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Providence, RI, United States

Grant
Agency: Department of Health and Human Services | Branch: National Institutes of Health | Program: SBIR | Phase: Phase I | Award Amount: 300.00K | Year: 2016

DESCRIPTION provided by applicant The avian origin H N influenza virus that emerged in humans in China in presents a unique challenge to vaccine development because it is poorly immunogenic Neutralizing antibodies are not detected in acute phase infection Anti H antibody responses are significantly delayed and exhibit low avidity in comparison with antibodies generated following seasonal influenza vaccination and infection Furthermore unadjuvanted H N vaccines developed using conventional approaches elicit weak hemagglutinin inhibition HAI antibody titers in clinical trials Adjuvanted formulations may overcome this limitation but present significant regulatory challenges because adverse effects have recently been associated with adjuvanted influenza vaccines Alternative vaccine approaches are needed to redress the low immunogenicity of H N and circumvent safety risks Because HAI titers are directly related to effector CD T cell frequencies induced by vaccination we hypothesize that a vaccine strategy that enhances effector CD T cell activation will improve H N vaccine efficacy without requiring adjuvant formulation In published studies we observed that the T cell epitope content of H N virus differs significantly from more immunogenic influenza subtypes H N contains fewer T cell epitopes and some epitopes stimulate regulatory T cells Tregs that may help the virus evade effector responses needed for protection These findings suggest that H N vaccine design that carefully addresses the T cell subsets primed by immunization will overcome limitations of conventional vaccine approaches The goal of this research program is to produce an unadjuvanted influenza H N virus like particle VLP vaccine that augments effector CD T cell responses and diminishes Treg effects for enhanced protection against disease This new SBIR program will apply cutting edge computational and experimental methods that EpiVax has successfully applied against influenza and other viral and bacterial pathogens as well as deep experience in influenza VLP production and vaccine testing in collaboration with Dr Ted Ross at the University of Georgia Two different engineered VLP strategies will be tested i addition of effector epitopes and ii removal of Treg epitopes Using these prototype effector T cell epitope enhanced VLP vaccines in the proof of concept program described here we will evaluate the vaccines for immunogenicity and efficacy and move forward in a Phase II program to further optimize efficacy and complete safety toxicity studies in the run up to clinical trial PUBLIC HEALTH RELEVANCE The avian origin H N influenza virus that emerged in humans in China in presents a unique challenge to vaccine development because it is poorly immunogenic Neutralizing antibodies are not detected in acute phase infection Anti H antibody responses are significantly delayed and exhibit low avidity in comparison with antibodies generated following seasonal influenza vaccination and infection Furthermore unadjuvanted H N vaccines developed using conventional approaches elicit weak hemagglutinin inhibition HAI antibody titers in clinical trials Adjuvanted formulations may overcome this limitation but present significant regulatory challenges because adverse effects have recently been associated with adjuvanted influenza vaccines Alternative vaccine approaches are needed to redress the low immunogenicity of H N and circumvent safety risks Because HAI titers are directly related to effector CD T cell frequencies induced by vaccination we hypothesize that a vaccine strategy that enhances effector CD T cell activation will improve H N vaccine efficacy without requiring adjuvant formulation In published studies we observed that the T cell epitope content of H N virus differs significantly from more immunogenic influenza subtypes H N contains fewer T cell epitopes and some epitopes stimulate regulatory T cells Tregs that may help the virus evade effector responses needed for protection These findings suggest that H N vaccine design that carefully addresses the T cell subsets primed by immunization will overcome limitations of conventional vaccine approaches The goal of this research program is to produce an unadjuvanted influenza H N virus like particle VLP vaccine that augments effector CD T cell responses and diminishes Treg effects for enhanced protection against disease This new SBIR program will apply cutting edge computational and experimental methods that EpiVax has successfully applied against influenza and other viral and bacterial pathogens as well as deep experience in influenza VLP production and vaccine testing in collaboration with Dr Ted Ross at the University of Georgia Two different engineered VLP strategies will be tested i addition of effector epitopes and ii removal of Treg epitopes Using these prototype effector T cell epitope enhanced VLP vaccines in the proof of concept program described here we will evaluate the vaccines for immunogenicity and efficacy and move forward in a Phase II program to further optimize efficacy and complete safety toxicity studies in the run up to clinical trial


Two major obstacles confronting HIV vaccine design have been the extensive viral diversity of HIV-1 globally and viral evolution driven by escape from CD8(+) cytotoxic T-cell lymphocyte (CTL)-mediated immune pressure. Regions of the viral genome that are not able to escape immune response and that are conserved in sequence and across time may represent the "Achilles' heel" of HIV and would be excellent candidates for vaccine development. In this study, T-cell epitopes were selected using immunoinformatics tools, combining HLA-A3 binding predictions with relative sequence conservation in the context of global HIV evolution. Twenty-seven HLA-A3 epitopes were chosen from an analysis performed in 2003 on 10,803 HIV-1 sequences, and additional sequences were selected in 2009 based on an expanded set of 43,822 sequences. These epitopes were tested in vitro for HLA binding and for immunogenicity with PBMCs of HIV-infected donors from Providence, Rhode Island. Validation of these HLA-A3 epitopes conserved across time, clades, and geography supports the hypothesis that epitopes such as these would be candidates for inclusion in our globally relevant GAIA HIV vaccine constructs.


Grant
Agency: Department of Health and Human Services | Branch: | Program: SBIR | Phase: Phase I | Award Amount: 299.91K | Year: 2007

DESCRIPTION (provided by applicant): This new Phase I SBIR proposal addresses the continuing worldwide need for a tuberculosis (TB) vaccine. We detail a novel multivalent strategy that aims to elicit immunity to prevent reactivation of latent TB. This epitope-driven, DNA-prime, protein-boost TB vaccine has been in development since 1997, when our immunoinformatics tools were first applied to identify T cell epitopes from TB proteins. In progress made during the three years of NIH and Sequella/Aeras TB Foundation support, we completed mapping of three sets of TB epitopes including novel epitopes predicted directly from the TB CDC1551 genome. In the next phase of the research program, building on our own experiences and our collaborations, we seek to develop the optimal vaccination strategy, using HLA transgenic mice as the model for in vivo study. Before the start of the performance period, we will make the final epitope selections. In the course of the SBIR award period, selected epitopes will be formulated as DNA and peptide/protein vaccines. By means of a prime-boost vaccination strategy, we will optimize key vaccination parameters (administration route, antigen targeting, adjuvant) to induce the greatest immunogenicity as assessed by cytokine production of stimulated immune cells. Next, we will determine the protective efficacy of the optimized TB vaccine against the standard bacilli Calmette-Gu rin (BCG) vaccine and as a boost in HLA transgenic mice pre-vaccinated with BCG. Successful completion of this work will set the stage for Phase II development that will partner the vaccine with improved recombinant BCG vaccines and assess efficacy in additional strains of HLA transgenic mice.


Grant
Agency: Department of Health and Human Services | Branch: | Program: SBIR | Phase: Phase I | Award Amount: 263.87K | Year: 2007

DESCRIPTION (provided by applicant): Hemophilia A patients are prone to develop inhibitory immune responses to the very therapy they require: Factor VIII protein replacement. Up to 30% of all hemophiliacs and greater than 50% of severe hemophiliacs produce antibodies (inhibitors) in response to treatment. Immunogenicity to Factor VIII (FVIII) is its most significant complication: immunogenicity not only reduces or eliminates the therapeutic efficacy, but also requires that FVIII be delivered by invasive routes since less invasive routes are known to further increase the immunogenicity of therapeutic proteins. To address this problem, it is necessary to develop a less immunogenic FVIII that will provide hemophiliacs with the benefits of prophylactic Factor VIII therapy without the interference of neutralizing antibodies. Neutralizing antibody formation, the root cause of FVIII therapy failure, is a process dependent on antigen presenting cell signaling to helper T cells. We thus propose to develop a de- immunized version of FVIII by T-cell epitope modification. FVIII contains highly immunogenic T- cell epitopes that are excellent targets for mutation in order to prevent T cell-dependent antibody formation. The aims of this Phase I SBIR are to (1) identify and select the key immunodominant T-cell epitopes in FVIII that are responsible for its immunogenicity, (2) strategically modify those epitopes using point amino acid changes as guided by EpiVax' validated immunoinformatics tools and techniques and (3) to demonstrate that reengineered individual FVIII domains have reduced immunogenicity in a mouse model of hemophilia. A series of FVIII domain variants bearing single epitope modifications will be produced and their immunogenicity will be evaluated. The focus of a Phase II SBIR will be studies of FVIII constructs bearing multiple epitope modifications (combinations of the modifications identified during Phase I). These research and development programs will lead to the development of a commercially available and fully functional Factor VIII protein that has significantly reduced immunogenicity as confirmed in HLA transgenic mice and Factor VIII deficient mice. Epitope-driven deimmunization of factor VIII 12,000 Americans have the blood clotting disorder Hemophilia A, and as such are susceptible to a host of complications from chronic bleeding of the joints to life threatening blood loss due to traumatic injury. This proposal describes a plan to produce an improved clotting protein (Factor VIII) that could be used to treat hemophiliacs since the current treatment is often rejected by the body. The proposed reengineered protein will be evaluated in a mice that have a hemophilia as well as in mice that have a human- like immune system.


Grant
Agency: Department of Health and Human Services | Branch: | Program: SBIR | Phase: Phase I | Award Amount: 757.71K | Year: 2012

DESCRIPTION (provided by applicant): The goal of this new SBIR program is to produce a combined clotting Factor VIII replacement and immunomodulatory therapy that will provide FVIII-specific tolerance induction at therapeutic doses for Hemophilia A patients. Hemophiliacs with lt 1% functional FVIII are classified as severe and must receive regular doses of replacement factor. A major issue with successful FVIII replacement therapy for Hemophilia A is overcoming the neutralizing antibody response against FVIII that is seen in up to 30% of hemophiliacs and 50% of patients with severe disease. These inhibitors delay or inhibit clotting by interfering with FVIII binding to its ligands. A number of treatments for inhibitors exist but these approaches are either not fully successful or still experimental and present a large health risk for the patient. There is an urgent need for a safe, biologically rational and cost effective approach to induce long-term immune tolerance to FVIII. Tregitopes are immunoglobulin-derived natural regulatory T-cell (nTreg) epitopes that expand a subset of circulating nTregs, leading to suppression of inflammation and, when administered with a target antigen, adaptive tolerance. Since publication of this discovery in 2008, we have shown that presentation of Tregitopes at the surface of antigen presentation cells (APCs) to nTregs drives tolerogenic pathways in both APCs and nTregs, and induces target-antigen specific adaptive Tregs that interface with the same APC. Thus, as a natural immune system 'off switch,' Tregitopes have great potential as therapeutics to induce immunological tolerance to co-administered proteins. We therefore propose to couple Tregitopes to FVIII to produce a novel combined replacement and tolerance induction therapy. In this Phase I proof-of concept application, we propose to (i) demonstrate that FVIII-Tregitope modulates human T cell responses and establish correlates of tolerance induction that may be used in clinical trial design and (ii) demonstrate FVIII-Tregitope-mediated tolerance induction in an in vivo hemophilia model, which enables evaluation of Tregitope efficacy on the key outcome - elimination of inhibitors. In future Phase II studies, we will transition to recombinant production of FVIII-Tregitope, a process too complex and costly for proof-of-concept studies. ProBioGen, our Phase II collaborator, is a leading company with expertise in activities central to the manufacture of recombinant human FVIII, including cell line engineering, upstream fermentation, downstream purification, liquid pre-formulation of bulk drug substance and in-process analytics including titer determination and chromogenic determination of FVIII bioactivity. In addition, we have established a strong collaboration with a large Pharma that has experience in the regulatory and clinical trial aspects of FVIII drug development and anticipate that FVIII-Tregitope will move into clinical studies once we achieve the goals of the SBIR program. PUBLIC HEALTH RELEVANCE: Hemophilia A patients do not develop immune tolerance to the very treatment they require, replacement clotting Factor VIII. This research program aims to demonstrate that Factor VIII, when linked to immunosuppressive segments of immunoglobulin, is tolerogenic atnormal therapeutic dosing levels.

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