Skip to main content

ISCOMs as a Vaccine Delivery System

  • Chapter
  • First Online:
Subunit Vaccine Delivery

Abstract

Immune stimulating complexes (ISCOMs) are lipid-based particles that have shown potential as adjuvants and carriers for antigens aiming at prophylactic or therapeutic vaccination upon injection as well as via mucosal and cutaneous administration. Both cellular and humoral immune responses have been reported after vaccination with antigens using ISCOM adjuvants, and some are in clinical trials. The adjuvant particles are formed by self-assembly of phospholipid, saponin, and cholesterol at well-defined ratios from mixtures of the components. In aqueous dispersion, they appear as cage-like structures with a hollow center and approximately 40–60 nm in size. The present chapter discusses state-of-the-art with regards to formulation design, characterization, and assessment of the mechanisms of action for ISCOMs with examples from our own research, along with addressing the different routes of administration referring to the clinical status of ISCOMs as adjuvants. The future perspectives of using ISCOMs as vaccine adjuvants are presented.

This is a preview of subscription content, log in via an institution to check access.

Access this chapter

Chapter
USD 29.95
Price excludes VAT (USA)
  • Available as PDF
  • Read on any device
  • Instant download
  • Own it forever
eBook
USD 89.00
Price excludes VAT (USA)
  • Available as EPUB and PDF
  • Read on any device
  • Instant download
  • Own it forever
Softcover Book
USD 119.99
Price excludes VAT (USA)
  • Compact, lightweight edition
  • Dispatched in 3 to 5 business days
  • Free shipping worldwide - see info
Hardcover Book
USD 169.99
Price excludes VAT (USA)
  • Durable hardcover edition
  • Dispatched in 3 to 5 business days
  • Free shipping worldwide - see info

Tax calculation will be finalised at checkout

Purchases are for personal use only

Institutional subscriptions

References

  • Alving CR, Peachman KK, Rao M, Reed SG (2012) Adjuvants for human vaccines. Curr Opin Immunol 24:310–315

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  • Andersson C, Sandberg L, Wernérus H, Johansson M, Lövgren-Bengtsson K, Ståhl S (2000) Improved systems for hydrophobic tagging of recombinant immunogens for efficient iscom preparation. J Immunol Methods 238(1–2):181–193

    Article  CAS  PubMed  Google Scholar 

  • Bal SM, Ding Z, van Riet E, Jiskoot W, Bouwstra JA (2010) Advances in transcutaneous vaccine delivery: do all ways lead to Rome? J Control Release 148:266–282

    Article  CAS  PubMed  Google Scholar 

  • Bangham AD, Horne RW, Glauert AM, Dinglejt LJA (1962) Action of saponin on biological cell membranes. Nature 196:952–955

    Article  CAS  PubMed  Google Scholar 

  • Barr IG, Mitchell GF (1996) ISCOMs (immunostimulating complexes): the first decade. Immunol Cell Biol 74:8–25

    Article  CAS  PubMed  Google Scholar 

  • Behboudi S, Morein B, Rönnberg B (1995) Isolation and quantification of Quillaja saponaria Molina saponins and lipids in iscom-matrix and iscoms. Vaccine 13:1690–1696

    Article  CAS  PubMed  Google Scholar 

  • Bengtsson KL, Morein B, Osterhaus ADME (2011) ISCOM technology-based Matrix M™ adjuvant: success in future vaccines relies on formulation. Expert Rev Vaccines 10:401–403

    Article  Google Scholar 

  • Berti F, Adamo R (2013) Recent mechanistic insights on glycoconjugate vaccines and future perspectives. ACS Chem Biol 8:1653–1663

    Article  CAS  PubMed  Google Scholar 

  • Brito LA, Malyala P, O’Hagan DT (2013) Vaccine adjuvant formulations: a pharmaceutical perspective. Semin Immunol 25:130–145

    Article  CAS  PubMed  Google Scholar 

  • Chea EK, Fernández-Tejada A, Damani P, Adams MM, Gardner JR, Livingston PO, Ragupathi G, Gin DY (2012) Synthesis and preclinical evaluation of QS-21 variants leading to simplified vaccine adjuvants and mechanistic probes. J Am Chem Soc 134:13448–13457

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  • Combadiere B, Mahe B (2008) Particle-based vaccines for transcutaneous vaccination. Comp Immunol Microbiol Infect Dis 31:293–315

    Article  PubMed  Google Scholar 

  • Cox JC, Sjölander A, Barr IG (1998) ISCOMs and other saponin based adjuvants. Adv Drug Deliv Rev 32(3):247–271

    Article  PubMed  Google Scholar 

  • Cruz-Bustos T, González-González G, Morales-Sanfrutos J, Megía-Frenández A, Santoyo-González F, Osuna A (2012) Functionalization of immunostimulating complexes (ISCOMs) with lipid vinyl sulfones and their application in immunological techniques and therapy. Int J Nanomedicine 7:5941–5956

    CAS  PubMed Central  PubMed  Google Scholar 

  • Dalsgard K (1974) Saponin adjuvants. 3. Isolation of a substance form Quillaja saponaria Molina with adjuvant activity in food-and-mouth disease vaccines. Arch Gesamte Virsuforschung 44:243–254

    Article  Google Scholar 

  • DiStefano D, Antonello JM, Bett AJ, Medi MB, Casimiro D, ter Meulen J (2013) Immunogenicity of a reduced-dose whole killed rabies vaccine is significantly enhanced by ISCOMATRIX™ adjuvant, Merck amorphous aluminium hydroxylphosphate sulfate (MAA) or a synthetic TLR9 agonist in rhesus macaques. Vaccine 31:4888–4893

    Article  CAS  PubMed  Google Scholar 

  • Fossum C, Hjertner B, Ahlberg V, Charerntantanakul W, McIntosh K, Fuxler L, Balagunaseelan N, Wallgren P, Bengtsson KL (2014) Early inflammatory response to the saponin adjuvant Matrix-M in the pig. Vet Immunol Immunopathol 158:53–61

    Article  CAS  PubMed  Google Scholar 

  • Frech SA, Dupont HL, Bourgeois AL, McKenzie R, Belkind-Gerson J, Figueroa JF, Okhuysen PC, Guerrero NH, Martinez-Sandoval FG, Meléndez-Romero JH, Jiang ZD, Halpern J, Torres OR, Hoffman AS, Villar CP, Kassem RN, Flyer DC, Andersen BH, Kazempour K, Breisch SA, Glenn GM (2008) Use of a patch containing heat-labile toxin from Escherichia coli against travellers’ diarrhea: a phase II, randomized, double-blind, placebo-controlled field trial. Lancet 371:2019–2025

    Article  CAS  PubMed  Google Scholar 

  • Fries LF, Smith GE, Glenn GM (2013) A recombinant viruslike particle influenza A (H7N9) vaccine. N Engl J Med 369:2564–2566

    Article  CAS  PubMed  Google Scholar 

  • Gregory AE, Titball R, Williamson D (2013) Vaccine delivery using nanoparticles. Front Cell Infect Microbiol 3:1–13

    Article  Google Scholar 

  • Helgeby A, Robson NC, Donachie AM, Beacock-Sharp H, Lövgren K, Schön K, Mowat A, Lycke NY (2006) The combined CTA1-DD/ISCOM adjuvant vector promotes priming of mucosal and systemic immunity to incorporated antigens by specific targeting of B-cells. J Immunol 15:3697–3706

    Article  Google Scholar 

  • Henriksen-Lacey M, Bramwell VW, Agger EM, Andersen P, Perrie Y (2010) Liposomes based on dimethyldioctadecylammonium promote a depot effect and enhance immunogenicity of soluble antigen. J Control Release 142:180–186

    Article  CAS  PubMed  Google Scholar 

  • Höglund S, Dalsgaard K, Lovgren K, Sundquist B, Osterhaus A, Morein B (1989) ISCOMs and immunostimulation with viral antigens. Subcell Biochem 15:39–68

    Article  PubMed  Google Scholar 

  • Hook S, Rades T (2013) Immune stimulating complexes (ISCOMs) and Quil-A containing particulate formulations as vaccine delivery systems. In: Flower DR, Perrie Y (eds) Immunomic discovery of adjuvants and candidate subunit vaccines. Immunomics reviews, vol 5. Springer, New York, pp 233–261. doi:10.1007/978-1-4614-5070-2_12

    Chapter  Google Scholar 

  • Huang CM (2007) Topical vaccination: the skin as a unique portal to adaptive immune responses. Semin Immunopathol 29:71–80

    Article  CAS  PubMed  Google Scholar 

  • Jiang W, Swiggard WJ, Heufler C, Peng M, Mirza A, Steinman RM, Nussenzweig MC (1995) The receptor DEC-205 expressed by dendritic cells and thymic epithelial cells is involved in antigen processing. Nature 375:151–155

    Article  CAS  PubMed  Google Scholar 

  • Kamstrup S, San MR, Doberti A, Grande H, Dalsgaard K (2000) Preparation and characterisation of quillaja saponin with less heterogeneity than Quil-A. Vaccine 18:2244–2249

    Article  CAS  PubMed  Google Scholar 

  • Kersten GF, Crommelin DJ (1995) Liposomes and ISCOMs as vaccine formulations. Biochim Biophys Acta 1241:117–138

    Article  PubMed  Google Scholar 

  • Kersten GF, Crommelin DJ (2003) Liposomes and ISCOMs. Vaccine 21:915–920

    Article  CAS  PubMed  Google Scholar 

  • Kersten GF, Teerlink T, Derks HJ, Verkleij AJ, van Wezel TL, Crommelin DJ, Beuvery EC (1988) Incorporation of the major outer membrane protein of Neisseria gonorrhoeae in saponin-lipid complexes (iscoms): chemical analysis, some structural features, and comparison of their immunogenicity with three other antigen delivery systems. Infect Immun 56:432–438

    CAS  PubMed Central  PubMed  Google Scholar 

  • Kersten GF, Spiekstra A, Beuvery EC, Crommelin DJ (1991) On the structure of immune-stimulating saponin-lipid complexes (iscoms). Biochim Biophys Acta 1062:165–171

    Article  CAS  PubMed  Google Scholar 

  • Kirkby N, Samuelsen P (2006) Composition for vaccination. US 2006/0147509 A1, 6 July 2006

    Google Scholar 

  • Könnings C, Copland MJ, Davies NM, Rades T (2002) A method for the incorporation of ovalbumin into immune stimulating complexes prepared by the hydration method. Int J Pharm 241:385–389

    Article  PubMed  Google Scholar 

  • Lendemans DG, Myschik J, Hook S, Rades T (2005) Cationic cage-like complexes formed by DC-cholesterol, Quil-A, phospholipid. J Pharm Sci 94:1794–1807

    Article  CAS  PubMed  Google Scholar 

  • Lendemans DG, Egert AM, Myschik J, Hook S, Rades, T (2006) On the dilution behaviour of immuno-stimulating complexes (ISCOMs). Pharmazie 61:689–695

    CAS  PubMed  Google Scholar 

  • Lendemans DG, Egert AM, Hook S, Rades T (2007) Cage-like complexes formed by DOTAP, Quil-A and cholesterol. Int J Pharm 332:192–195

    Article  CAS  PubMed  Google Scholar 

  • Lövgren K, Morein B (1988) The requirement of lipids for the formation of immunostimulating complexes (iscoms). Biotechnol Appl Biochem 10:161–172

    PubMed  Google Scholar 

  • Lycke N (2004) From toxin to adjuvant: the rational design of a vaccine adjuvant vector, CTA1-DD/ISCOM. Cell Microbiol 6:23–32

    Article  CAS  PubMed  Google Scholar 

  • Madsen HB (2010) Penetration and interaction of ISCOM nanoparticles with the skin. PhD thesis, University of Copenhagen. ISBN 978-87-92199-87-4

    Google Scholar 

  • Madsen HB, Ifversen P, Madsen F, Brodin B, Hausser I, Nielsen HM (2009) In vitro cutaneous application of ISCOMs on human skin enhances delivery of hydrophobic model compounds through the stratum corneum. AAPS J 4:728–739

    Article  Google Scholar 

  • Madsen HB, Arboe-Andersen HM, Rozlosnik N, Madsen F, Ifversen P, Kasimova MR, Nielsen HM (2010) Investigation of the interaction between modified ISCOMs and stratum corneum lipid model systems. Biochim Biophys Acta 1798:1779–1789

    Article  CAS  PubMed  Google Scholar 

  • McBurney WT, Lendemans DG, Myschik J, Hennessy T, Rades T, Hook S (2008) In vivo activity of cationic immune stimulating complexes (PLUSCOMs). Vaccine 26:4549–4556

    Article  CAS  PubMed  Google Scholar 

  • Morein B, Bengtsson KL (1998) Functional aspects of iscoms. Immunol Cell Biol 76:295–299

    Article  CAS  PubMed  Google Scholar 

  • Morein B, Sundquist B, Höglund S, Dalsgaard K, Osterhaus A (1984) ISCOM, a novel structure for antigenic presentation of membrane proteins from enveloped viruses. Nature 308:457–460

    Article  CAS  PubMed  Google Scholar 

  • Morein B, Ekström J, Lövgren K (1990) Increased immunogenicity of a non-amphipathic protein (BSA) after infusion into iscoms. J Immunol Methods 128:177–181

    Article  CAS  PubMed  Google Scholar 

  • Morelli AB, Becher D, Koernig S, Silva A, Drane D, Maraskovsky E (2012) ISCOMATRIX: a novel adjuvant for use in prophylactic and therapeutic vaccines against infectious diseases. J Med Microbiol 61:935–943

    Article  CAS  PubMed  Google Scholar 

  • Mottram PL, Leong D, Crimeen-Irwin B, Gloster S, Xiang SD, Meanger J, Ghildyal R, Vardaxis N, Plebanski M (2007) Type 1 and 2 immunity following vaccination is influenced by nanoparticle size: formulation of a model vaccine for respiratory syncytial virus. Mol Pharm 4:73–84

    Article  CAS  PubMed  Google Scholar 

  • Mowat AM, Smith RE, Donachie AM, Furrie E, Grdic D, Lycke N (1999) Oral vaccination with immune stimulating complexes. Immunol Lett 65:133–140

    Article  CAS  PubMed  Google Scholar 

  • Myschik J, Lendemans DG, McBurney WT, Demana PH, Hook S, Rades T (2006) On the preparation, microscopic investigation and application of ISCOMs. Micron 37:724–734

    Article  CAS  PubMed  Google Scholar 

  • Nordly P, Madsen HB, Nielsen HM, Foged C (2009) Status and future prospects of lipid-based particulate delivery systems as vaccine adjuvants and their combination with immunostimulators. Exp Opin Drug Deliv 6:1–16

    Article  Google Scholar 

  • Özel M, Hoglund S, Gelderblom HR, Morein B (1989) Quaternary structure of the immunostimulating complex (iscom). J Ultrastruct Mol Struct Res 102:240–248

    Article  PubMed  Google Scholar 

  • Pearse MJ, Drane D (2005) ISCOMATRIX adjuvant for antigen delivery. Adv Drug Deliv Rev 57:465–474

    Article  CAS  PubMed  Google Scholar 

  • Pedersen JS, Oliveira CLP, Hübschmann HB, Arleth L, Manniche S, Kirkby N, Nielsen HM (2012) Structure of ISCOM matrices and ISCOMs in suspension determined by small-angle X-ray scattering. Biophys J 102:2372–2380

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  • Pham HL, Ross BP, McGeary RP, Shaw PN, Hewavitharana AK, Davies NM (2006) Saponins from Qillaja saponina Molina: isolation, characterization and ability to form immune stimulatory complexes (ISCOMs). Curr Drug Deliv 3:389–397

    Article  CAS  PubMed  Google Scholar 

  • Reddy ST, van der Vlies AJ, Simeoni E, Angeli V, Randolph GJ, O’Neil CP, Lee LK, Swartz MA, Hubbell JA (2007) Exploiting lymphatic transport and complement activation in nanoparticle vaccines. Nat Biotechnol 25:1159–1164

    Article  CAS  PubMed  Google Scholar 

  • Scheerlinck J-PY, Greenwood DLV (2008) Virus-sized vaccine delivery systems. Drug Discov Today 13:882–887

    Article  CAS  PubMed  Google Scholar 

  • Sjölander A, Bengtsson KL, Johansson M, Morein B (1996) Kinetics, localization and isotype profiling of antibody responses to immune stimulating complexes (iscoms) containing human influenza virus envelope glycoproteins. Scand J Immunol 43:164–172

    Article  PubMed  Google Scholar 

  • Sjölander A, Bengtsson KL, Morein B (1997) Kinetics, localization and cytokine profile of T-cell responses to immune stimulating complexes (iscoms) containing human influenza virus envelope glycoproteins. Vaccine 15:1030–1038

    Article  PubMed  Google Scholar 

  • Sjölander A, Cox JC, Barr IG (1998) ISCOMs: an adjuvant with multiple functions. J Leukoc Biol 64:713–723

    PubMed  Google Scholar 

  • Soltysik S, Wu J-Y, Recchia J, Wheeler DA, Newman MJ, Coughlin RT, Kensil CR (1995) Structure/function studies of QS-21 adjuvant: assessment of triterpene aldehyde and glucuronic acid roles in adjuvant function. Vaccine 13:1403–1410

    Article  CAS  PubMed  Google Scholar 

  • Sun H-X, Xie Y, Ye Y-P (2009) ISCOMs and ISCOMATRIX™. Vaccine 27:4388–4401

    Article  CAS  PubMed  Google Scholar 

  • Vujanic A, Wee JLK, Snibson KJ, Edwards S, Pearse M, Quinn C, Moloney M, Taylor S, Scheerlinck J-PY, Sutton P (2010) Combined mucosal and systemic immunity following pulmonary delivery of ISCOMATRIX™ adjuvanted recombinant antigens. Vaccine 28:2593–2597

    Article  CAS  PubMed  Google Scholar 

  • Vujanic A, Sutton P, Snibson KL, Yen H-H, Scheerlinck J-PY (2012) Mucosal vaccination: lung versus nose. Vet Immunol Immunopathol 148:172–177

    Article  CAS  PubMed  Google Scholar 

  • Wang P, Dai Q, Thogaripally P, Zhang P, Michalek SM (2013) Synthesis of QS-21 based immunoadjuvants. J Org Chem 78:11525–11534

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  • Zhang Y, Wang L, Ruan W, Zhang J, Yao P, Zhou S, An J (2014) Immunization with recombinant 3-1E protein in AbISCO®-300 adjuvant induced protective immunity against Eimeria acervulina infection in chickens. Exp Parasitol 141:75–81

    Article  CAS  PubMed  Google Scholar 

Download references

Author information

Authors and Affiliations

Authors

Corresponding author

Correspondence to Hanne M. Nielsen .

Editor information

Editors and Affiliations

Rights and permissions

Reprints and permissions

Copyright information

© 2015 Springer Science+Business Media New York

About this chapter

Cite this chapter

Nielsen, H.M., Hübschmann, H.B., Rades, T. (2015). ISCOMs as a Vaccine Delivery System. In: Foged, C., Rades, T., Perrie, Y., Hook, S. (eds) Subunit Vaccine Delivery. Advances in Delivery Science and Technology. Springer, New York, NY. https://doi.org/10.1007/978-1-4939-1417-3_8

Download citation

Publish with us

Policies and ethics