Novel Vaccines: Adjuvants & Delivery Systems - Day 1

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Wednesday, August 18

12:15pm Registration



1:45 Chairperson’s Opening Remarks

Susan Dana Jones, Ph.D., Vice President and Senior Consultant, BioProcess Technology Consultants

Cytokines and Toll-Like Receptor Ligands as Adjuvants to Improve the Quality as well as Quantity of T Cell Immune Responses

Jay BerzofskyJay A. Berzofsky, M.D., Ph.D., Chief, Vaccine Branch, Center for Cancer Research, National Cancer Institute (NCI), National Institutes of Health

We have examined cytokines and synergistic combinations of toll-like receptor agonists as defined molecular adjuvants to improve not only the quantity, but perhaps more importantly, the quality of the T cell immune response to vaccines. In particular, we find that IL-15 as an adjuvant can select for higher avidity CD8+ T cells that are more effective at clearing virus infections and tumors, and can also substitute for CD4+ T cell help to induce long-lived memory CD8+ T cell responses. We have also found two double combinations of TLR ligands that can synergistically increase the magnitude of CD8+ T cell response as measured by tetramer staining, as well as increase the activation of dendritic cells. However, only a triple combination of TLR ligands was sufficient to induce strong protection against a vaccinia virus challenge of mice, and this protection depended not on a further increase in T cell numbers, but rather an increase in their functional avidity. Biography 

2:30 Modulating Vaccine Responses with Innate Immunity

Bali PulendranBali Pulendran, Ph.D., Professor, Pathology, Emory University School of Medicine

Despite their great success, we understand little about how effective vaccines stimulate protective immune responses. Two recent developments promise to yield such understanding: the appreciation of the crucial role of the innate immune system in sensing microorganisms and tuning immune responses, and advances in systems biology. In this presentation, I will discuss how these developments are yielding insights into the mechanism of some of the most successful vaccines ever developed. Furthermore, such developments promise to address a major challenge in vaccinology: that the efficacy of a vaccine can only be ascertained retrospectively, upon infection. The identification of molecular signatures induced rapidly after vaccination, which correlate with and predict the later development of protective immune responses, would represent a strategy to prospectively determine vaccine efficacy. Such a strategy would be particularly useful when evaluating the efficacy or immunogenicity of untested vaccines, or in identifying individuals with sub-optimal responses amongst high risk populations, such as infants or the elderly. We have recently used a systems biology approach to identify early gene signatures that correlate with, and predict the later immune responses in humans vaccinated with the live attenuated yellow fever vaccine YF-17D, or with the influenza vaccines. I will review these studies, and discuss their broader implications for vaccinology.  Biography 

3:00 TLR3 Adjuvants Improve Oral Gene-Based Immunization

Sean Tucker, Ph.D., Founder, VP Research & CSO, Vaxart, Inc.

Oral gene-based vaccination has several potential advantages over current injected vaccines.  Among these advantages are the ability to quickly distribute vaccines to areas of the world where medical care is inadequate or disrupted, to permit rapid transition from antigen gene to product through well-characterized manufacturing methods, and potentially, to avoid the problems of pre-existing immunity to the vector. The problem is that oral vector vaccination has generally performed poorly in larger animal models. Vaxart has developed an expressed TLR3 adjuvant that has substantially improved the oral vaccine performance, making oral immunization better than an injected vaccine and protective against diseases such as influenza and Venezuelan Equine Encephalitis. Unlike an injected vector, the immune responses generated are substantially selective against the antigen of choice, making this a platform, not a single use technology. Biography 

3:30 Ice Cream Bar Refreshment Break with Exhibit and Poster Viewing



4:15 Toll-Like Receptor 4: The Use of MPL in Vaccines – Efficacy and Safety Evaluation

Nathalie GarconNathalie Garçon, Pharm.D., Ph.D., VP, Head of Global Adjuvant Centre for Vaccine Development, GSK Biologicals

Improved understanding of the important role of TLR signalling in the induction of adaptive immune responses has led to the discovery of TLR agonists. A strong immunostimulant and a specific TLR4 agonist guiding the immune system towards a Th1 response is lipopolysaccharide (LPS).  3-O-desacyl-4′-monophosphoryl lipid A (MPL), a derivative of LPS, is to date the best characterised TLR-4 agonist, and is part of the adjuvant combination AS04, an Adjuvant System consisting of MPL adsorbed onto a particulate form of aluminium salt.  As LPS, MPL acts via TLR4 pathway, resulting in a transient and localised enhanced production of cytokines and chemokines leading to the maturation and migration of APCs to the draining lymph nodes. This results in improved adaptive immune responses as evidenced by increased antibody titres and memory cells. Preclinical data show that MPL has no direct impact on effector T and B cells.  AS04 is currently used in licensed vaccines for HBV (FENDrix™) and HPV (Cervarix). An AS04-containing candidate vaccine, for HSV, is currently in phase III clinical trials.  AS04 has consistently demonstrated its ability to induce a high neutralising antibody response. Both the HPV vaccine and HSV candidate vaccine elicited increased antibody levels at the site of infection via transudation from the serum to the mucosa. The HPV and HBV vaccines induced more durable protective antibody levels, thus decreasing the number of vaccine doses required.  In clinical studies, AS04-formulated HPV and HBV vaccines have been shown to have acceptable reactogenicity and safety profiles comparable to classic aluminium adjuvanted vaccines.  Biography 

4:45 Enhancement of Response to Vaccines with the Use of an Immune Modulating Peptide, Thymosin Alpha 1

Israel RiosIsrael Rios, M.D., CMO & Senior VP, SciClone Pharmaceuticals, Inc.

Thymosin alpha 1 (trade name Zadaxin®) is a 28 amino acid immune-stimulating peptide that was originally isolated from thymic tissue and is now produced by solid-phase peptide synthesis. Thymosin alpha 1 has been shown to activate toll-like receptor 9 (TLR9), a cell surface receptor that plays a key role in triggering the body’s innate and adaptive immune responses, allowing significant increases in antibody production and clearance of viral infections. In preclinical studies, treatment with thymosin alpha 1 led to increased influenza-specific CTL responses following vaccination. In clinical testing in immune compromised or elderly subjects, bi-weekly doses of thymosin alpha 1 given for 3 to 4 weeks after vaccination resulted in improved response to hepatitis B or seasonal influenza vaccine. Thymosin alpha 1 is one of only a few immunomodulating compounds that have been approved for human use and does not appear to induce the side effects and toxicities commonly associated with agents in this class such as interferon and interleukin-2. Taken together, these observations support the rationale for further clinical investigation of thymosin alpha 1 as an adjunct to vaccination. Biography 

5:15 Vaccine Immune-Enhancing Delivery Systems:
From Danger Signals to a Nutritive Approach in Vaccine and Adjuvant Design

Michael VajdyMichael Vajdy, Ph.D., CEO, EpitoGenesis, Inc.

Since the dawn of ancient and modern vaccination strategies the focus of vaccine developers has been to activate danger signals in the host cells in order to mimic the pathogen. While this approach has yielded several effective vaccines which in some cases have eliminated the disease altogether, in some other cases it has proven toxic. Indeed, as recently as two years ago a live attenuated based HIV vaccine was proven to be unsafe. Also recently, a mutant toxin-based adjuvant also proved to be unsafe in Phase I Clinical trials. In this talk I will give an overview of various popular vaccine adjuvant and delivery systems, leading to our own approach in this area: Given the crucial issue of vaccine safety we opted for an approach in vaccine design in which we addressed the safety issue first. Thus, we selected components of a nutritive vaccine immune enhancing delivery system (NIDS) based on their proven safety in humans as edible nutrients. We have now tested the NIDS mixed with antigens from viral and bacterial pathogens in animal studies and demonstrated higher antibody and CD4-derived cytokine responses compared to vaccinations without NIDS. Our studies demonstrate that this approach is effective and by definition safe and may lead to a new era in vaccine and adjuvant design. Biography 

5:45 Vaccine Adjuvants and Regulatory Considerations

Bill EganWilliam M. Egan, Ph.D., Vice President, PharmaNet Consulting

Live-attenuated viral and bacterial vaccines (including vectored vaccines), as well as many older generation vaccines (such as the various killed, whole-cell vaccines), were “self-adjuvanted,” incorporating molecular motifs that are recognized by, and activate, the innate immune system. Many newer vaccines, such as those based on recombinant proteins, will require vaccine adjuvants and, moreover, will often require non-aluminum salt based adjuvants. The development of appropriate adjuvants for particular vaccines, both from efficacy as well as safety viewpoints, will, ideally, be based on the known mechanisms of action of the potential adjuvants; these considerations may, as well, be influenced by the intended vaccine recipient population, for example, neonates or the elderly. Regulatory decisions, either to allow a clinical trial to proceed or, eventually, to license a product, will be based on perceived or demonstrated risks and benefits associated with the particular vaccine and its associated adjuvant. This presentation will discuss a number of factors (such as, adjuvant manufacture and characterization, pre-clinical studies supporting efficacy and safety, risk-minimization strategies, and eventual Phase 4 studies) that may be incorporated into such risk-benefit algorithms. Biography 

6:15  End of Day

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