Babies born with Pompe disease require life-long treatment with enzyme-replacement therapy (ERT). Despite the human origin of the therapy, recombinant human lysosomal acid α glucosidase (GAA, rhGAA), ERT unfortunately leads to the development of high titers of anti-rhGAA antibody, decreased effectiveness of ERT, and a fatal outcome for a significant number of children who have Pompe disease. The severity of disease, anti-drug antibody (ADA) development, and the consequences thereof are directly related to the degree of the enzyme deficiency. Babies born with a complete deficiency GAA are said to have cross-reactive immunologic material (CRIM)-negative Pompe disease and are highly likely to develop GAA ADA. Less frequently, GAA ADA develop in CRIM-positive individuals. Currently, GAA-ADA sero-positive babies are treated with a combination of immunosuppressive drugs to induce immunological tolerance to ERT, but the long-term effect of these regimens is unknown. Alternative approaches that might redirect the immune response toward antigen-specific tolerance without immunosuppressive agents are needed. Methods leading to the induction of antigen-specific regulatory T cells (Tregs), using peptides such as Tregitopes (T regulatory cell epitopes) are under consideration for the future treatment of CRIM-negative Pompe disease. Tregitopes are natural T cell epitopes derived from immunoglobulin G (IgG) that cause the expansion and activation of regulatory T cells (Treg). Teaching the immune system to tolerate GAA by co-delivering GAA with Tregitope peptides might dramatically improve the lives of CRIM-negative babies and could be applied to other enzyme replacement therapies to which ADA have been induced.
Ticks are notorious vectors of disease for humans, and many species of ticks transmit multiple pathogens, sometimes in the same tick bite. Accordingly, a broad-spectrum vaccine that targets vector ticks and pathogen transmission at the tick/host interface, rather than multiple vaccines against every possible tickborne pathogen, could become an important tool for resolving an emerging public health crisis. The concept for such a tick protective vaccine comes from observations of an acquired tick resistance (ATR) that can develop in non-natural hosts of ticks following sensitization to tick salivary components. Mice are commonly used as models to study immune responses to human pathogens but normal mice are natural hosts for many species of ticks and fail to develop ATR. We evaluated HLA DR3 transgenic (tg) "humanized" mice as a potential model of ATR and assessed the possibility of using this animal model for tick protective vaccine discovery studies. Serial tick infestations with pathogen-free Ixodes scapularis ticks were used to tick-bite sensitize HLA DR3 tg mice. Sensitization resulted in a cytokine skew favoring a Th2 bias as well as partial (57%) protection to infection with Lyme disease spirochetes (Borrelia burgdorferi) following infected tick challenge when compared to tick naïve counterparts. I. scapularis salivary gland homogenate (SGH) and a group of immunoinformatic-predicted T cell epitopes identified from the I. scapularis salivary transcriptome were used separately to vaccinate HLA DR3 tg mice, and these mice also were assessed for both pathogen protection and epitope recognition. Reduced pathogen transmission along with a Th2 skew resulted from SGH vaccination, while no significant protection and a possible T regulatory bias was seen in epitope-vaccinated mice. This study provides the first proof-of-concept for using HLA DR tg "humanized" mice for studying the potential tick protective effects of immunoinformatic- or otherwise-derived tick salivary components as tickborne disease vaccines.
This book is unlike any other tome that might have the same words - "bioinformatics" and "Vaccine" in its title or subtitle. Unlike those other books, which are usually compendia of chapters penned by different authors and compiled into one volume, this book was written from start to finish by one extremely dedicated and erudite individual. The author has done an excellent job of covering the many topics that fall under the umbrella of computational biology for vaccine design, demonstrating an admirable command of subject matter in fields as disparate as object-oriented databases and regulation of T cell response. Simply put, it has just the right breadth and depth, and it reads well. In fact, readability is one of its virtues - making the book enticing and useful, all at once.
Abstract Development of effective vaccines against emerging infectious diseases can take years to progress from pathogen isolation/identification to clinical approval. As a result, conventional approaches fail to produce field-ready vaccines before the EID has spread extensively. The VaxCelerate Project’s goal is to create a platform capable of generating and pre-clinically testing a new vaccine against specific pathogen targets in less than 120 days. A self-assembling vaccine, consisting of a fusion protein M. tuberculosis MTBhsp70 and avidin (MAV), is at the core of the approach. Mixing the MAV with biotinylated pathogen specific immunogenic peptides yields a self-assembled vaccine (SAV). To minimize the time required, we used a distributed R&D model involving experts in protein engineering, bioinformatics, peptide synthesis/design and GMP/GLP manufacturing and testing. This approach was first tested using ovalbumin in C57Bl/6 mice, Flu (H1N1) specific peptides, and ultimately a Lassa fever virus (LFV) specific vaccine in transgenic HLA DR3 mice. Using a GLP validated assay we demonstrated that the MAV assembled LFV induced significantly increased class II peptide specific interferon-CD4+ T cell responses in transgenic mice compared to peptide or MAV alone controls. The use of an identical design for each vaccine may facilitate accelerated regulatory review and by developing safety assessment tools that are more relevant to human vaccine responses than current preclinical models.
Immunogenicity is a significant problem associated with protein therapeutics, but can be predicted in advance by in silico, in vitro, and in vivo tools, which can identifiy sequences within the therapeutic protein that, when processed by T-cells, elicit an immune response. Recent developments in T-cell-dependent immunology relating to the immunogenicity of therapeutic products include the description of toll-like receptor ligands and the identification and classification of regulatory T-cells. A limitation in determining the relative immunogenicity of potential therapeutic proteins is the variance in the immunogenicity determined by in vitro or in vivo techniques in animal and human models. However, given the sophistication and high-throughput capacity of existing in silico tools and the availability of precise in vitro validation assays, accurate prediction of immunogenicity for therapeutic protein products, and more rapid translation of research discoveries into clinical success, may be within reach.
Abstract Development of Graves' disease is related to HLA-DR3. The extracellular domain (ECD) of human TSH receptor (hTSH-R) is a crucial antigen in Graves' disease. hTSH-R peptide 37 (amino acids 78–94) is an important immunogenic peptide in DR3 transgenic mice immunized to hTSH-R. This study examined the epitope recognition in DR3 transgenic mice immunized to hTSH-R protein and evaluated the ability of a mutant hTSH-R peptide to attenuate the immunogenicity of hTSH-R peptide 37. DR3 transgenic mice were immunized to recombinant hTSH-R-ECD protein or peptides. A mutant hTSH-R 37 peptide (ISRIYVSIDATLSQLES: 37m), in which DR3 binding motif position 5 was mutated V>A, and position 8 Q>S, was synthesized. 37m should bind to HLA-DR3 but not bind T cell receptors. DR3 transgenic mice were immunized to hTSH-R 37 and 37m. Mice immunized to hTSH-R-ECD protein developed strong anti-hTSH-R antibody, and antisera reacted strongly with hTSH-R peptides 1–5 (20–94), 21 (258–277), 41 (283–297), 36 (376–389), and 31 (399–418). Strikingly, antisera raised to hTSH-R peptide 37 bound to hTSH-R peptides 1–7 (20–112), 10 (132–50), 33 (137–150), 41, 23 (286–305), 24 (301–320), 36, and 31 as well as to hTSH-R-ECD protein. Both antibody titers to hTSH-R 37 and reaction of splenocytes to hTSH-R 37 were significantly reduced in mice immunized to hTSH-R 37 plus 37m, compared with mice immunized to hTSH-R 37 alone. The ability of immunization to a single peptide to induce antibodies that bind hTSH-R-ECD protein, and multiple unrelated peptides, is a unique observation. Immunogenic reaction to hTSH-R peptide 37 was partially suppressed by 37m, and this may contribute to immunotherapy of autoimmune thyroid disease.
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