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Margaret A Liu

Publications and source records attributed to Margaret A Liu.

8 recordsLinked to original sources
PubMed2006

Gene-based vaccines: recent technical and clinical advances.

DNA vaccines have been widely used in efforts to develop vaccines against various pathogens as well as for cancer, autoimmune diseases and allergy. DNA vaccines offer broad efficacy (particularly for their ability to generate both cellular and humoral immunity), ease of construction and manufacture and the potential for world-wide usage even in low-resource settings. However, despite their successful application in many preclinical disease models, their potency in human clinical trials has been insufficient to provide protective immunity. Nevertheless, two DNA vaccines were recently licensed for use in animals (horse and fish), underscoring the potential of this technology. Here, we describe recent advances in increasing the potency of these vaccines, in understanding their immunological mechanisms, and in their applications and efficacy in clinical trials so far.

Animals↗
PubMed2006

DNA vaccines: recent developments and future possibilities.

The field of DNA vaccines continues to advance and several new strategies to augment the immunogenicity of DNA vaccines are under evaluation. The majority of these studies are in the early preclinical stage, but some DNA vaccines have moved into clinical trials. In this review, we describe some of the more recent efforts aimed at increasing the immunogenicity of DNA vaccines, including the use of genetic adjuvants and plasmid-based expression of viral replicons. In addition, we discuss the possibility of using DNA vaccines to address emerging infectious agents where they may provide an advantage over other vaccine strategies and we review some areas where DNA vaccines have been used to target self-antigens.

Bioterrorism↗
PubMed2005

DNA vaccines: progress and challenges.

In the years following the publication of the initial in vivo demonstration of the ability of plasmid DNA to generate protective immune responses, DNA vaccines have entered into a variety of human clinical trials for vaccines against various infectious diseases and for therapies against cancer, and are in development for therapies against autoimmune diseases and allergy. They also have become a widely used laboratory tool for a variety of applications ranging from proteomics to understanding Ag presentation and cross-priming. Despite their rapid and widespread development and the commonplace usage of the term "DNA vaccines," however, the disappointing potency of the DNA vaccines in humans underscores the challenges encountered in the efforts to translate efficacy in preclinical models into clinical realities. This review will provide a brief background of DNA vaccines including the insights gained about the varied immunological mechanisms that play a role in their ability to generate immune responses.

Animals↗
PubMed2005

Probing prime substrate binding sites of human dipeptidyl peptidase-IV using competitive substrate approach.

Dipeptidyl peptidase-IV is a cell surface protease which plays an important role in glucose homeostasis through proteolytic inactivation of incretin hormones, primarily glucagon like peptide-1 (GLP-1). Substrate N-terminal amino acid (S2-S1) specificity is rather clearly defined, while no substantial information is available on the significance of amino acid interactions towards the C-terminus after the scissile bond (so called prime S1'-S4' or distant S5'-S28' sites). In the present study the increasing length of the peptide towards prime sites (S1'-S4') resulted in approximately 7-fold decrease in Km. Moreover, the Km for GLP-1 cleavage was comparable to that of an S2-S4' peptide, suggesting that few, if any, important enzyme-substrate interactions occur beyond the active site. Effect of substrate length on kcat was less obvious, but kcat/Km showed an increasing trend when His-Ala-pNA (representing the natural two N-terminal residues) was compared to GLP-1. To probe the impact of increasing substrate length on the free energy of activation (as has been suggested for elastase and chymotrypsin) we performed temperature studies. To adequately interpret thermodynamic data we sought to understand what steps limit the kcat expression. Steady-state parameters of the reactions catalyzed by serine proteases are composed of microscopic constants describing binding, acylation, and deacylation steps. Viscosity and pre-steady-state studies suggested that His-Ala-pNA cleavage is limited in the deacylation half-reaction, most likely the product release step. Thus, the free energy of activation, as calculated from the Eyring equation, is underestimated (at least for His-Ala-pNA) and the effect of substrate length on the acylation step (and transition-state stabilization) could not be unambiguously assessed.

Binding Sites↗
PubMed2005

Human clinical trials of plasmid DNA vaccines.

This article gives an overview of DNA vaccines with specific emphasis on the development of DNA vaccines for clinical trials and an overview of those trials. It describes the preclinical research that demonstrated the efficacy of DNA vaccines as well as an explication of the immunologic mechanisms of action. These include the induction of cognate immune responses, such as the generation of cytolytic T lymphocytes (CTL) as well as the effect of the plasmid DNA upon the innate immune system. Specific issues related to the development of DNA as a product candidate are then discussed, including the manufacture of plasmid, the qualification of the plasmid DNA product, and the safety testing necessary for initiating clinical trials. Various human clinical trials for infectious diseases and cancer have been initiated or completed, and an overview of these trials is given. Finally, because the early clinical trials have shown less than optimal immunogenicity, methods to increase the potency of the vaccines are described.

Clinical Trials as Topic↗
PubMed2003

Gene vaccines.

Gene vaccines are a new approach to immunization and immunotherapy in which, rather than a live or inactivated organism (or a subunit thereof), one or more genes that encode proteins of the pathogen are delivered. The goal of this approach is to generate immunity against diseases for which traditional vaccines and treatments have not worked, to improve vaccines, and to treat chronic diseases. Gene vaccines make use of advances in immunology and molecular biology to more specifically tailor immune responses (cellular or humoral, or both) against selected antigens. They are still under development in research and clinical trials. The mechanisms for inducing cellular (as opposed to humoral) responses against a particular antigen have been elucidated. Gene vaccines provide a means to generate specific cellular responses while still generating antibodies, if desired. In addition, by delivering only the genes that encode the particular proteins against which a protective or therapeutic immune response is desired, the potential limitations and risks of certain other approaches can be avoided. This article describes the rationale for, immunologic mechanisms involved in, and design of gene vaccines under development. Preclinical and clinical studies of these vaccines are discussed for various clinical applications, focusing on infectious diseases.

Animals↗
PubMed2002

Ethical issues for vaccines and immunization.

Vaccination is the only type of medical intervention that has eliminated a disease successfully. However, both in countries with high immunization rates and in countries that are too impoverished to protect their citizens, many dilemmas and controversies surround immunization. This article describes some of the ethical issues involved, and presents some challenges and concepts for the global community.

Child↗