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Day 1 - Monday, November 8, 2010

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

[FEATURED PRESENTATION]
 

8:00

AIDS Vaccine Development: The Decade Ahead

Wayne Koff, Ph.D., Senior Vice President and CSO, International AIDS Vaccine Initiative

During the past few years, there has been incremental progress towards the development of a safe and effective HIV vaccine. These advances have included: the first demonstration of protection against HIV in human efficacy trials, identification of new and potentially more vulnerable targets on HIV for vaccine designs to elicit broadly neutralizing antibodies, and demonstration of control of infection in rhesus monkeys immunized with novel viral vector based immunogens. Our laboratories at IAVI, together with our collaborators, have focused on the challenges associated with designing effective vaccine candidates to elicit broadly neutralizing antibodies and cellular immune responses against HIV. Our immunogen design efforts to elicit broadly neutralizing antibodies have included: 1) screening of HIV+ subjects to identify the subset with broad and potent HIV-specific neutralizing antibodies; 2) identification of monoclonal antibodies (mAbs) from such subjects and determining, at the molecular level, the target binding sites on HIV of such mAbs; and 3) designing and screening immunogens to mimic the binding sites of the mAbs with the goal of eliciting broadly neutralizing antibodies. These efforts, have led to the identification of several HIV+ “elite neutralizers”, new broad and potent monoclonal antibodies against HIV, and the screening of the first generation of candidate immunogens. Our efforts to design immunogens capable of controlling HIV infection have focused on the development of replicating viral vector based immunogens, due in large part to the failure of non-replicating vectors to provide any benefit with respect to control of HIV infection e.g. suppression of viral load, in human efficacy trials. Our aim is to mimic the efficacy conferred by live-attenuated SIV with vectors safe for human use. The selection and prioritization of vectors is based on our current hypotheses for why live-attenuated SIV outperforms other vaccine strategies regarding prevention and control of SIV. These hypotheses include the persistent replication of the vector, targeting the gut-associated lymphoid tissues where SIV and HIV establish a beach-head early post-infection, and finally the potential need to target the vector directly to CD4+ CCR5+ cells. The decade ahead will likely include human efficacy trials of novel vaccine candidates, the advancement of replicating viral vector based candidates to clinical trials, and continued progress towards identification of immunogens that elicit broadly neutralizing antibodies.

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

8:30

Approaches and Pathways for Global Vaccine Development: FDA Perspective

Marion Gruber, Ph.D., Deputy Director, Office of Vaccines Research and Review, FDA

The development of safe and effective vaccines against global infectious diseases such as tuberculosis, malaria and human immunodeficiency/acquired immunodeficiency syndrome (AIDS) as well as enteric diseases is of critical public health importance. Development and availability of vaccines primarily targeting those and other serious and life-threatening diseases specifically for use in the developing country setting will benefit U.S. and global health. This presentation will explain FDA guidance on development and licensure of vaccines targeted against infectious diseases or conditions endemic in areas outside the United States.

Benefits of talk:
- to clarify applicable regulations, statutes and guidance applicable in the development of these products
- to provide recommendations for regulatory pathways to use in the development of vaccines against global infectious diseases
- to clarify several misconceptions surrounding the development of vaccines to protect against global infectious diseases in regard to U.S. regulatory requirements
- to inform about FDA’s international partnerships to address scientific and regulatory issues regarding vaccine development against global infectious diseases

8:55

Dengue Vaccines: Progress and Challenges to Their Use

Scott B. Halstead, MD, Adjunct Professor, Uniformed Services University of the Health Sciences

Infections with mosquito-borne dengue viruses types 1 – 4 are a major cause of human morbidity in all tropical countries with a total population at risk of 3 billion persons. Sequential infections with different viruses occur and these often result in severe and fatal disease. Control of mosquito vectors of dengue, once a promising method for reducing disease burden, has everywhere failed. Control of this huge infectious disease requires effective and safe tetravalent dengue vaccines. Two major companies, sanofipasteur and GSK have licensed tetravalent dengue vaccines which are now in clinical trials. In addition, the US NIH and CDC have constructed tetravalent dengue vaccines that are in advanced development. The first results from efficacy trials may be available in 2011 or 2012. Early vaccine formulations have required multiple doses to achieve tetravalent neutralizing antibody responses. The unique challenge posed by dengue viruses is the possibility that primary or secondary vaccine failure may leave vaccinees susceptible to infection with wild-type viruses and such infections might be severe. These outcomes may be prevented by vaccinating to achieve herd immunity or by modifying immunization schedules to achieve protective immunity with one or two doses. The current status of dengue vaccine development will be presented and discussed.

Benefits: 1) current portfolio of dengue vaccines will be presented; 2) the global epidemiology and burden of dengue illness will be reviewed; 3) unique features of the immunopathology of dengue virus infections will be reviewed; 4) suggestions for improving dengue vaccine safety will be made.

9:20

Rapid Manufacturing of H1N1 Vaccine Using Cell Culture Technology

Peter Khoury, Ph.D., MBA, Vice President, Global Marketing, Baxter BioScience, Vaccines

9:45

Development of the PfSPZ Vaccine, an Attenuated Sporozoite Malaria Vaccine

Stephen Hoffman, M.D., CEO and CSO, Sanaria

10:10

Networking and Refreshment Break

10:40


 

A Self-Assembling Polypeptide Nanoparticle Is Able To Induce High-Affinity, High-Titer Antibodies And Cellular CD8+ T-cell Responses Without The Need For Adjuvant: Implications For A Single Component, Multi-Functional Vaccine For Malaria

David Lanar, Ph.D., Chief, Dept. of Molecular Engineering, Walter Reed Army Institute of Research

11:05

Immunogenicity of a Multi-Component Vaccine for Malaria

Katarina Radoševic, Vice President of Immunology and Head of Innovation Team, Crucell Holland B.V.

Heterologous prime-boost vaccination regimens combining complementing types of vaccines are highly promising approach for vaccines against diseases such as malaria, for which a broad and sustainable immunity is required. In this study we evaluated immune responses induced with vaccination regimens based on two recombinant low seroprevalent adenoviruses expressing P. falciparum CS antigen, rAd35.CS (subgroup B) and rAd26.CS (subgroup D), in combination with a yeast-produced complete CS protein. Our results show that (i) both adenovectors induce potent CS-specific T-cell and antibody responses and efficiently boosts each other in mice and rabbits, (ii) the yeast-produced CS protein is highly potent in inducing high CS-specific humoral responses in mice, and (iii) a three-component heterologous vaccination comprised of CS protein and two adenovectors elicits a more robust and sustainable immune response as compared to either one- or two-component regimens.
The results obtained strengthen the promise of the heterologous prime-boost vaccines for malaria and justify their further investigation.

What type of vaccine is required for poverty related diseases, including malaria?
Why are adenovector-based vaccines suited as malaria vaccine?
How combining different types of vaccines influences the type of immune response induced?
Are combination vaccines feasible?

11:30

Advances in TB and Malaria Vaccines

Jerry Sadoff, M.D., Chief Medical Officer & Head of Development, Crucell

TB and Malaria are two ancient diseases where no effective vaccines are available. The vaccine for TB, BCG, has limited efficacy for infants and no proven efficacy for adolescents/adults. Vaccines are being designed for both diseases that target different stages of the disease. Initial clinical work for both diseases has been directed at preventing acquisition of productive infection. The early stage of P. Falciparum malaria, the sporozoite or liver stage requires both antibody and cellular immunity as demonstrated by recent human challenge studies. The most successful malaria vaccine, the RTSS recombinant CS protein-Hepatitis B particle with AS0-1 adjuvant developed by a consortium of the US military, the Malaria Vaccine Initiative has protected from human challenge and in Phase IIB proof of concept studies and is in Phase III efficacy trials. It induces antibodies and CD4-T cells directed against the CS antigen. Higher levels of cellular immunity have been induced by prime boost regimens such as Ad35 expressing CS boosted with RTSS. Heterologous prime boost regimens with BCG or recombinant BCG followed by viral vectored TB vaccines such as MVA-85A or Ad 35 expressing Ag 85A, Ag85B and Ag 10.4, or recombinant proteins such as M72 in ASO-1 adjuvant or Ag85B-Tb10.4 in IC31 adjuvant induce cellular responses in humans and are being tested in Phase II and Phase IIB efficacy trials in Africa. These first generation Malaria and TB vaccines will be succeeded by vaccines containing more antigens to control early disease and later stages of infection. This talk highlights the latest advances in vaccine technology and heterologous prime boost regimens, induction and measurement of cellular immunity, vaccine vectors and adjuvants.

 11:55

Lunch

1:30

Manufacturing Virus-Like Particle Based Influenza Vaccines

Rahul Singhvi, Sc.D., MBA, President and CEO, Novavax

Recombinant Virus like particles (VLP) technology can be used to create influenza vaccine candidates that are well tolerated and immunogenic. Manufacturing these complex particles is a challenge. This talk will cover some of these challenges and strategies to overcome them to achieve a cost effective manufacturing platform that reduces capital requirements and leads to competitive cost of goods.

1:55

Vaccines Against Group B Streptococcus

Jon Telford, Ph.D., Research Director, Novartis

Invasive group B streptococcus (GBS) disease is a leading cause of morbidity and mortality in the neonate in the US and globally. GBS infection results in bacteremia and sepsis, particularly in the first week of life, and meningitis, particularly beyond the first week of life. Development of an effective GBS vaccine would have a significant impact on disease prevention. Epidemiologic studies have demonstrated that natural immunity to the capsular polysaccharide (CPS) that coats the bacterium is protective: low levels of maternal antibody to CPS correlates with neonatal disease susceptibility. Accordingly, programs at Novartis Vaccines & Diagnostics have focused on the development of effective antenatal vaccines capable of inducing anti-GBS antibody. Challenges to vaccine design include the diversity of GBS serotypes (nine) and the poor immunogenicity of polysaccharides in general, as well as the need for a durable response that can be transferred to the newborn. To address these challenges we have prepared Crm-197 CPS-glycoconjugates representing multiple GBS serotypes. Additionally, from extensive analysis of the genome of 8 GBS isolates we identified, cloned and tested over 300 putative surface proteins as vaccine candidates. These studies identified promising novel proteins that induce protection in mice from GBS challenge. Further study identified these protein as pilus-like structures, not previously identified among important gram positive pathogens. Given the relative conservation of these proteins and their effectiveness at inducing protective immunity, they may prove an important component of an effective GBS vaccine approach.

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

2:20

Vectored Delivery of scFv Antibodies for the Preclinical Treatment of Neurological Diseases

Howard Federoff, M.D., Ph.D., Executive Vice President for Health Sciences, Georgetown University

Protein misfolding diseases that affect the nervous system include several of the neurodegenerative diseases such as Alzheimer’s disease, Parkinson’s disease, and the transmissible spongiform encephalopathies also known as the Prionoses. The shared biochemical feature and pathological characteristics of these diseases such that proteins of native structure undergo unfolding and pathogenic refolding to cause inflammation, cellular injury, dysfunction and cell death, represent an opportunity for therapeutics development. Over the last several years we have developed a strategy wherein single chain fragment variable (scFv) antibodies that recognize specific pathogenic proteins, are engineered, cloned into and expressed from viral vectors. In this presention, I will illustrate in preclinical animal models of Prion disease and Alzheimer’s disease how such therapy is envisaged translating to human clinical disease. This work has been supported by the NINDS, NIA, and DoD.
Benefits:
1. Commonality of therapeutic targeting: the misfolded protein
2. Illustration of scFv identification of cognate pathogenic antigens
3. Demonstration of scFv delivery to achieve anatomic distribution of pathogenic process
4. Evidence for efficacy in several preclinical models of neurodegenerative disease

2:45

[Oral Presentation from Exemplary Submitted Abstracts]

To be considered for Oral Presentation, please submit an abstract here.

3:15

Networking and Refreshment Break

Session III: Regulatory & Government Policy
Moderator: Daniel Zimmerman, Ph.D., Senior Vice President Research and Development, Cellular Immunology, CEL-SCI Corporation

3:45

Regulation of Therapeutics

Bindu George, M.D., CBER, OCTGT, FDA

4:10

Health Reform:  Implications for U.S. Vaccine Policy

Alexandra Stewart, J.D., Assistant Research Professor, Department of Health Policy, George Washington University

[FEATURED PRESENTATION]
 

4:35

HHS and Opportunities for Advanced Development and Acquisition of Biodefense Products

Gerald Kovacs, Ph.D., Director, Biomedical Advanced Research and Development Authority (BARDA)

The Biomedical Advanced Research and Development Authority (BARDA) provides an integrated, systematic approach to the development and procurement of necessary vaccines, therapeutics, and diagnostic tools for public health emergencies. BARDA’s portfolio of medical countermeasures (MCMs) targets chemical, biological, radiological, and nuclear (CBRN) agents, as well as pandemic influenza and other emerging infectious diseases. This presentation will highlight the current and future MCMs in development against CBRN threat agents, what has been procured, the solicitation processes being used by BARDA, how the USG has integrated its military and civilian portfolios, and how best to engage BARDA in your product development planning.

• Understanding of HHS’ current needs for CBRN MCMs
• How much funding is proposed to be available for MCM development through 2011
• How the government manages its civilian and military portfolios of MCMs
• The process by which to best engage BARDA in your product development portfolio
• What legislation governs BARDA

5:05

Networking Reception and Poster Session

Top of the page

Day 2 - Tuesday, November 9, 2010

6:30

Continental Breakfast

6:55

Chairman's Review of Day One

Ken Rosenthal, Ph.D., Professor, Northeastern Ohio Universities College of Medicine (NEOUCOM)

Session IV: New Technologies in Vaccine Development
Moderator: Ken S. Rosenthal, Ph.D., Professor, Microbiology, Immunology and Biochemistry, NEOUCOM Northeastern Ohio Universities College of Medicine

7:00

Prioritization of Vaccine Targets for Development

Angela Shen, Ph.D., Director, Policy and Vaccine Development, NVPO, HHS

Vaccines are one of the most cost-effective tools for improving the public’s health, and new and effective vaccines are needed to address existing and emerging diseases. However, research and development is costly and resources are limited. Prioritization in a vaccine catalogue and characterization of barriers to new development can provide a roadmap for the next generation of vaccines. Toward this end, the US government, through the Institute of Medicine, is developing a transparent process to facilitate this need. The Federal government and industry can use this process and list to inform strategic priorities and guide resources to further the development and licensure of new vaccines as national priorities to public health.

7:25

Advances in the Development of Vaccines for Neglected Tropical Diseases

Anne DeGroot, M.D., CEO and CSO, EpiVax

While whole killed, whole protein, or live attenuated vaccines have been the standard bearers for protective vaccines in the last century, concerns about vaccine safety and new vaccine design techniques are contributing to a newer emphasis on T cell-driven vaccines based on the minimum number of T and B-cell epitopes that stimulate protective, but not necessarily sterile, immunity. The recent Thai HIV vaccine trial and the skewed distribution of novel H1N1 (less illness in older adults who may have had cross reactive immune responses) suggest that T cell-driven vaccines deserve consideration for further development. Accordingly, we have used bioinformatics sequence analysis tools, epitope-mapping tools, microarrays and high-throughput immunology assays to discover the minimal essential vaccine components for novel H1N1, Smallpox, Tularemia, H. pylori and Tuberculosis. As will be described in this presentation, this approach has resulted in the development of four candidate vaccines of which three have been shown to be protective against viral or bacterial challenge. Protective efficacy of 100% (vaccinia); 90% (H. pylori), and 57% (tularemia) have been achieved in HLA-transgenic (humanized) mouse models. In the case of the smallpox vaccine, protective efficacy was achieved without any evidence of vaccine-induced antibody against the challenge virus, suggesting that cell-mediated immune response was sufficient for protection. Vaccines comprised of the minimum essential epitopes may have a significant advantage over conventional vaccines, as the careful selection of the components may diminish undesired side effects such as have been observed with whole pathogen and protein subunit vaccines. We will provide new data showing protection against lethal challenge with vaccinia, tularemia, and tuberculosis and discuss the anticipated clinical development of these and similar vaccines.

7:50

TLR-modified Nanoparticles as Efficient Vaccine Development Vectors

Tarek Fahmy, Ph.D., Associate Professor, Yale University

Pathogens are continually emerging and changing; therefore, there is a need for flexible vaccine delivery systems. Vaccines have eliminated smallpox and nearly eliminated polio, two of the worst global infectious diseases. By contrast, vaccines for many other infectious diseases, such as human immunodeficiency virus (HIV) and malaria, are poorly developed or simply unavailable. There are a number of significant scientific challenges that have limited the development of vaccines for deadly diseases. First, few if any approaches are available that efficiently prime cell-mediated immunity by direct intracellular delivery of an antigen. Second, ‘tunable’ adjuvants, that is, adjuvants that can be engineered to optimize the magnitude and direction of an immune response are not available. Third, most vaccine approaches are parenteral (i.e. subcutaneous or intramuscular injection) which has made it difficult to deploy vaccines in underdeveloped countries where medical support systems, resources, and even refrigeration are limited. Therefore, there is a critical need for safe and stable vaccine systems that would address these factors.
Here we describe a biological mechanism-driven design approach for vaccines. We focus on the application of biodegradable nanoparticles constructed from FDA-approved polymers (poly (lactic-co-glycolic acid) (PLGA), surface-modified with Toll-like receptor ligands for constructing a general vaccine system. We demonstrate the utility of this system in eliciting both humoral and cellular immunity by subcutaneous and oral routes of administration in a model of West Nile infection. The application is motivated by the fact that there are no current vaccines against West Nile infection, an NIAID recognized priority pathogen.

8:15

Fc Receptor-Targeted Vaccines; From Potential to Mucosal Protection

Edmund J. Gosselin, Ph.D., Professor, Albany Medical College

Numerous studies have demonstrated that targeting immunogens to Fc receptors (FcR) on antigen (Ag) presenting cells can enhance humoral and cellular immunity in vitro and in vivo. However, until recently, the ability of such immunogens to enhance protection against infection has not been addressed. Furthermore, despite the potential advantages of targeting Ag to FcR at mucosal sites, very little is known regarding the role of FcR in mucosal immunity, or the efficacy of FcR-targeted mucosal vaccines. In this talk, the potential for FcR-targeted mucosal vaccines to protect against intracellular and extracellular mucosal pathogens will be discussed. Two independent targeting strategies will be described. One, utilizing mAb-Ag complexes and the other an FcR-targeted-Ag fusion protein, both administered intranasally. Results from challenge studies will be presented demonstrating enhanced protection against F. tularensis, a Category A intracellular mucosal pathogen, and S. pneumoniae, a more common extracellular mucosal pathogen, respectively. The potential mechanisms of action behind this strategy will also be discussed. Specific advantages of this strategy are as follows:

• This represents a novel mucosal vaccine approach.
• Traditional adjuvants are not required.
• Humoral and cellular immune responses are enhanced.
• Extracellular and Intracellular infections can be targeted.
• This strategy can be applied to killed and recombinant vaccines.

8:40

A High Throughput Screen for Small Molecule Haptens Binding to an HIV-1 Neutralizing Antibody Yields Vaccine Leads

Joseph Joyce, Director, Vaccines Basic Research, Merck

Several broadly neutralizing antibodies (bNAbs) specific for HIV-1 have been described, however, efforts to generate complementary immunogens capable of eliciting bNAb responses have failed, to date. Instead of using constrained peptides to mimic the neutralizing epitope on HIV glycoproteins, our approach has been to screen a large and diverse small molecule collection in a high throughput format to identify and characterize small molecular haptens that bind to the HIV-1 neutralizing human monoclonal antibody, D5. The screen produced approximately 150 "hits" that fall into 3 major structural classes, of which the benzyl piperidine and spiro-indole series were the most represented. Plasma from HIV-infected subjects, but not normal controls, was found to contain antibodies capable of binding to haptens represented in the benzyl piperidine series. Five haptens resulting from optimization of HTS hits were conjugated to a carrier protein and used to immunize mice resulting in the generation of high-titered anti-hapten antibody responses. Serum from a small fraction of the immunized mice was shown to react with a protein mimetic of the HIV-1 gp41 N-heptad repeat trimer, suggesting that this approach, when optimized, could lead to the identification of novel HIV-1 vaccine candidates.

Benefits:
(1) Novel paradigm for discovery of potential vaccine leads
(2) Concept of small molecules as mimotopes of conformational protein surfaces
(3) Increase awareness that NHR region of gp41 is a viable target for neutralizing antibody
(4) Present novel finding that D5 epitope is recognized among a subset of HIV+ patient sera which displays broad neutralizing antibody specificity.

9:05

Humoral and Cellular Immunity with Nanoemulsion Adjuvant via a Novel Mechanism of Mucosal Immune Induction: Are We Closer to an Ideal Adjuvant?

Paul Makidon, DVM, Ph.D., Director of Vaccine Development, The Michigan Nanotechnology Institute for Medicine and Biological Sciences

Nanoemulsions (NE) are new mucosal vaccine adjuvants which elicit strong systemic antibody and cell-mediated (Th-1 and Th-17) responses to co-administered antigens. We sought to define the mechanism of NE adjuvant activity since they do not appear to induce inflammatory response. NE enhances antigen internalization by bone marrow derived DC in vitro and trafficking by ciliated epithelial cells and NALT in vivo. NE-associated antigen appears to target mucosal DC, which efficiently traffic to draining lymphoid tissue. Intranasal immunization of NE-based vaccines results in immunity without influx of inflammatory cells or induction of inflammatory signaling, with the exception of epithelial cell production of IL-6. We have explored the associated critical innate and adaptive signaling pathways. Activation of innate immunity was investigated in TLR2 and TLR4-deficient and germ-free mice. NE induces expression of co-stimulatory molecules MHC-class II, CD80, CD86 and B7-H1 in monocyte derived DC. Triggering the adaptive immune events and signaling by antigen APC was examined in vivo using CD80, CD86, IL-6, IL-12, or IL-12R?1 deficient mice. Neither TLRs, CD86, IL-12, IL12Rß nor IL-6 appear to be necessary for robust IgG response with NE adjuvant. In contrast, CD80/CD86 double knockout and CD40 deficient mice failed to produce humoral immunity with NE. However, analysis of antigen-specific splenic cytokine secretion indicated that IL-6, TLR2 and 4, CD40/80/86, IL-12 and IL-12Rß are essential for the NE-dependent activation of cellular responses. These results provide insights into how NE uniquely facilitate the induction of immunity in the absence of local inflammation via distinct innate and adaptive pathways.

9:30

Networking and Refreshment Break

10:00

Archaeal Lipid Mucosal Vaccine Adjuvant and Delivery (AMVAD) Technology: A Promising Mucosal Vaccine Approach for Respiratory Infections

Girish Patel, Ph.D., Principal Research Officer, National Research Council of Canada

Safe, effective, non-replicating mucosal adjuvants/vaccines are being actively sought for the prevention of infections that are caused by pathogens which invade the mammalian host through the vast mucosal surfaces. Archaeal lipid mucosal vaccine adjuvant and delivery (AMVAD) formulations obtained by the interaction of multivalent cations with archaeosomes (liposomes made from archaeal polar lipids), promote robust antigen-specific mucosal and systemic immune responses upon intranasal (i.n.) administration. The antigen-AMVAD formulations comprise of larger, particulate, aggregated structures with aqueous compartments. Intranasal immunization of mice with antigen/AMVAD vaccine elicits antigen-specific IgA responses in nasal and vaginal mucosa, in the intestinal tract (feces, bile), and in serum. Additionally, antigen-specific systemic immune responses (serum IgG, IgG1, IgG2a), including CD8+ cytotoxic T lymphocyte (CTL) response, are also induced. The responses are sustained over time, and are subject to strong memory boost responses. In a murine model of respiratory tularemia caused by Francisella tularensis LVS (an intracellular pathogen), i.n. immunization of mice with AMVAD vaccine formulated using F. tularensis cell free extract (LVSCE) as the antigen, showed protective efficacy. Compared to naïve and antigen alone immunized mice which died or had to be euthanized by 7-8 day post-challenge, the AMVAD vaccinated group had longer survival times and 20% of the mice recovered from an intranasal 50xLD50 challenge. Some insights into the mechanism of adjuvanticity and advantages of the self-adjuvanting, non-replicating AMVAD mucosal vaccine technology will be discussed.

Benefits of talk:
Introduction to a novel, mucosal adjuvant/vaccine delivery technology
Proof-of-concept data showing efficacy in a murine model of respiratory infection
Potential applications and the advantages of archaeal lipid mucosal vaccine adjuvant and delivery (AMVAD) technology

10:25

LEAPS Peptide and LEAPS-Dendritic Cell Vaccines Act as Adjuvant and Immunogen to Prevent Infection and Treat Disease

Ken Rosenthal, Ph.D., Professor, Northeastern Ohio Universities College of Medicine (NEOUCOM)

The Ligand Epitope Antigen Presentation System (LEAPS. TM) converts an epitope as small as 8 amino acids into an immunogen. Tandem synthesis of the J peptide sequence (from beta-2-microglobulin) with an epitope creates an immunogen that promotes T helper 1 immune responses. Previous studies in our labs showed that vaccines with epitopes of 8-20 amino acids from HIV (peptide from the gag protein(JH)), and M. tuberculosis conjugated to the J peptide were immunogenic and HSV-1 vaccines (e.g. peptide from glycoprotein D (JgD)) elicited protection in mice from challenge. Also, peptides from human collagen (CEL-2000) or myosin (JMy-1) attached to the J peptide prevent the progression of autoimmune disease in mouse models of rheumatoid arthritis or myocarditis diseases. The J-linked peptides act as adjuvants to promote IL12 production which directs immunity towards Th1 cellular and humoral responses and away from Th17 cellular inflammatory and autoimmune diseases. JgD and JH are sufficient to promote the differentation of precursor cells from mouse bone marrow or human monocytes to become IL12 producing dendritic cells capable of promoting interferon gamma and interleukin 2 production by T cells. Adoptive transfer of JgD treated bone marrow cells washed free of unbound peptide are sufficient to confer protective immunity against lethal challenge by herpes simplex virus. Adoptive transfer of other LEAPS-dendritic cell vaccines could provide protection or therapy for other diseases.

• Peptide vaccine that acts as both adjuvant and immunogen to promote and direct the immune response.
• J-LEAPS-dendritic cell approach to immune modulation and protection from infection or treatment of chronic diseases.
 

10:50

Innovative Vaccine Adjuvants for Induction of Cellular Immunity

Vincent Serra, Ph.D., CEO, WittyCell

Wittycell S.A.S. is a privately owned company pioneering a new approach in the development of vaccine adjuvants based on the stimulation of innate immune responses through iNKT cells.Wittycell develops the adjuvant WTCc, a strong enhancer of immune responses which has been shown to induce antigen-specific protection against viruses or tumour challenge in various models. The development of WTCc is derived from the decision to target systems that enhance innate immunity, particularly iNKT (invariant natural killer T) cells and the iNKT-dendritic cell interactions that amplify adaptive immune responses.
The most unique feature of WTCc is its ability to induce strong antigen-specific cytotoxic T-cell responses in classical preclinical models using benchmark adjuvants, e.g. CpG. This distinct characteristic, combined with a good toxicity profile and clear industrial manufacturing feasibility makes WTCc an attractive candidate for many applications, including mass vaccination. After successful demonstration of the NTK activity and adjuvant effect of WTCc in mice and monkey using different indications and further confirmation of the NTK activity induced by WTCc in humans, Wittycell nominated WTCc as the first clinical candidate. Wittycell had initiated a full GMP and GLP preclinical package, filled an IMPD to start end of 2010 an HBV clinical Phase I/IIa in normal volunteers to evaluate clinical and laboratory safety, tolerability profiles and determine efficacy based on Ab and T cell induction. With positive results, the development of the WTCc adjuvant will be pursued in a large panel of indication to develop therapeutic vaccines internally or throw sublicense agreement.

Benefits of the talk :
New adjuvant family with known mechanism of action,
Potent CD8 activity and Ab response
Synthetic compounds with low cost of goods
PoC in large setting of indication, under prophylactic and therapeutic strategy

11:15

FIV-Cat Model for HIV1 Vaccine

Janet Yamamoto, Ph.D., Professor, University of Florida

Three major areas where animal models can aid in the development of an effective HIV-1 vaccine for humans include:  1) the determination of an effective vaccine design, 2) the characterization of the types of immunity required for prophylactic protection against AIDS viruses, and 3) the identification of the vaccine epitopes that confer protective immunity.  To achieve these objectives, the dual-subtype feline immunodeficiency virus (FIV) vaccine was developed using inactivated whole-viruses from long-term survivor cats and was released successfully as a commercial FIV vaccine in U.S. in 2002.  The combined protection rates of the prototype and commercial FIV vaccines against global FIV isolates and recombinants are as follows:  100% FIV_Pet (California subtype A), 89% FIV_FC1 (Florida subtype B), 61% FIV_Bang (Massachusetts subtype A/B), 44% FIV_NZ1 (New Zealand subtype F’/C), and 40% FIV_UK8 (Glasgow subtype A).  The dual-subtype FIV vaccine serves as a proof of concept that sufficient levels of immunity can be generated when a majority of the viral immunogens (in an appropriate adjuvant) is presented to the host.  This vaccine induced both virus neutralizing antibodies (VNAs) and FIV-specific T-cell activity.  In passive transfer studies, vaccine-induced VNAs were effective against viruses with homologous envelope sequences such as those within the same subtypes as the vaccine viruses.  In adoptive-cell transfer studies of MHC-matched inbred cats, vaccine-induced CD3⁺CD4⁺ and CD3⁺CD8⁺ T-cell immunity conferred protection against VNA-resistant heterologous-subtype virus.  Preliminary studies demonstrate the vaccine epitopes required for protection reside on the FIV core (p24) and reverse transcriptase (RT-p66) proteins, but not on FIV matrix.  Currently more viral regions are being evaluated alone and in combination in cats.  In recent studies, HIV-1 p24 vaccine (with cytokine adjuvant) conferred protection against low-dose challenges with FIV strains from multiple subtypes (AIDS, 19:1457, 2005).  Moreover, the PBMC from HIV-1 infected human subjects had both interferon-γ (IFNγ) and T-cell proliferation responses to FIV p24 peptides; whereas the HIV-1 p24-immunized cats responded to similar HIV-1 p24 epitopes as those recognized by the HIV-1 infected subjects.  Overall these results suggest that evolutionarily-conserved epitopes on HIV-1 and FIV can be useful as vaccine immunogens for humans.      

11:40

Exploit of Nanogel-based Delivery System for Adjuvant-Free Intranasal Vaccines

Yoshikazu Yuki, Ph.D., Assistant Professor, Institute of Medical Science, University of Tokyo

Mucosal vaccination has been considered to be an ideal strategy in departure from the current needle/syringe required vaccine, since it is now proven to induce comparable or improved levels of protective immunity against most of infectious diseases. Further, mucosal vaccine can effectively induce antigen (Ag)-specific immunity in the front line of aero-digestive and reproductive mucosa where most of pathogens invade the host. The current vaccine generally required adjuvant for the induction of maximum protective immunity, however it sometime causes exaggerated and undesired responses. An ideal mucosal vaccine thus should be adjuvant free form. (1) Here we developed a novel intranasal vaccine-delivery system with a nanometer-sized hydrogel (“nanogel”) consisting of a cationic type of cholesteryl group–bearing pullulan (cCHP). (2) Because the cCHP nanogel possesses chaperone-like activity, a nontoxic subunit fragment of Clostridium botulinum type-A neurotoxin BoHc/A administered intranasally with cCHP nanogel (cCHP-BoHc/A) continuously adhered to the nasal epithelium and was effectively taken up by mucosal dendritic cells (DCs) after the release from cCHP nanogel. (3) Vigorous botulinum neurotoxin A (BoNT/A)–neutralizing serum IgG and secretory IgA antibody responses were induced without co-administration of mucosal adjuvant. (4) Importantly, intranasally administered cCHP-BoHc/A did not accumulate in the olfactory bulbs or brain. (5) Moreover, intranasally immunized PspA (pneumococcal surface protein A) with cCHP nanogel induced strong PspA–specific systemic and mucosal immune responses with protective immunity. (6) These results indicate that cCHP nanogel can be used as a universal protein-based antigen-delivery vehicle for adjuvant-free intranasal vaccination.

12:05

Lunch

1:10

Challenges and Successes of Measuring Antigen-Specific T cell Responses to Vaccines

Magdalena Tary-Lehmann, Chief Scientific Officer, Cellular Technology Limited

T cell immunity is critically involved in combating infections and cancer, and plays a pathogenic roles in autoimmune diseases and allergies. Therefore, monitoring antigen-specific T cells and their effector functions is crucial for the understanding of these diseases and for proper assessments of the efficacy of specific immune therapies such as vaccines. Yet, unlike the detection of antibodies, reliable measurement of T cell-mediated immunity has remained a major challenge, due to several factors. One such factor is that the antigen-specific T cells of interest typically occur at very low frequencies in test samples, such as peripheral blood. Another factor is that for the reliable measurement of T cell function(s) it is imperatively necessary that the test conditions don’t change the functionality of T cells in vitro as compared to the one in vivo. The many variables that can affect T cell functionality have earned T cell assays the reputation of being rather fragile, with even minor changes of test conditions potentially having a major impact on the test results. A major breakthrough in the field of T cell monitoring has been the introduction of protocols that facilitate cryopreservation of PBMC such that, upon thawing, the cells retain their full functionality. This has enabled the generation of “reference PBMC” as ideal tools for assay development and standardization. We will present data from two vaccine trials, a human vaccinia trial and a macaque dengue trial.

Benefits of talk:
• Comparison of readout systems (FACS, ELISPOT, ELISA) used for high-throughput cytokine T cell assays
• Validation of peripheral blood mononuclear cells (reference samples) for use in pre-clinical and clinical studies
• Detection of antigen-specific cytokine responses by T cells after vaccination in human and macaque studies

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

1:35

Advances in the Development of Vaccines for Neglected Tropical Diseases

Maria Bottazzi, Ph.D., Associate Professor and Chairman, Dept. of Microbiology and Tropical Medicine, George Washington University

The Human Hookworm Vaccine Initiative (HHVI) is a product development-public private partnership (PD-PPP) founded to develop recombinant protein vaccines targeting neglected tropical diseases, a group of chronic, debilitating, and poverty-promoting infections (i.e. hookworm and schistosomiasis). In 2004-05, the Na-ASP-2 Hookworm Vaccine was manufactured and a Phase 1 trial for safety and immunogenicity was conducted in a healthy adult US population and previously exposed population in Brazil. Due to a post-vaccination immediate-type systemic rash observed in several subjects during the phase 1 clinical trial in Brazil, efforts were undertaken to conduct serological assessments to evaluate levels of IgE antibodies specific for each vaccine candidate. Two lead candidate hookworm antigens targeted to block hookworm anemia and with no evidence of pre-vaccination IgE were selected for development, Necator americanus (Na)-GST-1 a glutathione S-transferase involved in hookworm heme detoxification and the Na-APR-1, an aspartic protease used by adult hookworms to degrade host hemoglobin after blood ingestion. Furthermore, the lead candidate schistosome antigen Schistosoma mansoni (Sm)-TSP-2 surface tetraspanin, was also selected to advance into process development. A summary of the current advances on the vaccine development efforts for these diseases will be presented.

2:00
 

Development and Pre-Clinical Evaluation of a 15-Valent Pneumococcal Conjugate Vaccine

Jon Heinrichs, Ph.D., Director, Microbial Vaccines, Merck

The incidence of invasive pneumococcal disease (IPD) caused by the 91 serotypes of Streptococcus pneumoniae (PN) varies geographically and temporally as a result of changing epidemiology and vaccination. Prevnar® (Pfizer), the first licensed pneumococcal conjugate vaccine (PCV), comprises polysaccharides (PS) from 7 serotypes conjugated to the mutant diphtheria toxin carrier protein, CRM197. In the United States, this vaccine has been highly efficacious in reducing the incidence of IPD caused by vaccine serotypes; however, the incidence of non-vaccine serotypes (e.g., 19A, 22F, and 33F) has increased resulting in the need for vaccines with higher valencies. Recently, a 13-valent vaccine (Prevnar-13™; Pfizer) has been licensed in the U.S. For expanded coverage, we have developed a 15-valent PCV containing PS from serotypes 1, 3, 4, 5, 6A, 6B, 7F, 9V, 14, 18C, 19A, 19F, 22F, 23F and 33F conjugated to CRM197 and formulated on aluminum phosphate adjuvant. The vaccine was tested in infant rhesus monkeys since they, like human infants, do not respond to unconjugated PS. Infant (2-3 month old) rhesus monkeys were vaccinated 3 times with PCV-15 or Prevnar® at 2 month intervals, and serotype-specific IgG antibodies were measured using a multiarray electrochemiluminescence (ECL) assay. The results indicate that antibody responses to PCV-15 and Prevnar® were comparable for the 7 common serotypes and that post-vaccination responses to PCV-15 were > 10-fold higher than baseline for the 8 added serotypes. The sera were also tested in a multiplexed opsonophagocytosis assay (MOPA), and robust functional antibody titers were observed to all 15 serotypes in PCV-15.

2:25

Secrets of NIH SBIR and STTR Grant Applications

Greg Milman, Ph.D., Director, Office for Innovation and Special Programs, NIAID, NIH

When the going (funding) gets tough, the tough go shopping (for grants and contracts). As NIH success rates enter single digits and venture capital funding diminishes, academic investigators and small companies collaborate to apply for NIH Small Business Funds (SBIR & STTR).

Attend this session of the 8th Annual Vaccines Conference to hear funding secrets of the $750 million NIH SBIR and STTR programs. Learn:

* How to decide between SBIR or STTR programs
* What is flexible and what is not in SBIR and STTR eligibility rules
* Success rates for NIH applications
* Strategies for producing winning proposals
* How to receive more than the "Normal" amount of funds
* NIH Material Transfer Agreements, Licenses, and Cooperative Research and Development Agreements
* NIH Pipeline to Partnerships (P2P)
* NIH SBIR/STTR Collaboration Opportunities and Research Partnerships (CORP)
* NIH SBIR Technical Assistance Programs

Attending this session could be time well-spent if it helps you obtain funding.

2:50

Public Perceptions of Vaccines’ Safety, Effectiveness, and Cost Effectiveness of Vaccines

Raymond Strikas, M.D., FACP, Medical Officer, NVPO, HHS

3:15

Conference Concludes