Review
Immunomodulatory biomaterials

https://doi.org/10.1016/j.ijpharm.2008.06.030Get rights and content

Abstract

Vaccination is one of the most successful medical interventions for the prevention of disease in the twentieth century. However, with the development of new and less reactogenic vaccine antigens, which take advantage of molecular recombinant technologies, comes the need for more effective adjuvants that will facilitate the induction of adaptive immune responses. In this context, immunomodulatory biomaterials, particularly the ones based on biodegradable polymers, show great promise. This article discusses the various classes of immunomodulatory biomaterials and advocates a cross-disciplinary approach that brings together molecular concepts from various fields to rationally design vaccine adjuvants with immunomodulatory properties.

Introduction

Vaccines are one of the most successful interventions for infectious diseases. However, major challenges remain in vaccine design, including improving their efficacy significantly and developing new vaccines for emerging diseases. Current vaccines typically include an antigen or live attenuated microorganism, an adjuvant to enhance the immune response, and a delivery system to target delivery to the right location (Pashine et al., 2005). An adjuvant is an agent that stimulates the immune system, increasing the response to a vaccine, while not having any specific antigenic effect. Adjuvants perform one or more of three main functions. (i) They provide a “depot” for the antigen for slow release; (ii) they facilitate targeting of the antigen to immune cells and enhance phagocytosis, and (iii) they modulate and enhance the type of immune response induced by the antigen alone (Cox et al., 2006, Trujillo-Vargas et al., 2005, Lutsiak et al., 2006, Petrovsky, 2006). Adjuvants may also provide the danger signal the immune system needs in order to respond to the antigen as it would to an active infection (Janeway et al., 2001). Thus, adjuvants play a significant role on every aspect of the immune response.

However, currently very few adjuvants and delivery systems are licensed for human use, with alum being the most common one. Adjuvants and delivery systems play a much more significant role in newer vaccines consisting of isolated antigens as opposed to live microorganisms. However, most current adjuvants only stimulate one immune pathway, as described below. Therefore the development of immunomodulatory biomaterials as adjuvants and delivery systems can have a significant impact on vaccines. This review discusses the current approaches to designing immunomodulatory adjuvants and presents some future research trends in this area. We begin with a brief discussion of the immune response.

Section snippets

Immune response mechanisms

A physiological immune response begins with the antigen presenting cell (APC). This is the crucial step of the activation of the immune system. The best APCs responsible for activation of helper T cells, killer T cells and B cells are dendritic cells (DCs). Immature DCs are found under the skin and mucous membranes where they sample surrounding for possible pathogens through pattern recognition receptors. After detecting pathogen, these cells engulf it via phagocytosis and pinocytosis and

Limitations of current vaccines

Current vaccine designs do not target the DC system. DCs can readily stimulate T cells and can operate at mucosal surfaces, where early protection is needed in many infections, while existing vaccines are weak stimulators of T cells. T-cell activation is only guaranteed by repeated encounters with persistent low levels of antigens (Zinkernagel, 2006). Therefore therapeutic strategies based on modulating the immune response may significantly expand treatment options and circumvent the problem of

Immunomodulators

The list of potential molecular targets for modulators of innate immunity is quite extensive (Germain, 2004). In cancer patients, for example, the immune system is non-specifically stimulated with immunomodulators in addition to treatment (Hanks et al., 2005). Several immunomodulatory agents are currently being investigated as adjuvants. Examples include natural compounds (calf thymic hormones, glucans), synthetic compounds (oligodeoxynucleotides containing CpG motifs, maramyl peptides,

The promise of polymeric biomaterials

The adjuvants discussed above, while promising, suffer from several drawbacks. Pathogens have evolved mechanisms against host immune systems. Moreover, toxicity is a huge concern with several of these adjuvants. Synthetic polymers with specific characteristics can be used as adjuvants and immunomodulators as an alternative to the microbially derived adjuvants currently being investigated. This is a relatively new interdisciplinary area involving a marriage of immunology and materials chemistry.

Discussion and conclusions

In summary, good immunostimulatory vaccine adjuvants activate DCs to mature and migrate to the draining lymph node, coincident with induction of the cytokine profile appropriate to the desired immune response mechanism (i.e., IFN-γ, IL-2, and IL-12 for the Th1 response and IL-4, IL-5, and IL-6 for the Th2 response). Like adjuvants that target DCs, some immunostimulatory vaccine adjuvants also interact with TLR proteins. Regardless of the mechanism of adjuvanticity, vaccine adjuvants must

Acknowledgments

B.N. gratefully acknowledges financial support from the U.S. Department of Defense – Office of Naval Research (ONR Award #N00014-06-1-1176). The authors would like to thank M.J. Wannemuehler, M.J. Kipper, M.P. Torres, and J.H. Wilson-Welder for useful discussions. The authors also wish to acknowledge support from the Institute for Combinatorial Discovery at Iowa State University.

References (85)

  • C.O. Elson et al.

    Mucosal adjuvants

  • J.T. Evans et al.

    A single vaccination with protein-microspheres elicits a strong CD8 T-cell-mediated immune response against Mycobacterium tuberculosis antigen Mtb8.4

    Vaccine

    (2004)
  • F.D. Finkelman et al.

    Cytokines: making the right choice

    Parasitol. Today

    (1992)
  • L.C. Freytag et al.

    Mucosal adjuvants

    Vaccine

    (2005)
  • K.F. Griffin et al.

    Protection against plague following immunisation with microencapsulated V antigen is reduced by co-encapsulation with IFN-gamma or IL-4, but not IL-6

    Vaccine

    (2002)
  • J. Hanes et al.

    New advances in microsphere-based single-dose vaccines

    Adv. Drug Deliv. Rev.

    (1997)
  • J. Hanes et al.

    Degradation of porous poly(anhydride-co-imide) microspheres and implications for controlled macromolecule delivery

    Biomaterials

    (1998)
  • M. Hebben et al.

    Modified vaccinia virus Ankara as a vaccine against feline coronavirus: immunogenicity and efficacy

    J. Feline Med. Surg.

    (2004)
  • W. Jiang et al.

    Stabilization of a model formalinized protein antigen encapsulated in poly(lactide-co-glycolide)-based microspheres

    J. Pharmaceut. Sci.

    (2001)
  • J. Johansson et al.

    Identification of adjuvants that enhance the therapeutic antibody response to host IgE

    Vaccine

    (2004)
  • T. Jones et al.

    Intranasal Protollin/F1-V vaccine elicits respiratory and serum antibody responses and protects mice against lethal aerosolized plague infection

    Vaccine

    (2006)
  • D.S. Katti et al.

    Toxicity, biodegradation and elimination of polyanhydrides

    Adv. Drug Deliv. Rev.

    (2002)
  • M.J. Kipper et al.

    Design of an injectable system based on bioerodible polyanhydride microspheres for sustained drug delivery

    Biomaterials

    (2002)
  • N. Kumar et al.

    Polyanhydrides: an overview

    Adv. Drug Deliv. Rev.

    (2002)
  • K.W. Leong et al.

    Polyanhydrides for controlled release of bioactive agents

    Biomaterials

    (1986)
  • E. Mata et al.

    Adjuvant activity of polymer microparticles and Montanide ISA 720 on immune responses to Plasmodium falciparum MSP2 long synthetic peptides in mice

    Vaccine

    (2007)
  • E.A. McNeela et al.

    Manipulating the immune system: humoral versus cell-mediated immunity

    Adv. Drug Deliv. Rev.

    (2001)
  • A. Moore et al.

    Immunization with a soluble recombinant HIV protein entrapped in biodegradable microparticles induces HIV-specific CD8+ cytotoxic T lymphocytes and CD4+ Th1 cells

    Vaccine

    (1995)
  • B. Narasimhan et al.

    Surface-erodible biomaterials for drug delivery

    Adv. Chem. Eng.

    (2004)
  • C.N. O’Brien et al.

    Formulation of poly(dl-lactide-co-glycolide) microspheres and their ingestion by bovine leukocytes

    J. Dairy Sci.

    (1996)
  • R.S. Raghuvanshi et al.

    Improved immune response from biodegradable polymer particles entrapping tetanus toxoid by use of different immunization protocol and adjuvants

    Int. J. Pharm.

    (2002)
  • G.A.W. Rook et al.

    Do successful tuberculosis vaccines need to be immunoregulatory rather than merely Th1-boosting?

    Vaccine

    (2005)
  • E. Shen et al.

    Mechanistic relationships between polymer microstructure and drug release kinetics in bioerodible polyanhydrides

    J. Control. Release

    (2002)
  • M.P. Torres et al.

    Amphiphilic polyanhydrides for protein stabilization and release

    Biomaterials

    (2007)
  • B.M. Vogel et al.

    Synthesis of novel biodegradable polyanhydrides containing aromatic and glycol functionality for tailoring of hydrophilicity in coltrolled drug delivery devices

    Biomaterials

    (2005)
  • D.L. Woodland

    Jump-starting the immune system: prime-boosting comes of age

    Trends Immunol.

    (2004)
  • D.K. Xing et al.

    Physicochemical and immunological studies on the stability of free and microsphere-encapsulated tetanus toxoid in vitro

    Vaccine

    (1996)
  • S. Akira et al.

    Toll-like receptors: critical proteins linking innate and acquired immunity

    Nat. Immunol.

    (2001)
  • H.O. Alpar et al.

    Potential of particulate carriers for the mucosal delivery of DNA vaccines

    Biochem. Soc. Trans.

    (1997)
  • F. Annunziato et al.

    Phenotypic and functional features of human Th17 cells

    J. Exp. Med.

    (2007)
  • J. Banchereau et al.

    Dendritic cells and control of immunity

    Nature

    (1998)
  • J. Banchereau et al.

    Immunobiology of dendritic cells

    Ann. Rev. Immunol.

    (2000)
  • Cited by (0)

    View full text