Day 1 :
Biological Mimetics, Inc.,USA
Keynote: Decoding immune evading mechanisms of pathogens: Reordering of immunodominance for new and improved vaccines
Time : 11:20-11:40
Dr. Nara currently holds the Endowed Eugene Lloyd Chair, Professor in Vaccinology, founding Center Directorrnfor the Center for Advanced Host Defense, Immunobiotics, and Translational Comparative Medicine in thernDepartment of Biomedical Sciences, in the College of Veterinary Medicine at Iowa State University, adjunctrnprofessor Microbiology, Carver College of Medicine, University of Iowa and also is the Chief Executive Officer,rnPresident, Chairman & co-founder of Biological Mimetics, Inc. Dr. Nara holds a M.Sc. in Immunopharmacology,rna combined Doctor of Veterinary Medicine and Ph.D. (retro-virology/oncogenesis) from The OhiornState University, 4 year combined residency in Comparative Pathology and NIH post-doctoral Fellowship at thernArmed Forces Institute of Pathology and a NIH respectively.
Over the last 250 years, the use of vaccines, a mainstay of preventative medicine and public health has proven tornbe one of the most successful and cost-effective medical interventions ever discovered. Despite these greatrnadvances to human and animal health of the past 5 decades; the basic technology on which it was created fromrndoes not for the most part work against the many remaining pathogens of humans and animals. This is mainly duernto evolved immune evading strategies making them inherently resistant due to strain-restricted immunity/antigenicrnvariation/poor memory/disease-enhancement/incomplete and/or shortened immunity and thus represents a majorrngap in our understanding of the complex evasion mechanisms evolved by the pathogens.
Deceptive Imprinting is at the heart of a new understating of how mutable pathogens create a molecularrndiversion (decoy) at the level of both the innate and acquired immune host defense systems-- much like howrnmetallic chaff would confuse a radar system trying to locate a missile or plane. On an immunologic levelrnimmunodominance and antigenic variation are coupled such that host immune responses are directed to less orrnnon-protective B and T cell epitopes. To circumvent this host evading mechanism we have developed a firstrngeneration technology called Immune Refocusing that has been designed specifically to reorder the non-protectivernimmunodominance by identifying/mapping the decoy epitopes and molecularly removing or attenuating it thusrnredirecting the host immune system to the more protective regions of the microbe.
This lecture will bring together new paradigm shifting first principals of Deceptive Imprinting, immunology, newrninsight from querying pathogen genomes through Pressure Point Technology and application of the technologyrnof Immune Refocusing. These paradigm shifting scientific insights have opened up fresh new approaches torntechnical advancement and the development of new antigens that can be used for vaccines and deriving newrnmonoclonal antibodies toward inducing improved and broader protective immunity.
CNRS Universite Paris Descartes, France
Keynote: The achilles heel in HIV-1: The conserved caveolin-1 binding domain in the transmembrane envelope glycoprotein gp41 is a B- and T-cell epitope target for vaccine development
Time : 11:40-12:00
Ara Hovanessian (Director of Research 1, CNRS Chevalier dans lOrdre National du Merite) did his Ph.D. at the University of London and at the NIMR in Mill Hill. Then as a senior investigator and `Chef d Unite, he spent 26 years at the Institut Pasteur in Paris in close collaboration with Luc Montagnier. Since 2004, he is at CNRSUniversiternParis Descartes where he conducts two major projects: 1) on the development of a synthetic vaccine forrnAIDS, and 2) on the development of synthetic peptides for cancer therapy. His research discoveries include therninterferon-induced 2 -5 oligoadenylate synthetases (1512 PubMed articles) and the protein kinase PKR (3132rnPubMed articles). He has more than 40 patents on the diagnosis of HIV-2 and HIV-2 envelope glycoproteins,rnInhibitors of HIV entry, synthetic vaccines against HIV, surface-nucleolin as a target in cancer therapy. He has published > 190 papers (PubMed) 75% of which he is the first or the last author.
Generation of a broadly effective vaccine against HIV-1 is complicated due to the extremely fast level of mutation of its genomic sequence, and the high degree of variability between various viral clades. Consequently, arnconserved functional sequence in the HIV genome may represent the "Achilles' heel" of HIV for the development of an efficient vaccine. In 1997-1998 we discovered that nucleolin also exists at the cell surface where it serves as a low affinity receptor for various growth factors and microorganisms including HIV-1. Further studies using equilibrium density fractionation using sucrose gradient of Triton X-100 extracts from freshly HIV-1 infected cells, revealed the coexistence of viral matrix, gp41, reverse transcriptase, and newly synthesized HIV-1 DNA with components of lipid raft microdomains containing also caveolin-1 and surface nucleolin. Caveolin-1 is constitutively expressed in cells but being cholesterol binding protein it is insoluble in non-ionic detergents.rnConsequently the presence of caveolin-1 with the HIV-1 replication complex indicates its Triton X-100rnsolubilisation during the HIV-1 entry process. We identified a distinct caveolin-1 binding motif in in thernectodomain of gp41 which is conserved in every single HIV-isolate, 623WNNMTWMEW631.This strongrnconservation as well gp41 binding to caveolin-1, suggest that there is a constant selective pressure to preserve this sequence for a specific function in the HIV infectious cycle. By a series of studies, we demonstrated that the synthetic CBD1 peptide (SLEQIWNNMTWMQWDK), corresponding to the consensus caveolin-1 binding domain of HIV-1 gp41, is characterized by a distinct structure that accounts for its capacity to penetrate the cell membrane, bind caveolin-1 present at the internal side of the plasma membrane, thus suggesting that the CBD1-rnepitope could be functional for translocation of gp41 within the plasma membrane. Importantly, the CBD1 peptide is capable of eliciting the production of broadly neutralizing antibodies in rabbits, mice, and macaques. Further studies in mice indicated that HIV-neutralizing antibodies against CBD1 react with multiple conformational epitopes that overlap the highly conserved caveolin-1 binding motif (CBM: IWNNMTWMQW) with the Nterminalrnconserved isoleucine residue. The CBM-based peptides IWNNMTWMQW and IWNNMTW when fused to a T helper epitope are immunogenic by inducing high titer CBM-specific antibodies capable of neutralizingrnHIV-1 infection. In our final study, the efficacy of the CBD1-based peptide-cocktail vaccine-formulation wasrnevaluated in cynomolgus macaques to resist SHIV challenge via the mucosal rectal route. Among the five vaccinated macaques, three became infected with a slight delay compared to the controls; and two resisted eightrnweakly SHIV challenges. Interestingly, vaccinated animals maintained CD4 T cell counts, and CM memory cellsrn(CD95+CD28+) were not depleted during the acute phase of infection. Most importantly challenge with SHIVrnboosted at once antigen specific memory T-cell response. The initiation of a recall memory T cell response induced by the native CBD1 epitope presented by the input challenge SHIV gp41 enforces the potentiality of our vaccine strategy. Moreover, as immune responses against the CBD1-epitope are not detectable in HIV-infected individuals; CBD1-based vaccines could have applications as a therapeutic vaccine in AIDS patients.