Monday, July 21, 2014
Sign up for an immersive DNA Vaccine Conference experience
7:30am - 8:45am
Continental Breakfast in Exhibit/Poster Area
Meet other conference attendees, network, and fuel up for a day filled with groundbreaking research and poignant panels.
Plenary Speaker Session
8:45am - 9:10am
Chairman's Welcome to DNA Vaccines 2014, Dr. David Weiner
Dr. David B. Weiner
Professor of Pathology and Laboratory Medicine, University of Pennsylvania
9:10am - 9:50am
MERS Virus - a Novel Emerging Challenge in Infectious Disease
Dr. Heinz Feldmann
Chief, Laboratory of Virology, National Institute of Allergy and Infectious Diseases
9:50am - 10:10am
Next Steps for Control of TB
Dr. David Hokey
Senior Director of Immunology & Animal Studies, Aeras
10:10am - 10:30am
Multivalent Approach to Vaccine Design: Requirement for DNA Priming Prior to Ad Vector Boost to Induce Sterile Immunity Against Malaria with a Multi-antigen Vaccine
Dr. Martha Sedegah
Senior Scientist and Director of the Clinical Immunology Research Lab , US Naval Medical Research Center
We performed two malaria vaccine clinical trials; the first used a heterologous prime (DNA) and adenovirus-5 (Ad) boost (DNA/Ad trial), each containing the same malaria antigens, circumsporozoite protein (CSP) and apical membrane antigen-1 (AMA1), and achieved sterile protection in four of 15 immunized volunteers. In the second trial, the Ad vaccine alone without the DNA-prime (AdCA trial), given as a single dose was not protective. A two-dose regimen of the Ad vaccine expressing CSP was also not protective. We therefore concluded that DNA-priming was essential to induce protection. In our efforts to better understand protective immune responses in the DNA/Ad trial, and to explore the effect of DNA-priming on the Ad immune responses, we found that the DNA/Ad vaccine induced higher CD8+ T cells interferon-gamma (IFN-γ) and effector IFN-γ responses in the protected compared to the non-protected volunteers. Interestingly the magnitude of these activities was similar in non-protected volunteers in the AdCA alone trial. Upon further analysis, we found that protection was associated with predominantly monofunctional CD8+ T cell IFN-γ effector memory responses that exceeded central memory responses, and were predominantly directed to single 9mer epitopes within AMA1, later matched to HLA B*57 and A*03 restricted epitopes. In summary, our data showed that DNA-priming was essential for the induction of protective immunity against malaria.
10:30am - 11:00am
Coffee/Networking Break in Exhibit/Poster Area
Infectious Diseases Session
11:00am - 11:30am
Novel Recombinant Vaccines Based on Replication-defective Flavivirus Vectors
Dr. Maryann Giel-Moloney
Deputy Director – Virology Discovery Group Cambridge, Sanofi Pasteur
M. Giel-Moloney, A.P. Goncalvez, F. David, M. DiasFigueiredo, B. Feilmeier, T. Mebatsion, J. Catalan, M. Vaine, C. Ventura, T.U. Vogel, R. Stanislaus, R. Oomen, H. Kleanthous, K.V. Pugachev
Institution: Sanofi Pasteur, 38 Sidney Street, Cambridge, MA 02139
The RepliVax® vaccine platform (RV) is based on flavivirus RNA genomes that are rationally attenuated by deletion and do not generate a productive infection similar to replication-competent virus. RV vectors are highly attenuated, capable of inducing robust antibody and T cell responses, and efficacious as shown for vaccine candidates against several flaviviruses, including Tick-borne encephalitis (TBE). A single dose of RV-TBE induced a robust neutralizing antibody response in monkeys which was more durable than 3 doses of an inactivated TBE vaccine control. RV-TBE induced similar genes and temporal expression patterns in macaques as has been observed for YF-17D vaccinated humans. In addition to developing RV for flavivirus vaccine candidates, we have engineered West Nile (WN)-based RV vectors to express non-flavivirus immunogens. The full length rabies virus G gene was cloned into the RV-WN genome and the chimeric virus replicated to high titers (8 logs) in helper cells and expression of RabG was stably maintained through multiple rounds of in-vitro passaging. We evaluated RV-RabG in various animal models and the vaccine provided durable protection in mice and dogs induced protective levels of neutralizing antibodies in pigs. Conventionally, RV is administered as virus packaged in helper cells. Alternatively it can be given as nucleic acids (RNA or DNA). DNA immunization in mice with RV-WN plasmids induced neutralizing antibody titers comparable to vaccination with a single dose of RV-WN virus. Collectively, the data demonstrate RepliVax® is a vaccine platform with the potential to develop either traditional virion-based or alternatively nucleic acid based vaccines against both flavivirus or non-flavivirus pathogens.
® RepliVax is a registered trademark of the Board of Regents of the University of Texas System
11:30am - 11:50am
Dr. Connie Schmaljohn
Chief Scientist, U.S. Army Medical Research Institute of Infectious Diseases (USAMRIID)
11:50am - 12:10pm
Vice President, Research and Development, Ichor Medical Systems, Inc.
12:10pm - 12:30pm
Ebola Protection by SAM RNA
Dr. Pamela Glass
Chief, Viral Biology Department, USAMRIID
Protection of guinea pigs from Zaire ebolavirus (ZEBOV) challenge after vaccination with a SAM® vaccine expressing the ZEBOV envelope glycoprotein (GP)
Ebola virus infection causes an acute hemorrhagic fever following infection with a mortality rate that can approach 90% in some outbreaks. Currently, there are no approved therapeutics or vaccines for human use against filovirus infections. A number of vaccine candidates are in development including DNA, viral vector based, virus-like particles, and subunit vaccines. While each platform has had successes, many face obstacles which threaten advancement through licensure. DNA vaccines are a flexible platform and are broadly effective in small animal models, yet they have generally lacked potency in human clinical trials. Recombinant viral vector technologies have the advantage of efficient delivery of the nucleic acid payload, but their utility is often hampered by anti-vector immunity, production limitations, and safety concerns. While safe, VLP and subunit vaccines are often less immunogenic than live-attenuated vaccines and production limitations can exist. Messenger RNA (mRNA) vaccines were previously considered unrealistic. However, many of the obstacles have been surmounted, and recently there has been a revival in the use of non-amplifying mRNA vaccines for cancer, allergy, and gene therapy. In collaboration with Novartis, a SAM® Ebola vaccine expressing ZEBOV GP was examined for efficacy against lethal guinea pig (gp)-adapted ebolavirus challenge. The SAM vaccine platform, now in pre-clinical development, is based on a synthetic, self-amplifying mRNA, delivered by a synthetic non-viral delivery system. For these experiments, the Ebola SAM vaccine was formulated with a cationic nanoemulsion (CNE) or lipid nanoparticle (LNP) delivery system for intramuscular delivery. Two different doses and dosing schedules were examined. Complete protection from lethal gp-adapted ebolavirus challenge by both the intraperitoneal and aerosol routes was achieved in animals vaccinated with the SAM Ebola vaccines formulated with both non-viral delivery systems.
12:30pm - 1:30pm
1:30pm - 2:10pm
NAB for HIV
Dr. Dennis Burton
Professor, Department of Immunology and Microbial Science , The Scripps Research Institute
2:10pm - 2:30pm
Dr. Matti Sällberg - Karolinska Institutet
Dr. Matti Sällberg
Professor and Biomedical Scientist, Karolinska Institutet
2:30pm - 2:45pm
Closed Linear DNA Encoding Influenza HA Produced by a Completely Synthetic Process Effectively Induces Protective Immunity Against Live Viral Challenge with PR8 Virus in Mice
Dr. Lisa Caproni
Touchlight Genetics Ltd
2:45pm - 3:00pm
Easy Needle-free Intradermal Delivery and Vector Optimization of a Broad Protective Polyvalent Influenza-A DNA Vaccine for Pigs and Humans
Dr. Anders Fomsgaard
Statens Serum Institute
Marie Borggrena, Jens Nielsena, and Anders Fomsgaard a,b, for the UNISEC Consortiumc
aVirus R&D Laboratory (ViFU), Statens Serum Institut, DK-2300 Copenhagen, Denmark
bInfectious Disease Research Unit, Clinical Institute, University of Southern Denmark
cPartly funded by EU contribution FP7-HEALTH towww.UNISECconsortium.eu (“Universal influenza vaccine secured”)
Influenza vaccines inducing a broad cross-reactive immune response would be of great advantage for improved protection against both seasonal and emerging influenza viruses in humans and pigs. We have developed an alternative influenza vaccine based on DNA expressing 6 selected influenza proteins of pandemic origin (H1,N1,H3,N2,NP,M)1. Intradermal immunisation with electroporation induced HI antibodies >40 HAI/ml between 7-10 days after second vaccination in pigs and induced protection against challenge with virus homologous and heterologous to the HA/NA DNA vaccine. Subsequently, we aimed to optimize and ease delivery suitable for pig herds using needle-free delivery to the skin. We successfully adapted our DNA formulation to the IDAL (Intra Dermal Application of Liquids) device (MSD) designed for pigs and obtained antibody responses comparable with those obtained by i.d. electroporation when tested in the rabbit model. We further aimed to enhance the DNA vaccine performance, production yield, and safety by changing our 1st generation DNA vaccine vector backbones (pSSI and wrg7079) to the antibiotic-free 3nd and 4rd generation vectors NTC8385 and NTC9385 (Nature Technologies)2, respectively. The improvements encourage for clinical trials.
1Bragstad K et al. Vaccine 2013;31:2281-228
2Williams JA. Vaccines 2013;1:225-249;doi:10.3390/vaccines1030225
3:00pm - 3:30pm
Coffee/Networking Break in Exhibit/Poster Area
3:30pm - 3:50pm
Therapy Approaches for HIV
Dr. Pablo Tebas
Professor of Medicine; Director and Principal Investigator, AIDS Clinical Trial Unit Research Site , University of Pennsylvania
3:50pm - 4:10pm
Cutaneous and Mucosal HIV Vaccination
Dr. Robin Shattock
Professor of Mucosal Infection and Immunity, Imperial College London
It is generally accepted an effective prophylactic HIV-1 vaccine it is likely to require both humoral and cellular responses and may be critically dependent upon the generation of neutralising antibodies. This presentation reports the use of different DNA plasmid technologies to efficiently express a model trimeric CN54-gp140 envelope glycoprotein and priming strategies using concurrent intradermal (ID) and intramuscular (IM) vaccination. To augment vaccine-elicited T and B cell responses, the impact of DNA transfection has been assessed in combination with different boosting regimes using viral vectors and/or homologous protein. Concurrent ID and IM vaccination resulted in significantly elevated IFN-* T cell and high avidity vaccine antigen-specific IgG B cell responses in mice, a hallmark of B cell maturation. Sequential protein boosting of the concurrent DNA strategy further augmented antigen-specific IgG responses but had little impact on T cell reactivity. A compressed regime where DNA and protein were co-administered had limited impact on response but provided significant regime shortening. Route optimisation has been explored to maximize the impact of protein boosting and demonstrated that a subcutaneous inoculation increased antigen-specific antibody avidity to a greater extent than either intramuscular, intranasal or transcutaneous administration. The fully optimised vaccine regime of a concurrent DNA intramuscular and intradermal prime strategy followed by a subcutaneous protein boost vaccination was also capable of eliciting humoral responses with high antibody affinty and that were capable of neutralising HIV-1 pseudoviruses from diverse clades (A, B and C) in an alternative larger animal model, the rabbit. These strategies are currently being evaluated in human phase I trials.
4:10pm - 4:30pm
T Cell Immunology in the HIV Infected Lymph Node: Opportunities and Challenges for Therapeutic Vaccine Strategies
Dr. Michael Betts
Associate Professor, Microbiology, University of Pennsylvania
The lymph node (LN) is a centrally important tissue for latent HIV reservoirs in HAART treated HIV infected subjects. As such, HIV cure-based strategies designed to invoke CD8+ T cell cytotoxicity (CTL)-mediated killing of latently infected CD4+ T cells must consider not only function and magnitude, but also tissue localization. Previous data from mouse models has suggested that while CD8+ T cells can be readily found in LN, their functional properties are temporally regulated such that cytolytic effector function is only fully realized after LN egress. To address this in the context of HIV infection, we have directly examined the functional properties of LN-derived CD8+ T cells from uninfected, chronic, and HAART treated HIV infected subjects. Our data reveal distinct differences in CD8+ T cell function and localization within the LN of HIV infected and uninfected subjects, and further differences between treated and untreated HIV infected subjects. In particular, after initiation of HAART, there is a rapid decrease in the proportion of LN CD8+ T cells that express key markers associated with cytolytic function. Together our results indicate that therapeutic vaccination strategies designed to re-invigorate HIV-specific CD8+ T cell function will need to remodel the trafficking and cytolytic properties of these cells for effective HIV reservoir clearance in the LN.
4:30pm - 4:45pm
Expanded Epitope Recognition by Vaccination with DNA Encoding Novel Immunogens Comprising HIV Conserved Elements
Dr. Barbara Felber
Principal Investigator, NCI,
Barbara K. Felber, Xintao Hu, Viraj Kulkarni, Antonio Valentin, Margherita Rosati, Candido Alicea, Morgane Rolland, Sylvie Le Gall, Niranjan Y. Sardesai, Beatriz Mothe, Christian Brander, James I. Mullins, George N. Pavlakis
Background: HIV sequence diversity and potential “decoy” epitopes are hurdles in the development of an effective AIDS vaccine. To target immune responses towards invariable viral regions we engineered DNA-based immunogens encoding conserved elements (CE) of HIV-1 selected on the basis of stringent conservation, functional importance, and association with immune control.
Methods: Macaques were immunized by IM injection followed by electroporation with DNA plasmids expressing CE or complete immunogens (gag, env), alone or in heterologous prime-boost regimens. Immune responses elicited by CE from gag (HIV, SIV) and env (HIV) were compared to those obtained upon vaccination with DNA expressing the complete antigens.
Results: Macaques vaccinated with CE gag or CE env DNA developed robust CE-specific cytotoxic T cells (Granzyme B+, CD107+). CE-specific T cells were found only in ~50% of animals vaccinated with DNA encoding the complete antigen and these responses targeted fewer CE per animal. Importantly, boosting CE-primed macaques with DNA expressing full-length antigen increased both magnitude and breadth of the CE responses.
Although designed as CTL vaccine, p24CE DNA vaccine induced Ab responses able to recognize p55gag and targeting a broad range of linear epitopes. In contrast, antibodies induced by p55gag DNA vaccination failed to recognize p24CE or linear CE epitopes. Interestingly, boosting of p24CE DNA primed macaques with p55gag DNA increased Abs recognizing HIV p24gag as well as p24CE proteins, thereby inducing broadest immunity.
Conclusions: Combination of conserved elements and full-length immunogen provides a novel strategy to increase the magnitude and breadth of cellular and humoral immunity while targeting efficiently the conserved regions of the virus. This allows for the development and expansion of subdominant responses and greater breadth of immune response.
Dr. Niranjan Y. Sardesai - Inovio
Dr. Darrel Irvine - Massachusetts Institute of Technology
Dr. Holbrook Kohrt - Stanford
Dr. George Pavlakis - National Cancer Institute
Dr. Connie Schmaljohn - USAMRIID
Dr. Jeffrey Ulmer - Novartis