Day 1 :
Senior Director of Product Development at VaxInnate Corporation,
Keynote: Novel quadrivalent influenza vaccine produced in E. coli elicits protective HAI titers in healthy adults
Time : 09:35-10:05
Scott Umlauf has completed his PhD from the University of Wisconsin-Madison and carried out Postdoctoral studies at the National Institutes of Health in the lab of Ronald Schwartz. He is currently the Senior Director of Product Development at VaxInnate Corporation, a biotechnology company which combines innate immune stimulation with disease antigens to generate novel fusion protein vaccines.
We have produced a novel, quadrivalent influenza vaccine candidate comprising the globular head domain of the HA antigen fused standard production strains of E. coli. Due to the presence of flagellin, which serves as an innate immune stimulator via TLR5,the seasonal vaccine does not require exogenous adjuvant. Optimal formats of HA globular head length and insertion sites within flagellin were selected by a panel of in vitro and in vivo methods, including the generation of HAI titers in multiple animal species. As the product consists of soluble monomeric proteins, we have also developed a suite of novel potency methods. The release and stability assay package measures the concentration of the vaccine components by reversed phase UPLC, the biological activity of both HA and flagellin moieties by Capture ELISA and the presence of neutralizing epitopes by a Neutralization Inhibition Assay (NIA). A rabbit model of toxicology has been developed which is sensitive to the innate stimulation of flagellin and generally predictive of the appearance of clinical symptoms by vaccine format and dose. A prototype quadrivalent vaccine was tested in young healthy adults. Total dose levels of 8-12 mcg (2-3 mcg per component) were found to be safe and immunogenic. Seroprotection levels varied from 91-100% across the 4 strains. Serocoversion rates ranged from 71-100% for subjects with starting titers <40.
Vice President and Head, Infectious Diseases at ChemDiv, Inc,
Keynote: Pre-clinical characterization of AV5080, a new oral influenza neuraminidase inhibitor, active against oseltamivir-resistant virus
Time : 10:05-10:35
Vadim Bichko is Vice President and Head, Infectious Diseases at ChemDiv, Inc. (San Diego, US). He also serves as a Chief Scientific Officer of Viriom, Ltd.(US), a ChemDiv-Roche Alliance company, developing HIV and HBV antivirals. He received his PhD in Molecular Biology in 1986 from the University of Latvia in Riga, Latvia, and subsequently held various academic positions at Fox Chase Cancer Center in Philadelphia, US, Max-Plank Institute for Biochemistry in Munich, Germany, and the Institute of Organic Synthesis in Riga, Latvia. He is the author of numerous publications and patents in molecular virology.
This study is focused on the discovery and development of new oral small molecule influenza neuraminidase inhibitors, active against Oseltamivir-resistant virus strains. A number of compounds was designed, synthesized and evaluated for antiviral properties in vitro and in vivo. A 3D Molecular docking, assisted by a pharmacophore model, was applied to rank compounds within different series by the predicted antiviral potency. The most promising compound, AV5080[(3R,4R,5S) 5-[(diaminomethylene)amino] 3-(1-ethylpropoxy) 4[(fluoroacetyl)amino]cyclohex-1-ene-1-carboxylic acid], is currently in pre-clinical development for treatment of influenza. This compound was stable in rat, dog and human plasma (>93% remaining after 24 h). AV5080 demonstrated picomolar activity against influenza neuraminidase in vitro, similar or better than Oseltamivir (the IC50 values of 0.03 nM and 0.07 nM against NA of A/duck/Minnesota/1525/1981, H5N1, and A/ Perth/265/2009, H1N1, 275H, respectively). In the influenza-infected cultured MDCK cells, this compound demonstrated high potency against influenza strains A and B (EC90 = 0.71±0.24 nM, 28 times lower than that for Oseltamivir against A/California/07/2009/H1N1 isolate). Most importantly, AV5080 was highly active against Oseltamivir-resistant influenza strains. The efficacy of AV5080 in mice, challenged with a lethal dose of A/Aichi/2/1969/H3N2 isolate, was similar to that of Oseltamivir (90% and 100% survival rate at 25 mg/kg dose). In the safety pharmacology studies with AV5080 in vitro and in vivo (AMES test, chromosomal aberration, hERG test), no signs of geno-or cardiotoxicity was observed. In summary, AV5080 is a promising novel oral drug candidate for treatment of influenza, including Oseltamivir-resistant virus strains. Further preclinical development of AV5080 is warranted.
Deputy Director of Viral Immunology, Sanofi Pasteur Biologics LLC,
Time : 10:55-11:25
Joshua DiNapoli received his PhD in Microbiology and Immunology in the lab of Dr. Robert C. Rose at the University of Rochester School of Medicine and Dentistry in 2005. He went on to perform his post-doctoral work in the lab of Dr. Peter L. Collins at the National Institute of Allergy and Infectious Diseases from 2005 to 2010.He has since been with Sanofi Pasteur, where his current roles are Deputy Director of Viral Immunology and Research Lead for the Universal Flu Vaccine program.
Annual vaccination against seasonal Influenza A and B virus subtypes with well-matched inactivated virus (INV) vaccines are highly effective against upper respiratory tract (URT) Influenza infection and induced disease. Protection against infection is thought to be mediated principally by neutralizing antibodies targeting the receptor binding site (RBS) of the hemagglutinin globular head (HA1). Immune pressure on HA1 results in antigenic drift, necessitating worldwide surveillance with subsequent WHO recommendations on strain selection for manufacture of forthcoming seasonal influenza vaccines. rnrnThe development of Universal Influenza Vaccines (UIV) that could protect against matched as well as drifted or mismatched strains would provide significant improvement over standard of care (SOC). Additionally, a target product profile that also offers long-lasting immunity would be a substantial advantage of current annual vaccination practices, potentially enabling year-round manufacture. UIV that induce both breadth and durability across multiple influenza seasons would be paradigm shifting for the Influenza field and offer significant health care benefits. rnrnAs part of our universal influenza vaccine program, and using the H1 subtype as our proof of concept (POC), we have built consensus-based, computationally optimized broadly reactive antigens (COBRAs). These prototypes have been demonstrated to fold properly, bind conformation-specific mAbs (HA1 & HA2) as well as agglutinate red blood cells. Prototype H1N1 HA proteins were presented on virus-like particles (VLPs), tested in-vivo, and determined to elicit broadly cross-neutralizing functional antibody responses in multiple species and protect against homologous and heterologous virus challenge. This work demonstrates that we can induce broadly-reactive, protective immunity against H1N1 isolates using a consensus-based HA strategy focusing on the globular head, and has important implications for future universal antigen designs.