA complex will specifically bind and transfect antigen presenting cells and induce innate immune responses via activation of T helper cells whereby inducing strong immune responses. Moreover, this platform may conveniently be used for immunomonitoring CTL responses as it generates autologous antigen presenting cells, in vitro, expressing the antigen of interest.

  11:45

Was a New H1N1 Vaccine Necessary? T Helper Responses and their Contribution to Protection from Emerging and Re-Emerging Pathogens

Annie DeGroot, Ph.D., CEO & Founder, Epivax

Research performed in collaboration with Bill Martin, Matt Ardito, Elizabeth McClaine, Lenny Moise, and Toby Cohen (EpiVax), and Mark Buller, Sharon Frey (Saint Louis University, St. Louis, MO); Joe Desrosiers, (Institute for Immunology and Informatics, University of Rhode Island) Steven Gregory, and Steven Moss (Rhode Island Hospital, Providence RI); Jinhee Lee, Hardy Kornfeld (U. Mass Medical Center, Worcester MA).

The outbreak of a novel H1N1 influenza in the spring of 2009 took epidemiologists, immunologists and vaccinologists by surprise and galvanized a massive worldwide effort to produce millions of vaccine doses to protect against this single influenza strain. Because of the unique epidemiology of novel H1N1 influenza, we hypothesized that response to cross-conserved T cell epitopes might have contributed to diminished reports of influenza-like illnesses and confirmed novel H1N1 infection among older adults in the absence of cross-reactive humoral immunity. Our initial in silico analysis identified more than sixteen cross-conserved epitopes in the A/California/04/2009 (H1N1) sequence published in March 2009. A retrospective case controlled study performed in Mexico recently validated this hypothesis . Thus, even though whole protein, or live attenuated influenza vaccines have been the standard bearers, these findings should lead to consideration of existing seasonal flu vaccine as a therapeutic, T cell-directed alternative to mass novel H1N1 vaccination. The present flu season, for which stocks of H1N1 are limited and novel H1N1 is the dominant strain, may provide additional evidence for the effectiveness of T cell priming. I will review our T cell epitope analysis in this presentations, provide an argument in favor of T cell help for vaccines, and describe our recent in vivo work that proves the concept that epitope-driven vaccines have therapeutic and prophylactic potential. We have used epitope-mapping tools, micro arrays and high-throughput immunology assays to develop T cell epitope-based vaccine components for Smallpox, Tularemia, H.pylori and Tuberculosis. This approach has resulted in the development of five T cell epitope-driven vaccines; of which three have been shown to be protective against viral or bacterial challenge. Protective efficacy of 100% (Vaccinia); 90% (Helicobacter), and 57% (Tularemia) have been achieved in HLA-transgenic (humanized) mouse models.

  12:10

Lunch

  1:40

Pandemics: Don't Forget the Secondary Bacterial Infections and How to Prevent Them.

John Grabenstein, RPh., Ph.D., Senior Director, Adult Vaccine Medical Affairs, Merck

Influenza pandemics challenge healthcare systems, critical infrastructure, national economies, and national security. There is increasing recognition that the primary cause of death during the 1918 pandemic was secondary bacterial infection (principally Streptococcus pneumoniae) (Morens, et al, 2008; Brundage & Shanks, 2008). The emergence of influenza A/H5N1 and novel A/H1N1 viruses present the greatest risk of influenza pandemic since 1968. The next moderate-to-severe pandemic could include 4 to 10 million secondary bacterial infections in the U.S., in which pneumococcal infections caused by Streptococcus pneumoniae may play a major role. Pneumococcal vaccination can help prevent pneumococcal disease caused by those serotypes contained in the vaccine. Many National Governments began their pandemic mitigation efforts by investing in countermeasures such as influenza-virus vaccines and antiviral medications. Pandemic planning needs to go beyond addressing the virus alone to consider antibiotics and bacterial vaccines. This presentation will consider questions such as:
• Have national plans considered the limited shelf life and limited antigenic match of pre-pandemic virus vaccines?
• What options do countries without indigenous source of influenza vaccine have?
• What can be expected with resistance patterns of current antiviral medications? What about antibiotic resistance among bacteria?
• Considering time needed for manufacture, when should availability of pneumococcal vaccine supply factor into planning?
• Could pneumococcal vaccination reduce morbidity or healthcare-resource utilization?

Session II - Vaccines for Infectious Diseases
Moderator: Daniel Zimmerman, Ph.D., Senior Vice President Research and Development, Cellular Immunology, CEL-SCI Corporation

  2:05

Oral Gene-Based Vaccination; A Model Platform for Pandemic Influenza Response

Sean Tucker, Ph.D., VP Research, Vaxart

The recent H1N1 outbreak reminds us that the current technologies on the market for influenza vaccination are inadequate to meet the challenges posed by a rapidly spreading viral infection. Vaxart is developing an experimental vaccine against H1N1 using an oral vaccine platform. The platform consists of a replication defective adenovirus that expresses the influenza hemagglutinin (HA) protein and a dsRNA adjuvant. In a case study, Vaxart generated and initiated animal testing of a H1N1 candidate vaccine in just seventeen days after receiving the HA nucleic acid. Significant antibody titers against H1N1 were generated in this study. Prior work with avian influenza strains demonstrated that oral immunization with a Vaxart experimental vaccine could protect ferrets from lethal influenza challenge. Besides the speed of response, Vaxart’s oral platform has significant advantages in that the vaccine could be distributed without refrigeration and given in the form of pills or capsules. These features could facilitate rapid vaccine distribution during a pandemic, where limited contact with medical support may be necessary.


Benefits of talk:

Discussion of the challenges of vaccine distribution during a pandemic
Discussion of the advantages of oral vaccine delivery
Case study description of how fast an H1N1 candidate influenza vaccine can be made by a novel technology
Discussion of the results of an influenza challenge study after oral immunization
 

  2:30

The Stoichiometry of Antibody-Mediated Neutralization of West Nile Virus Infection: Factors that Govern Antibody Potency

Ted C. Pierson, Ph.D., Investigator, NIH

Flaviviruses are a group of small RNA viruses responsible for considerable morbidity and mortality worldwide. Humoral immunity is a critical aspect of host protection against flaviviruses; eliciting protective antibodies is a primary focus of ongoing vaccine development efforts for several of these viruses, including dengue virus (DENV). Complicating these efforts is the potential for antibodies elicited by natural infection or vaccination to modulate pathogenesis and enhance disease. The biochemical and functional properties of a protective antibody response are not known. Using West Nile virus (WNV) and DENV as models, we are working to define the factors that govern the potency of neutralizing antibodies, their potential for antibody-dependent enhancement of infection (ADE), and their mechanism of action. Using quantitative functional methods developed by our laboratory, we have defined the stoichiometric requirements for neutralization and ADE of WNV. This estimate of the number of antibodies required to neutralize and enhance WNV infection has provided a useful foundation to explore the genetic and biochemical complexity of factors that modulate antibody function. These concepts are being integrated into the development of functional approaches to map the composition and dynamics of the polyclonal response to flavivirus infection, with the goal of identifying epitopes recognized by antibodies that are important for neutralization and protection.

  2:55

Antigenic Distance and Pre-Dominant Strain Detection for H1N1

Michael W. Deem, John W. Cox Professor, Rice University

Influenza has a high evolution rate, which makes vaccine designing challenging. A mismatch between the vaccine strain and dominant circulating strain results in a decrease in vaccine efficacy and broader infection in the population. Efforts to design the vaccine for H1N1 influenza benefit from precise measures of antigenic distance between the vaccine and virus strains. We here introduce a sequence-based method to predict vaccine efficacy in humans. Historical epidemiological data show that this sequence-based method is as predictive as hemagglutination inhibition (HI) assay data from ferret animal model studies. Interestingly, the immune system typically recognizes H1N1 to a greater degree than H3N2, leading to greater vaccine efficacies against H1N1 than H3N2. The evolution rate of hemagglutinin in H1N1 is also greater than that in H3N2, presumably due to greater immune selection pressure. We also here consider a dimensional projection technique for early detection of new dominant strains from sequence data. We then define a metric to detect the emergence of dominant strains. We show on historical H3N2 data that this method is able to find a cluster around an incipient dominant strain before it becomes dominant. For example, for H3N2 as of 30 March 2009, we see the cluster for the new A/British Columbia/RV1222/2009 strain. Turning to H1N1 and the 2009 A(H1N1), we do not see evidence for antigenically novel 2009 A(H1N1) strains as of August 2009. This strain detection tool would appear to be useful for annual influenza vaccine selection.

Benefits: Attendees will learn about the peptope method to measure antigenic distance for H1N1. This distance will be shown to correlate with vaccine efficacy in humans. Attendees will learn about a new method to identify soon-to-be dominant influenza strains, before they become dominant.

Session III - Vaccines for Non-Infectious Diseases (Therapeutic)
Moderator: Daniel Zimmerman, Ph.D., Senior Vice President Research and Development, Cellular Immunology, CEL-SCI Corporation

  3:20

Monitoring of CTL Activity in Cancer Vaccine Clinical Trials

Anatoli Malyguine, M.D., Ph.D., Head, Laboratory of Cell Mediated Immunity, SAIC-Frederick, Inc., NCI at Frederick

Selection of ex vivo monitoring methods that provide the best measure of immune reactivity is important in determining correlations between clinical and immunologic responses to specific immunotherapy. Assays that can monitor both CTL frequency and function, such as ELISPOT assays, have gained increasing popularity for monitoring clinical trials.
We report that the GrB ELISPOT can be utilized to measure ex vivo antigen-specific reactivity of PBMC from melanoma patients (provided by Dr. S. Rosenberg, NCI) vaccinated with a peptide-based cancer vaccine and found that activity in the GrB ELISPOT was more closely associated with cytotoxicity in the 51Cr-release assay than the tetramer or IFN-??ELISPOT assays.
We also evaluated the applicability of the newly developed flow cytometric cytotoxicity assay (FC assay) for monitoring cancer vaccine trials. The assay simultaneously assesses target cell death by measuring target binding of the apoptosis marker Annexin V, and cytolytic effector cell activity and frequency by effector expression of the degranulation marker CD107a. PBMC from melanoma patients were used and excellent correlation between CD107a expression by FC assay and GrB secretion in the ELISPOT assay as well as Annexin V binding and the results of 51Cr release assay was observed. Combination of the ELISPOT assay and FC assay allows for a more comprehensive evaluation of low frequency tumor-specific CTL and their specific effector functions as well as the target cell death they induce. We also will discuss the selection of ex vivo monitoring methods that provide the best measure of immune reactivity which may be important in determining correlations between clinical and immunologic responses to specific immunotherapy.

  3:45

Refreshment Break and Networking

  4:15

Listeria-Based Therapeutic Cancer Vaccines

Dr. John Rothman, Executive VP: Science & Operations, Advaxis

Every year, more than 11 million people are diagnosed with cancer, resulting in the death of 7-8 million people worldwide. Despite all available therapies, cancer is still a major global health problem with rising numbers which are estimate to reach 16 million cases by 2020. Novel and effective treatments are an immediate need.
At Advaxis, we use live, attenuated strains of Listeria monocytogenes (Lm) for generating therapeutic cancer vaccines. Preclinical testing of these vaccines has proven their potential as cancer immunotherapeutics, as they are able to elicit strong and antigen specific T cell mediated immune responses. Immunization with Listeria-based vaccines also results in eradication of both implanted and spontaneous tumors in a variety of animal models for cancer. Our first recombinant vaccine, ADXS11-001 was tested in late stage cervix cancer patients. The encouraging results from this trial warranted further development of the technology toward other cancers.

  4:40

Immunotherapy for Prostate Cancer: Survival Data and a New Paradigm

James Gulley, M.D., Ph.D., Director, Clinical Trials Group, National cancer Institute, NIH

Recent clinical data suggests improvement in overall survival for patients with metastatic castration resistant prostate cancer treated with vaccine compared with placebo. This comes from two recent studies of sipuleucel-T (phase III) and PROSTVAC (phase II). These positive studies raise provocative questions about therapeutic vaccines for cancer patients largely about appropriate patient populations and appropriate endpoints.
A successful clinical trial must have an appropriate primary endpoint. Three randomized, placebo-controlled studies in metastatic castration-resistant prostate cancer have suggested a clinically significant survival advantage despite no improvement in time to progression and limited evidence of radiographic or PSA responses, implying that overall survival is the ideal endpoint for such trials. This new paradigm can be explained by the dynamic process induced by the vaccine generating continued downward pressure on the growth rate of the tumor that, over time, results in improved survival without the dramatic-but-temporary declines in tumor volume seen with other types of therapies (e.g., chemotherapy).
In addition to appropriate endpoints, patient selection is critical. Both the sipuleucel-T and PROSTVAC trials were done in patient populations of mCRPC that largely had predicted survival of >18 months using a validated nomogram. Another vaccine, GVAX failed to show improved survival compared with docetaxel, however this trial was largely in patients with shorter predicted survivals. This is supported by data from a smaller phase II study of patients treated with PROSTVAC who had large improvements in overall survival in the cohort of patients with a predicted survival of >18 months. This data suggests that patients who have longer predicted survivals (reflective of their more indolent disease or lower tumor burdens) may be more likely to benefit from vaccine and should be the ones tested in future definitive therapeutic vaccine clinical trials.

  5:05

Microbes and Microbial Products in the Prevention and Treatment of Human Allergic Asthma

Wangxue Chen, Ph.D., Senior Research Officer, National Research Council, Canada

Allergic asthma is a chronic inflammatory disease of the airways characterized by airway inflammation, excessive mucus production, reversible airway obstruction, and airway hyperreactivity (AHR). Asthma affects millions of people worldwide and this has substantial social and economic impact. Despite the increased incidence of allergic asthma, relatively few novel drug therapies and strategies with proven efficacies in clinical trials have been developed. Current treatments are sometimes accompanied by certain side effects and often require long-term daily administration. Thus, there is an urgent need for the development of new strategies for the management of asthma. In this regard, several microbes and their products (such as Mycobacterium spp., Bordetella spp., Listeria spp., the live vaccine strain of Francisella tularensis and their novel components, bacterial unmethylated CpG dideoxynucleotides, and endotoxin) have recently demonstrated their potential for the prophylactic and therapeutic treatment of asthma and allergic airway diseases. The use of microbes and microbial products for the prevention and treatment of asthma has potential additional advantages over current therapeutics in that they function by modulating the dysregulated immune balance underlying the mechanism of asthma development.

  5:30

Day 2 - Tuesday, November 10, 2009

Top of Page

7:30

Continental Breakfast

7:55

Welcome and Opening Remarks

Ken S. Rosenthal, Ph.D., Professor, Microbiology, Immunology and Biochemistry, NEOUCOM Northeastern Ohio Universities College of Medicine

Session IV - Regulatory & Government Policy
Moderator: Ken S. Rosenthal, Ph.D., Professor, Microbiology, Immunology and Biochemistry, NEOUCOM Northeastern Ohio Universities College of Medicine

  8:00

The Role of Federal Advisory Committees:  H1N1 Case Study

Angela K. Shen, Ph.D., Vaccine Specialist, National Vaccine Program Office, DHHS

  8:25

An Update on the National Vaccine Plan

Raymond Strikas, Ph.D., CAPT, U.S. Public Health Service, National Vaccine Program Office, DHHS

Purpose
The first National Vaccine Plan was published in 1994. The National Vaccine Program Office (NVPO), in collaboration with Department of Health and Human Services (HHS) units and other federal partners, is updating the Plan. The Public Health Service Act states that the National Vaccine Program Director [the Assistant Secretary of Health] shall coordinate and provide direction for vaccine activities, including research and development, safety and efficacy testing, licensing, production and procurement, distribution and use, evaluating effectiveness and adverse effects, governmental and nongovernmental activities, and federal funding. The Director shall prepare a plan for implementing these responsibilities, which shall establish priorities. It will describe optimal use of resources to carry out such priorities.

Methods
NVPO, HHS offices and agencies, with the Departments of Veterans Affairs and Defense, and the U.S. Agency for International Development, have written a draft strategic National Vaccine Plan (available at http://www.hhs.gov/nvpo/vacc_plan/). The updated Plan summarizes priorities for vaccine-related activities for the next 10 years. These priorities have been reviewed with the National Vaccine Advisory Committee, and by an expert committee of the Institute of Medicine (IOM). The IOM committee has discussed these priorities with stakeholders, and prepare a report to HHS. NVPO has solicited input about the Plan from a sample of the general public. The Plan should be completed in 2010.

Results
The goals of the draft strategic National Vaccine Plan include 1) Develop new and improved vaccines, 2) Enhance the safety of vaccines and vaccination practices, 3) Support informed vaccine decision-making by the public, providers, and policy-makers, 4) Ensure a stable supply of recommended vaccines and achieve better use of existing vaccines to prevent disease, disability and death in the United States, and 5) Increase global prevention of death and disease through safe and effective vaccination. The first four goals are similar to those in the 1994 Plan, while the fifth one is new. Changes in the immunization and vaccine enterprise since 1994 include increases in vaccine coverage and decreases in most vaccine-preventable diseases. However, outbreaks still occur, such as the U.S. mumps outbreak in 2006 and measles outbreaks in 2008, identifying the need for review of immunization policies and the effectiveness of existing vaccines. Challenges remain in assuring stable vaccine supplies, vaccine financing, and vaccine safety. Concerns exist about the feasibility of including all licensed vaccines in recommended vaccine schedules. Vaccination rate for adolescents and adults are below the national HealthyPeople 2010 objectives.

Conclusions
The updated draft National Vaccine Plan reflects changes in vaccine and the immunization enterprise since 1994, and offers direction for priorities and accountability in the prevention of infectious diseases by vaccines. The Plan requires non-federal stakeholder input to become an actionable National Vaccine Plan.

  8:50

Advanced Techniques for Detection and Identification of Microbial Contaminants Using the Ibis Universal Biosensor

Ranga Sampath, Ph.D., Director, Science & Technology, Ibis Biosciences

Shortages of tools for quickly and fully identifying and characterizing microbes are a significant challenge for any clinical microbiology laboratory. Typically, screening microbes with culture methods requires 24–72 hours, is labor intensive and technique dependent, and has limited sample throughput. Most critically, culture techniques do not provide the details that those in charge need to react appropriately and in a timely manner, further delaying corrective steps while adding to overall costs. Dr. Sampath’s discussion will highlight a PCR/Mass spectrometer based detection technology for identification and characterization of bacteria, viruses and fungi that overcomes the key limitations of traditional diagnostic methods. By combining the sensitivity of PCR with the accuracy of mass spectrometric detection, this technology generates a fingerprint that uniquely identifies an organism without apriori assumptions of the sample identity. This approach is capable of detecting known and unknown pathogens, as well as providing high-resolution genotyping and strain typing, drug resistance and virulence information. The discussion will include a description of the technology and capabilities, as well as results from independent external evaluations.

  9:15

Break

  9:45

Norman W. Baylor, Ph.D., Director, Office of Vaccines Research and Review Center for Biologics Evaluation and Research, FDA

  10:10

Novel Vaccine Formulations for Optimal Delivery of Immune Potentiators

Manmohan Singh, Head U.S., Vaccine Delivery and Formulation Research, Novartis

New generation vaccines have a strong need for an optimal delivery system and/or inclusion of a potent immune potentiator as most of the highly purified novel sub-unit antigens are poor immunogens by themselves. The delivery system may also help target the right cell compartment for maximum potency along with enhanced safety profile. The presentation will cover recent advances in vaccine delivery systems and review current immunopotentiators in clinical trials.

10:35

Antigenicity of a Novel HLA-DR Antibody-Conjugated Poxvirus Interleukin-18 Binding Protein-Derived Peptide as the Basis for a Novel Smallpox Vaccine

Alice P. Taylor, Center for Molecular Medicine and Immunology, Belleville, NJ

The most effective immunization against smallpox is administration of active vaccinia virus. However, rare but serious adverse events call for the development of a non-viral subunit vaccine. Subunit vaccines are often poorly immunogenic, so to enhance the immunogenicity of a sub-unit poxvirus vaccine, we conjugated epitopes to an antigen-presenting cell (APC)-targeting monoclonal antibody, L243 (anti-HLA-DR). Poxviruses use immunomodulating factors, like the viral interleukin-18 binding protein (vIL18BP), in early phase infection to cripple host immunity and establish infection. vIL18BP inactivates IL18, a key host pro-inflammatory cytokine that stimulates NK and CD4 cells to produce interferon-gamma. Therefore, neutralizing this factor by host immunity may confer resistance to poxvirus infection. To investigate the role of viral immunomodulating factors in host immunity, vIL18BP-derived peptides were designed and screened with PBMCs from smallpox-vaccinated (vaccinated) and un-vaccinated (naïve) human donors in proliferation assays. CD3+CD4+ and CD3+CD8+ cells from vaccinated, but not naïve, donors proliferated in response to the peptide, vIL18BP105 (P < 0.01). To enhance its immunogenicity, vIL18BP105 was conjugated to the anti-HLA-DR antibody, L243 (CIL18BP105), to target APCs in HLA-DR04 transgenic (tg) mice. Dose-dependent in vitro proliferation of splenocytes from CIL18BP105-innoculated mice was up to 3-fold over free vIL18BP105-innoculated or naïve controls (P < 0.05). CIL18BP105-innoculated tg mice also showed early and rapidly rising titers of peptide-specific antibodies, 4 times that of free vIL18BP105-injected controls at day 7 after the first boost. At a later time point, both CIL18BP105 and free vIL18BP105 induced IgG2a and IgG1, suggesting the initiation of both Th1 and Th2 immunity. These results suggest that mounting of a response against viral immunomodulatory factors may play a role in host immunity, and that HLA-DR antibody-conjugated sub-unit epitopes present an effective platform for generating Th1 and Th2 responses, both of which are required for immunity against poxvirus infection. Our goal is to use this approach to formulate a potent peptide-based subunit vaccine against smallpox and other pathogens or conditions. (This work was supported by the Defense Threat Reduction Agency and the U.S. Army Medical Research and Material Command Contract No. W81XWH-07-C-0076 awarded by the U.S. Army Medical Research Acquisition Activity).

Session V - Future Trends in Vaccine Discovery and New Vaccines
Moderator: Ken S. Rosenthal, Ph.D., Professor, Microbiology, Immunology and Biochemistry, NEOUCOM Northeastern Ohio Universities College of Medicine

  10:50

What We Have Learned and What We Don't Know; A Long Way to Develop a Successful Vaccine Against Malaria

Kazutoyo Miura, Ph.D., Head of Immunology, National Institute of Allergy and Infectious Diseases, NIH

In early 1960's, it was demonstrated that transfusion of IgG from malaria immune individuals reduces parasitemia in malaria patients, and it has been well-known that people who live in malaria endemic areas slowly, but eventually, do acquire immunity against Plasmodium falciparum, the most virulent species of malaria in humans. However, despites almost a half century of research, there is no malaria vaccine on the market, and still 2.4 billion people live in areas at risk. Malaria has a complicated lifecycle and the vaccine can be separated in three categories; pre-erythrocytic, blood-stage and transmission-blocking vaccines. The most advanced candidate, RTS,S, (one of the pre-erythrocytic vaccine candidates) has shown 30~40% efficacy in multiple phase 2 studies. However, vaccines against blood-stage malaria, which are responsible for the pathology associated with this disease, are far behind. Malaria Vaccine Development Branch at the National Institutes of Health has conducted multiple phase 1 and a phase 2 trial with blood-stage vaccine candidates. This talk mainly addresses immunological responses against the vaccine candidates in various populations.

  11:15

Successful Evaluation and Approval of More Effective T Cell Vaccines Require Comprehensive Immune Monitoring Strategies During Pre-Clinical and Clinical Trials Through Direct Assessment of T Cell Effector Functions

Thomas O. Kleen, Ph.D., Director, Business and Technology Development, Cellular Technology Limited

Adaptive cell mediated immunity (CMI), mainly by CD8+ and CD4+ T cells, has a central role in the host response to viral infections and cancers. Despite the technical advances that facilitated many of the remarkable insights into human immunology in basic research settings, the primary challenge for pharmaceutical, clinical and regulatory entities has been the translation of the gained theoretical knowledge into useful, practical tools that produce reliable, clinically relevant information in large trials while being economically feasible. The recent highly publicized failure of the Merck STEP trial represents at its core a perceived lack of clearly defined correlates of protection for T cell immunity. Objective parameters for efficacy are necessary to provide guidance for development and clinical trial evaluation, without such regulatory approval of more effective human T cell vaccines will remain elusive.
Much effort has been spent on the assessment of phenotypic complexities in combination with the size of such T cell populations, however recent research highlights that efficacy appears to be determined by the functional effector characteristics of individual antigen-specific T cells and their frequency. The inclusion of functional testing strategies can initially appear challenging, but early considerations to the standardization of specimen processing, cryopreservation, sample management and assay systems are vital steps for the successful design and execution of pre-clinical and clinical trials for T cell based vaccines. Performed correctly, immunogenicity testing for therapeutic biologics has the potential to accelerate time-to-market. Furthermore, several regulatory agencies, including the U.S. Food & Drug Administration (FDA), have recently emphasized the need for better prognostic models and the establishment of relevant biomarkers for novel vaccines that aim to elicit cellular immunity.

  11:40

Antu Dey, Investigator, Novartis

  12:05

Lunch

  1:05

CEL-2000 a Peptide Therapeutic Vaccine for Rheumatoid Arthritis

Daniel Zimmerman, Ph.D., Senior Vice President Research and Development, Cellular Immunology, CEL-SCI Corporation

CEL-2000 is a LEAPS peptide immunogen consisting of the J-immune cell binding ligand attached to a peptide from human collagen. Treatment of mice with CEL-2000 stopped the progression of rheumatoid arthritic-like disease in a murine model at least as well as etanercept with much fewer treatments. Improved outcomes in the collagen induced arthritis (CIA) model in DBA mice occurred for A) footpad swelling, B) Arthritic Index (AI) score, C) serum cytokines taken at start of therapy and 10 days later and D) histology of the hind paw and ankle at the end of the study period as compared to non-diseased or disease induced etanercept treated mice. CEL-2000 emulsified in MPA-003 (Mercia Pharma) was as effective as etanercept by all 4 sets of parameters. All therapies were started after the mice had developed an AI score of >1 and a group mean of >2.5 but < 7. CEL-2000 was also effective when administered in Seppic ISA51. CEL-2000 was safe, well tolerated with no evidence of serious adverse effects, and maintained its effectiveness for at least 90 days. CEL-2000 treatment increased levels of IL-12p70 while reducing IL17 and TNFalpha levels, the primary disease associated cytokines of rheumatoid arthritis. In contrast to etanercept, CEL-2000 provides an antigen-specific, immunomodulatory approach to treating rheumatoid arthritis.

CEL-2000 as an antigen specific treatment of rheumatoid arthritis.
CEL-2000 reduces the level of disease related TNF-a and IL-17 cytokines.
CEL-2000 was safe and well tolerated after multiple doses (5) over 90 days.

We also determined that vaccine interference existed if CEL-2000 is administered too soon (< 8 days) after the second disease inducing immunization of Bovine Collagen in Incomplete Freunds adjuvant but if administered afterward (> 14 days) was effective. This was most likely attributed to the effect of ICFA on DCs and not at the T cell or antibody level.

  1:30

Induction Of Persistent Mucosal Humoral And Cellular Responses Following Immunization Of Mice With HIV-1 Envelope Protein In Inulin-Derived Adjuvants In a DNA Prime-Protein Boost Vaccine Regimen

Anthony Cristillo, Associate Director, Product Development, Advances BioSciences Laboratories, Inc.

Background: Since HIV transmits primarily via mucosal route during sexual transmission; an ideal HIV-1 vaccine should induce both systemic and mucosal humoral and cellular responses. Although HIV envelope formulated with QS 21 or Alum elicits strong systemic antibody responses, mucosal antibody and T-cell responses are generally weak. Herein we examined the systemic and mucosal immune responses elicited following a DNA prime/protein boost HIV vaccine formulated with inulin-derived (Advax) adjuvants. Such adjuvants have been shown to be less reactogenic and can induce immune responses in systemic and mucosal compartments.
Methods: BALB/c mice were primed with plasmid DNA encoding HIV Env BaL by intramuscular route (IM) at week 0, 2 and 4 and boosted with gp120 protein formulated with different Advax adjuvants administered via IM or intranasal (IN) at week 9 and 11 either alone or in combination.

Results: Immunization with gp120 formulated in Advax-M adjuvant by IN route elicited anti-Env antibodies in serum and mucosal secretions including vaginal washes, fecal pellets, lung washes and saliva and this response was significantly enhanced in DNA primed animals. Although IgA antibodies were detected in mice immunized systemically with Advax-P adjuvant, levels were lower than that observed with Advax-M adjuvant. Use of both adjuvants where mice were immunized with gp120 formulated with Advax-M by IN route followed by Advax-P adjuvant by IM route or vise versa also elicited strong IgA responses in systemic and mucosal compartments persisting for a prolonged period. Robust induction of Th1 cytokines was noted following DNA prime/protein boost immunization as compared to protein only immunization with Advax-M or with the combination adjuvant approach.

Conclusions: These findings demonstrate that the DNA prime/protein boost vaccine strategy for HIV using inulin-based adjuvants elicits immune responses in systemic and mucosal compartments, thereby providing broad immunological responses for the protective efficacy against mucosal transmission of HIV-1.

  1:55

Corey Mallet, GlaxoSmithKline

  2:20

Conference Concludes