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Advanced Drug Delivery Reviews (v.57, #3)
Trends in particulate antigen and DNA delivery systems for vaccines
by Bruno Gander (Theme Editor) (pp. 321-323).
Need for new vaccine formulations and potential of particulate antigen and DNA delivery systems
by M. Friede; M.T. Aguado (pp. 325-331).
Immunity in response to particulate antigen-delivery systems by Tazio Storni; Thomas M. Kündig; Gabriela Senti; Pål Johansen (pp. 333-355).
Adjuvants and antigen-delivery systems are essential in inducing and modifying immune responses, and despite the variety of materials available for such use, mechanisms by which they support immunity appear to be little known. A common denominator for most antigen-delivery systems is their particulate nature. Together with a certain depot effect, it is the particulate nature that primarily decides whether the antigen-delivery system will be successful in inducing an immune response. If this first requirement is fulfilled, the chemical composition of the vaccine decides which type of immune response will develop, e.g. which isotype of antibodies the B cells will produce, and which cytokines the T cells will secrete, and can be controlled by combining the antigen with immunomodulatory or co-stimulatory molecules. It is our goal to provide an overview of the cellular and molecular factors involved in the induction of immunity and how such factors may influence the potency of an adjuvant or a vaccine. Such factors should then be implemented in the design of new vaccines or in tuning the properties of existing vaccines in order to reach the properties that are necessary for successful vaccination.
Keywords: Innate immunity; Adaptive immunity; Viruses; Bacteria; Particles; Vaccine design
Formulation aspects of biodegradable polymeric microspheres for antigen delivery by Harjit Tamber; Pål Johansen; Hans P. Merkle; Bruno Gander (pp. 357-376).
Biodegradable microspheres (MS) have proven to be very useful antigen delivery systems that are ingested by immunocompetent cells and provide prolonged antigen release and lasting immunity thanks to sustained release of the microencapsulated material. This review provides an applicable summary of different formulation routes for the purpose of producing safe, qualified and efficacious products of microencapsulated peptide and protein antigens. We have brought to attention, with case examples, not only the most common means of improving the quality of microsphere formulations, i.e., the use of stabilising additives, but also less commonly known and applied approaches, e.g., ion pairing, novel polymer systems, solid-state and other innovative microencapsulation methods.
Keywords: PLGA microspheres; Antigen stability; Antigen microencapsulation; Antigen release
DNA-loaded biodegradable microparticles as vaccine delivery systems and their interaction with dendritic cells by Samantha Jilek; Hans P. Merkle; Elke Walter (pp. 377-390).
This paper provides a review of the role of dendritic cells (DC) in microparticle-mediated immune response and the advantages of associating DNA to microparticles in order to increase the potency of DNA vaccination in vivo. To begin with, different methods for the preparation of DNA-loaded microparticle with poly(lactide) (PLA)/poly(lactide-co-glycolide) (PLGA) polymers are presented. Further, the effects of DNA-loaded microparticles on DC in vitro are extensively examined including transfection and stimulation of DC, a key feature of the immune response. Finally, in vivo tracking of DNA-loaded microparticles and induction of immune responses upon DNA-loaded microparticle administration in different animal models and with various routes of administration are reviewed.
Keywords: Microparticles; PLGA; PLA; Dendritic cells; DNA; Microparticle delivery; Immune response
Biodegradable poly(lactic-co-glycolic acid) microparticles for injectable delivery of vaccine antigens by Wenlei Jiang; Rajesh K. Gupta; Mangesh C. Deshpande; Steven P. Schwendeman (pp. 391-410).
Injectable biodegradable polymeric particles (usually microspheres) represent an exciting approach to control the release of vaccine antigens to reduce the number of doses in the immunization schedule and optimize the desired immune response via selective targeting of antigen to antigen presenting cells. After the first couple of decades of their study, much progress has been made towards the clinical use of antigen-loaded microspheres. Poly(lactide-co-glycolic acids) (PLGAs) have been studied most commonly for this purpose because of their proven safety record and established use in marketed products for controlled delivery of several peptide drugs. PLGA microspheres have many desirable features relative to standard aluminum-based adjuvants, including the microspheres' ability to induce cell-mediated immunity, a necessary requirement for emergent vaccines against HIV and cancer. This review examines several impediments to PLGA microparticle development, such as PLGA-encapsulated antigen instability and deficiency of animal models in predicting human response, and describes new trends in overcoming these important issues. PLGA microparticles have displayed unprecedented versatility and safety to accomplish release of one or multiple antigens of varying physical–chemical characteristics and immunologic requirements, and have now met numerous critical benchmarks in development of long-lasting immunity after a single injected dose.
Keywords: PLGA; Microspheres; Single-dose vaccine; Antigen stability; Controlled release; Microclimate pH; Immune response; Cell-mediated immunity
Biodegradable mucoadhesive particulates for nasal and pulmonary antigen and DNA delivery by H. Oya Alpar; S. Somavarapu; K.N. Atuah; V.W. Bramwell (pp. 411-430).
Biodegradable polymer and particulate carriers have been shown to be of considerable potential for the delivery of peptides, proteins and DNA in animal models. In the context of vaccine delivery to the upper and lower respiratory tracts, the use of mucoadhesive agents offers a strategy for the facilitation of increased residence time and increased vaccine efficacy. Additional concerns addressed here include the potential of uptake of vaccine formulations by the primary olfactory nerves in the nasal cavity, effective delivery to the lung, strategies to maximise the immunopotentiation of candidate vaccine formulations, as well as the evaluation of animal models and interpretation of engendered immune responses in terms of antigen-specific antibody production. Experimental data are presented that demonstrate the potential of muco- and bioadhesive agents in combination with liposomes for intranasal (i.n.) delivery of tetanus toxoid in mice. A delivery system utilising chitosan for the formulation of microspheres by the spray-drying method is described and assessed for intranasal vaccine delivery, and porous particles with potential for pulmonary administration are also outlined.
Keywords: Vaccine delivery; DNA vaccine; Protein/peptide delivery; Mucosal immunology; Vaccination strategy; Particulate delivery systems
Exploiting receptor biology for oral vaccination with biodegradable particulates by Neil Foster; Barry H. Hirst (pp. 431-450).
The effective delivery of antigens via the oral route is an extremely desirable goal. Mucosal delivery of antigens stimulates mucosal and systemic immunity without affecting maternal antibodies and reduces the need for sterile needles or trained personnel. To date, there are very few commercially available oral vaccines and despite numerous reports in the scientific literature to show the success of biodegradable antigen carriers, none of these have achieved commercial status. Nevertheless, many studies have shown the great potential of biodegradable antigen carriers for oral vaccination in preclinical studies, but a more rational approach may be to specifically target antigen-loaded biodegradable microspheres to cells in the mucosal immune system which transport and process antigens for T cell recognition. Modern cell and molecular biology techniques have unearthed a wealth of information regarding important receptors involved in the capture of luminal antigens by microfold or membranous (M) cells and receptors on dendritic cells (DCs) which may allow future targeting of antigens to specific DC phenotypes, thus directing the immune response appropriately.In this review, we consider the use of currently available biodegradable antigen carriers and speculate on how these may be improved to more efficiently target mucosal effector sites.
Keywords: M cell; Oral vaccination; Dendritic cell; Biodegradable carriers; Mucosal immunity; Targeted delivery
Virosomes for antigen and DNA delivery by Toos Daemen; Arjan de Mare; Laura Bungener; Jørgen de Jonge; Anke Huckriede; Jan Wilschut (pp. 451-463).
Specific targeting and delivery as well as the display of antigens on the surface of professional antigen-presenting cells (APCs) are key issues in the design and development of new-generation vaccines aimed at the induction of both humoral and cell-mediated immunity. Prophylactic vaccination against infectious diseases in general aims at the induction of humoral immune responses to prevent infection. This humoral immune response is mediated by antibody-producing B cells. On the other hand, therapeutic immunisation against virally infected cells and tumour cells requires the induction of cytotoxic T lymphocytes (CTLs) that can specifically recognise and lyse infected cells or transformed tumour cells. The induction of Major Histocompatibility Complex (MHC) class I restricted CTL activity is optimally achieved by synthesis of antigens within APCs, for example, after immunisation with live attenuated virus. However, immunisation with live vaccines bears the risk of causing disease. Therefore, alternative vaccine delivery systems, which enable introduction of nonreplicating antigen into the MHC class I presentation pathway, are sought. Furthermore, for the induction of effective humoral and cellular responses, MHC class II restricted activation of T helper cells (Th cells) is required. Among other delivery systems, as described in this theme issue of Advanced Drug Delivery Reviews, virosomes seem ideally suited for delivery of antigens into both MHC pathways. In this review, we will focus on the use of virosomes as carrier vehicles for the intracellular delivery of protein antigens and DNA, and the induction of a cellular immune response against encapsulated protein antigens and proteins expressed by virosome-associated plasmids.
Keywords: Abbreviations; APC; antigen-presenting cells; C; 12; E; 8; octa(ethyleneglycol)-; n; -dodecyl monoether; CAT; chloramphenicol acetyl transferase; CTLs; cytotoxic T lymphocytes; DCs; dendritic cells; DODAC; dioleoyldimethylammonium; DOTAP; dioleyloxypropyltrimethylammonium methyl sulphate; DTA; diphtheria toxin; F-protein; Sendai fusion protein; HA; influenza hemagglutinin; HAV; hepatitis A virions; HVJ; hemagglutinating virus of Japan; IRIVs; immunopotentiating reconstituted influenza virosomes; ISCOMs; immunostimulating complexes; M1; influenza matrix protein; MHC; Major Histocompatibility Complex; NA; influenza neuraminidase; NP; influenza nucleoprotein; HN-protein; Sendai hemagglutinin-neuraminidase protein; OVA; ovalbumin; PTH-rP; parathyroid hormone-related peptide; PVP-NP; hydrogel nanoparticles of cross-linked polyvinylpyrrolidone; pyrene-PC; pyrene-phosphatidylcholine; Th cells; T helper cells; VSV; vesicular stomatitis virusVirosomes; Antigen; DNA
ISCOMATRIX® adjuvant for antigen delivery by Martin J. Pearse; Debbie Drane (pp. 465-474).
The immunostimulating complex, referred to as ‘iscom’, was first described by Morein et al. in 1984 as a novel structure for antigenic presentation of membrane proteins from enveloped viruses with potent immunomodulatory capability . Since this discovery, many vaccines have been tested in animal models showing the induction of both humoral and cellular immune responses . The ISCOMATRIX® adjuvant is essentially the same structure as the iscom but without the incorporated antigen . Antigens can be formulated with the ISCOMATRIX® adjuvant to produce ISCOMATRIX® vaccines that can provide the same antigen presentation and immunomodulatory properties as the iscom but with much broader application as they are not limited to hydrophobic membrane proteins. Various ISCOMATRIX® vaccines have been tested in animal models and more recently in human clinical trials . These studies have shown that the ISCOMATRIX® adjuvant is safe and induces both humoral and cellular immune responses. The ability of the ISCOMATRIX® adjuvant to induce these broad immune responses is due to the combination of antigen presentation by both MHC class I and class II pathways, and the powerful immunomodulatory capability of the saponin. Additionally, the ISCOMATRIX® adjuvant is simple to manufacture and can be combined with a wide range of antigens making it suitable for the development of novel human vaccines.
Keywords: ISCOMATRIX; Adjuvant; ISCOM; Vaccine; Immunotherapy
PLGA microspheres for improved antigen delivery to dendritic cells as cellular vaccines by Ying Waeckerle-Men; Marcus Groettrup (pp. 475-482).
Dendritic cells (DC) are currently employed as cellular vaccines in clinical trials of tumor immunotherapy. In most trials, peptide epitopes derived from tumor antigens are being exogenously loaded onto human DC for binding to MHC class I molecules. While this is a convenient method, it suffers from the drawback that the persistence of class I/peptide complexes on the cell surface is in the order of a few hours. This drawback limits the success of vaccination. We have investigated biodegradable poly(d,l-lactide-co-glycolide) microspheres (PLGA-MS) as delivery tools for antigen loading of human monocyte-derived DC (hMoDC). Immature hMoDC readily take up PLGA-MS and present epitopes from encapsulated proteins or peptides both on MHC class I and class II. Interestingly, antigen presentation by hMoDC was markedly prolonged when hMoDC were charged with PLGA-MS-encapsulated as opposed to soluble antigens. The properties of hMoDC with respect to migration, cytokine secretion, survival and allostimulation were not adversely affected by the uptake of PLGA-MS. In this article, we will review the properties of PLGA-MS as an adjuvant and summarize recent data on their potential for antigen delivery to dendritic cells.
Keywords: Abbreviations; CTL; cytotoxic T lymphocytes; DC; dendritic cells; GM-CSF; granulocyte-macrophage colony-stimulating factor; IL; interleukin; LPS; lipopolysaccharides; mAb; monoclonal antibody; MoDC; monocyte-derived dendritic cell; MS; microspheres; PLGA; Poly(; d; ,; l; -lactide-co-glycolide); PBMC; peripheral blood mononuclear cellsDendritic cells; Microspheres; Poly(lactide-co-glycolide); Immunotherapy; Antigen processing; Vaccine delivery