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PubMed1996

Adjuvant activity of iscoms; effect of ratio and co-incorporation of antigen and adjuvant.

We have studied the importance of co-incorporation of antigen and adjuvant in iscoms and the effects of different ratios of adjuvant and antigen in the iscom particles. Immune responses to influenza virus antigens (flu-Ag) in iscoms were compared to those induced by flu-Ag mixed with iscom-matrix, i.e. antigen and adjuvant delivered in separate packages. Higher doses of Quil A were required with iscom-matrix to induce strong immune responses compared to iscoms containing the same amount of antigen. The immunogenic properties of iscoms were affected by the ratio between antigen and adjuvant in the particles. Both iscoms and flu-Ag mixed with iscom-matrix induced antigen-specific antibodies with similar IgG subclass distribution and activated spleen cells producing high levels of IL-2 and IFN-gamma in vitro.

Adjuvants, Immunologic↗
PubMed1998

The immunostimulating complex (ISCOM) is an efficient mucosal delivery system for respiratory syncytial virus (RSV) envelope antigens inducing high local and systemic antibody responses.

ISCOM is an efficient mucosal delivery system for RSV envelope proteins as measured by antibody responses in respiratory tract secretions and in sera of mice following two intranasal (i.n.) administrations. Intranasally administered RSV ISCOMs induced high levels of IgA antibodies both in the upper respiratory tract and in the lungs. In the lungs, a prominent and long-lasting IgA response was recorded, which still persisted 22 weeks after the second i.n. immunization when the experiment ended. Subcutaneous (s.c.) immunization only induced low IgA titres in the upper respiratory tract and no measurable response to RSV was found in the lungs. Differences were also noticed in serum between the i.n. and s.c. modes of immunization. ISCOMs given intranasally induced earlier, higher and longer lasting IgM and IgG1 serum anti-RSV antibody responses than those induced by the s.c. mode of administration. A low serum IgE response was only detectable at 2 weeks after i.n. immunization with ISCOMs and after s.c. immunization with an inactivated virus, but no IgE response was detectable after s.c. injection of ISCOMs. The serum IgA response was more pronounced following s.c. injection of inactivated virus than after i.n. application of ISCOMs, and a clear-cut booster effect was obtained with a second immunization. Virtually no serum IgA response was detected after the s.c. administration of ISCOMs. In conclusion, the high immune responses induced by RSV ISCOMs in the respiratory tract and serum after i.n. administration indicate prominent mucosal delivery and adjuvant properties of the ISCOMs, warranting further studies.

Administration, Intranasal↗
PubMed1997

Influence of Quillaja saponaria triterpenoid content on the immunomodulatory capacity of Epstein-Barr virus iscoms.

The immune responses to immunostimulating complexes (iscoms) containing recombinant Epstein-Barr virus (EBV) gp340 envelope protein was evaluated in BALB/c (H-2(d)) and CBA (H-2(k)) mice. Gp340-iscoms were used either with a low content of Quillaja triterpenoid adjuvant (L-iscoms) or supplemented with additional Quillaja adjuvant in the form of iscomatrix (S-iscoms). Class and subclass distribution of anti-gp340 antibodies, EBV-neutralizing antibodies, antigen-specific T cell proliferation and cytokine production were determined and these results compared to those obtained by immunization with non-adjuvated gp340. The H-2(d) and H-2(k) mice were characterized as low or high responders in respect to the level of specific anti-gp340 antibodies, secretion of IgG2a isotype, antigen-specific lymphoproliferative capacity, interferon-gamma (IFN-gamma) and interleukin-10 (IL-10) production in the basic immunizations with gp340. While presentation of the antigen in iscom formulations with low levels of Quillaja triterpenoids induces a moderate enhancement of the immune responses in the low responder H-2(d) mice, supplementation with high levels of iscomatrix immunomodulator was required to enhance the immune responses in the high responder H-2(k) mice. In both mouse strains subcutaneous immunization with S-iscoms resulted in a significant increase of IgG1- and IgG2a-specific antibodies, as well as in strong antigen-specific proliferative response confirmed by the simultaneous cytokine production. The enhanced antigen-specific secretion of IL-2 and IFN-gamma together with the abrogation of IL-10 and the absence of IL-4 indicates that the responses were driven towards a Th1-type rather than Th2-type immune response. The S-iscom formulations minimized the differences in immune responses between the two mouse strains, but the capacity of immune sera to neutralize EBV transformation in vitro remained completely strain-dependent. These data indicate that immune responses generated by iscoms can be manipulated by altering the triterpenoid composition of the iscoms and that the levels of triterpenoids can determine whether or not a Th1-type response is made.

Adjuvants, Immunologic↗
PubMed1999

Iscom is an efficient mucosal delivery system for Mycoplasma mycoides subsp. mycoides (MmmSC) antigens inducing high mucosal and systemic antibody responses.

The purpose of this study was to explore the iscom as a mucosal delivery system for Mycoplasma mycoides subsp. mycoides small colony (MmmSC) antigens. BALB/c female mice were immunised intranasally (i.n.) twice, 8 weeks apart with three different doses (3, 10 and 20 microg) or subcutaneously (s.c.) with 3 microg of M. mycoides antigens incorporated into iscoms. Mycoplasma cells were administered s.c. twice, 8 weeks apart at a dose of 3 microg or i.n. at 10 microg as for iscoms. Both i.n. and s.c. modes of immunisation with iscoms induced prominent primary serum antibody responses in a dose-dependent manner, which were efficiently boosted. Compared to whole mycoplasma cells, iscoms enhanced the total Ig and IgG subclass (IgG1, IgG2a and IgG2b) responses in serum and in lungs greatly, and this enhancement was more prominent after i.n. than after s.c. immunisation. By the i.n. mode of immunisation iscoms containing mycoplasma antigens induced a 60-fold higher IgA response in lungs than the whole cell antigen. Iscoms also induced substantially higher total Ig and IgG subclass responses in the lungs. By Western blot a reduced number of bands (7) were detected in lung secretion after both i.n. and s.c. immunisations with iscoms compared to a high number of bands (more than 30) detected by serum antibodies. Interestingly i.n. immunisation with iscoms induced antibodies in lungs as well as in serum to mycoplasma cell antigens which differed from those induced by s.c. immunisation as revealed by the Western blot patterns.

Animals↗
PubMed1993

HIV experimental vaccines based on the iscom technology using envelope and GAG gene products.

In previous experiments gp160 incorporated into iscom was shown to induce neutralizing antibodies to the homologous as well as the heterologous isolates of HIV-1 (Akerblom et al., AIDS Res., 1991). In the present work we have incorporated into iscoms three defined recombinant DNA products of HIV-1. The carboxy-terminal part of gp120 expressed in E. Coli-PB-1; a chimera containing parts of both p24 and p15 expressed in E. coli-GAG; and baculovirus gp160 cloned in baculovirus and produced in insect cells. Immune responses were induced by the iscom preparations to the homologous antigen as well as to defined recombinant products and to the synthetic peptide RP135 (aa 304-328) harboring a neutralizing epitope. Sera from mice immunized with PB1-iscoms and gp160 (baculo) iscoms were tested in a syncytie inhibition assay. The serum from a mouse immunized with PB1 iscoms reacted strongly with the synthetic peptide RP135 and also neutralized the homologous isolate HIV-1/IIIB with a neutralization titer of 1/64. Three gp160 (baculo) iscom antisera were tested, of which two reacted strongly with the synthetic peptide RP135 but did not neutralize the homologous isolate HIV-1/IIIB. High serum titers were induced in mice by the gp160 iscoms (2 micrograms) to homologous antigen and the recombinant DNA E. coli construct p121 covering part of gp41. The ceilings of the antibody responses were reached after two immunizations. The PB1- and GAG-iscoms required three immunizations to reach the ceiling of the antibody response.

AIDS Vaccines↗
PubMed1992

Soluble proteins incorporate into ISCOMs after covalent attachment of fatty acid.

The immune stimulating complex (ISCOM) is a potent adjuvant which has the ability to induce both humoral and cellular immune reactions to protein antigens when they are physically associated with the ISCOM structure. However, in general only proteins with an exposed hydrophobic domain can associate with ISCOMs. As many soluble proteins are available as candidate subunit antigens there is a requirement for a method which promotes efficient incorporation of soluble protein into ISCOMs. Here it is demonstrated that following covalent attachment of palmitic acid, two soluble proteins, cytochrome C and ovalbumin, quantitatively incorporate into ISCOMs. ISCOMs containing ovalbumin prepared in this way have been shown to be highly immunogenic, generating humoral, delayed-type hypersensitivity and class I restricted T-cell immune responses following both parenteral and oral administration. The technique of incorporating soluble proteins into ISCOMs by covalent attachment of fatty acid should be generally applicable and extends the use of the ISCOM as an adjuvant.

Antigens↗
PubMed1995

Peptide polymerisation facilitates incorporation into ISCOMs and increases antigen-specific IgG2a production.

Synthetic peptides can be tailor-made to include any B or T epitopes desired from a single or multiple antigens or organisms. However, peptides in general are not very immunogenic and have not proven easy to incorporate into immunogenic vaccines. ISCOMs is an adjuvant system that has the capability not only to enhance the humoral immunogenicity of a protein but has also been shown to induce cell-mediated immune responses in animals. Synthetic peptide ISCOM vaccines are few because of the difficulty in incorporation of these peptides into ISCOMs. We have shown in this study that non-immunogenic peptides could be made immunogenic by polymerisation, and these polymers could be incorporated into ISCOMs to give highly immunogenic vaccines. Synthetic 20mer peptides containing known B and T-helper epitopes from the E7 protein of the cervical cancer associated human papillomavirus type 16 (HPV16 E7) have been used here as model immunogens. We have compared the humoral immunity induced by these peptides as polymers or as copolymers with a lipid binding 20mer peptide (LAP 20), with or without incorporation into ISCOMs. Unpolymerised peptide elicited no measurable antibody. When polymerised peptide was administered with CFA, or in phosphate-buffered saline (PBS) without adjuvant, or incorporated into ISCOMs, antibodies recognising both the immunising peptide and HPV16 E7 protein were produced. For equal quantities of administered peptide (5 micrograms), ISCOMs gave higher titres of antibody than CFA or PBS. Polymerised peptides induced high antigen-specific IgG2a:IgG1 ratios, which increased with multiple immunisations. These data indicate that polymerised peptides could be incorporated into ISCOMs to form efficient immunogens which may elicit a Th1 type response.

Adjuvants, Immunologic↗
PubMed1995

Adjuvant activity of non-toxic Quillaja saponaria Molina components for use in ISCOM matrix.

It is well established that ISCOMs function efficiently as an antigen-presenting system and protective immunity has been evoked against a variety of infectious agents. The built-in saponin adjuvant from Quillaja saponaria Molina is responsible for the strong immunoenhancing activity displayed by the ISCOM. However, to allow the use of ISCOMs in human vaccines it is necessary to determine the immunological properties and toxicity of chemically defined Quillaja components. Thus, the present study was carried out in a mouse model to determine the adjuvant activity and toxicity of "free", isolated Quillaja components, as well as formulated into particles, i.e. ISCOM matrix. The purified Quillaja components and the ISCOM matrix formulations were examined for their adjuvant activity in a model system consisting of purified influenza virus antigen and Quillaja saponins. It was demonstrated that a Quillaja component, designated QH-C, either as a "free" component or in an ISCOM matrix, has a strong adjuvant activity, but little or no toxicity in the doses tested. In addition, QH-C in the form of ISCOM matrix does not induce any local reactions at the site of injection. Thus, ISCOMs containing the QH-C component, devoid of toxicity, but with strong adjuvant activity, can prove to be useful in adjuvant formulations for human use.

Adjuvants, Immunologic↗
PubMed1997

ISCOM vaccine against contagious bovine pleuropneumonia (CBPP). 1. Biochemical and immunological characterization.

A better vaccine than the existing ones against contagious bovine pleuropneumonia (CBPP) caused by Mycoplasma mycoides subsp. mycoides small colony type (MmmSC) would improve the chances for eradication of CBPP. In such an effort, immunostimulating complexes (ISCOMS) have been prepared from the whole detergent-solubilized cells of MmmSC and characterized biochemically and immunologically. The most efficient detergent for solubilization of the mycoplasma was MEGA-10 which yielded a high recovery of proteins in the ISCOMS. The ISCOMS showed the typical cage-like structure by EM and sedimented as 19S by sucrose gradient centrifugation. The protein pattern of the ISCOMS, analyzed in SDS-PAGE, revealed a great number of bands distributed along the gel as high and low molecular weight polypeptides. The Western blot developed with a serum from a CBPP infected animal detected a reduced number of polypeptides. In samples from whole mycoplasma cells and in ISCOMS, lectin blots revealed more than 20 carbohydrate structures. The ISCOMS induced a strong primary antibody response in mice measured by ELISA and the boost resulted in a 6-fold increase of the serum antibody response. The IgG response was distributed into various IgG subclasses with high IgG1, IgG2a and IgG2b titres while the IgG3 response was low. In cattle the ISCOM vaccine induced strong primary and long lasting secondary antibody responses of similar magnitudes as those of naturally infected animals as recorded by ELISA which persisted more than a year. IgG response was equally distributed in IgG1 and IgG2 subclasses. Also a cell-mediated immune response measured by proliferation assay was induced by low dose of ISCOMS. In the growth inhibition test, sera from vaccinated cattle readily inhibited colony growth already after the first immunization.

Animals↗
PubMed2002

Construction and characterization of an experimental ISCOMS-based hepatitis B polypeptide vaccine.

AIM: To characterize the biochemical and immunological properties of an experimental ISCOMS vaccine prepared from a novel therapeutic polypeptide based on T cell epitopes of HBsAg, and a heptatis B-ISCOMS was prepared and investigated. METHODS: An immunostimulating complexes(ISCOMS)-based vaccine containing a novel therapeutic hepatitis B polypeptide was prepared by dialysis method, and its formation was visualized by electron microscopy and biochemically verified by SDS-polyacrylamide gel electrophoresis. Amount of the peptide within ISCOMS was determined by Bradford assay, and specific CTL response was detected by ELISPOT assay. RESULTS: Typical cage-like structures of submicroparticle with a diameter of about 40nm were observed by electron microscopy. Results from Bradford assay showed that the level of peptide incorporation was about 0.33g.L(-1). At the paralleled position close to the sixth band of the molecular weight marker(3480kDa) a clear band was shown in SDS-PAGE analysis, indicating successful incorporation of polypeptide into ISCOMS. It is suggested that ISCOMS delivery system could efficiently improve the immunogenicity of polypeptide and elicit specific immune responses in vivo by the results of ELISPOT assay, which showed that IFN-gamma producing cells(specific CTL responses) were increased(spots of ISCOMS-treated group: 47+/-5, n =3; control group: 5+/-2, n =3). CONCLUSION: ISCOMS-based hepatitis B polypeptide vaccine is successfully constructed and it induces a higher CTL response compared with short polypeptides vaccine in vivo.

Animals↗
PubMed1997

[Iscom (Immuno Stimulating Complex)-vaccine of equine influenza virus--transmission electron microscopic investigation and literature review].

Vaccines on the base of immunostimulating complexes are very rare in human and veterinary practice. Until now, Iscom vaccines mainly have been developed for scientific experimental investigations. Synthesis and preparation of Iscom vaccines, mainly basing on the reviewed literature, as well as electron microscopical investigations of Iscom structures and the monitoring of vaccine fractions of Iscoms are described. The equine influenza Iscom vaccine, developed by the Mallinckrodt Veterinary GmbH, is one of the first commercial Iscom vaccine used in veterinary medicine. In comparison with other commercially used vaccines, depending on the high level of antigen presentation of Iscom structures, a ten times higher antibody response is to be expected by the use of Iscom vaccines.

Animals↗
PubMed1998

Iscom, a delivery system for parenteral and mucosal vaccination.

The iscom is a supramolecular spherical structure, about 40nm in diameter, built up by structure-forming and immunomodulating quillaja triterpenoids, lipids and antigens. Iscoms with a defined quillaja triterpenoid formulation named QH 703 are in human trials. The advantages of using the particulate iscom form of quillaja components are (i) that local reactions at the site of injection can be avoided; a manifold higher dose of quillaja components in iscoms than in free form can be injected without causing side effects; (ii) considerably lower doses of both quillaja components and antigens are required to obtain a certain level of immune response. The iscom particle targets the antigen and adjuvant components to both the endosomal and cytosolic pathways for antigen presentation, resulting in both MHC class I and class II restricted immune responses. Further, iscoms induce APC to produce IL-1, IL-6 and IL-12 and a TH1 type of response with enhanced IL-2 and IFN-gamma production. Iscoms are now constructed to target the mucosal lymphatic systems. Iscoms administered intranasally induce secretory IgA responses in lungs and distant mucosal membranes e.g. in the genital tract.

Drug Delivery Systems↗
PubMed1991

Secretory immune responses in the mouse vagina after parenteral or intravaginal immunization with an immunostimulating complex (ISCOM).

Immunostimulating complexes (ISCOMs) are subunit vaccines that are particularly effective in producing immunity against systemic viral infections, but their effectiveness against mucosal infections has received little attention. To study their ability to produce mucosal immune responses in the female reproductive tract, a model ISCOM was prepared containing sheep erythrocyte membrane proteins, and anti-erythrocyte IgA and IgG titres in mouse vaginal washings were measured after immunization at parenteral or local mucosal sites. The ISCOM was prepared by a modified procedure that resulted in incorporation of 10-15% of initial membrane protein compared with 1-5% previously reported. Electrophoretic analysis demonstrated that four out of five erythrocyte membrane proteins were incorporated into the ISCOM, and electron microscopic observations indicated that the ISCOM had a cage-like structure with a diameter of 40 nm, similar to previous ISCOMs. Immunization in the pelvic presacral space (p.s.-p.s.) stimulated significantly higher anti-erythrocyte IgA titres in vaginal fluid than were produced by intraperitoneal (i.p.-i.p.), subcutaneous (s.c.-s.c.), intravaginal (i.vag.-i.vag.), or i.p.-i.vag. immunizations with the same vaccine. Specific IgG titres were less dependent on the route of immunization, with p.s.-p.s., i.p.-i.p. and s.c.-s.c. administration all giving similar high titres while i.p.-i.vag. treatment induced lower titres. These observations using a model ISCOM indicate that mucosal immune responses against membrane proteins were elicited in the female reproductive tract, and that non-mucosal immunization in the pelvis was a more effective route of administration than local application of the ISCOM to the vaginal mucosa.

Adjuvants, Immunologic↗
PubMed2005

Applying biotin-streptavidin binding for iscom (immunostimulating complex) association of recombinant immunogens.

We have previously reported strategies for Escherichia coli production of recombinant immunogens fused to hydrophobic peptide or lipid tags to improve their capacity to be incorporated into an adjuvant formulation. In the present study, we have explored the strong interaction between biotin and SA (streptavidin) (K(D) approximately 10(-15) M) to couple recombinant immunogens to iscoms (immunostimulating complexes). Two different concepts were evaluated. In the first concept, a His(6)-tagged SA fusion protein (His(6)-SA) was bound to Ni(2+)-loaded iscom matrix (iscom without associated protein), and biotinylated immunogens were thereafter associated with the SA-coated iscoms. The immunogens were either biotinylated in vivo on E. coli expression or double biotinylated in vivo and in vitro. In the second concept, the recombinant immunogens were expressed as SA fusion proteins, which were directly bound to a biotinylated iscom matrix. A 53-amino-acid malaria peptide (M5), derived from the central repeat region of the Plasmodium falciparum blood-stage antigen Pf155/RESA, and a 232-amino-acid segment (SRS2') from the central region (from Pro-97 to Lys-328) of the major surface antigen NcSRS2 of the protozoan parasite Neospora caninum, served as model immunogens in the present study. All fusion proteins generated were found to be efficiently expressed and could be recovered to high purity using affinity chromatography. The association between the different immunogen-containing fusion proteins and the corresponding iscom matrix was demonstrated by analytical ultracentrifugation in a sucrose density gradient. However, some fusion proteins were, to a certain extent, also found to associate unspecifically with a regular iscom matrix. Furthermore, selected iscom fractions were demonstrated to induce high-titre antigen-specific antibody responses on immunization of mice. For the particular target immunogen SRS2', the induced antibodies demonstrated reactivity to the native antigen NcSRS2. We believe that the presented concepts offer convenient methods to achieve efficient adjuvant association of recombinant immunogens, and the advantages and disadvantages of the two concepts are discussed.

Animals↗
PubMed1990

Characterization of immunostimulating complexes (ISCOMS) of HIV-1.

HIV-1, strain HTLV-III, propagated in H9 cells and purified by sucrose gradient centrifugation, was used as native antigen source for the preparation of immunostimulating complexes, HIV-iscoms. The major antigen detected in the iscom was the cell-derived HLA-DR, which readily could be removed from the virus lysate by immunosorbent. In the iscoms the HIV structural proteins MA p17, p55 and TM gp41 were identified; SU gp120 was present in only minute amounts in the virus lysate. The iscom particles appeared well preserved after freeze drying with a round shape, approximately 35 nm in diameter, comprising morphological subunits, assembled with icosahedral symmetry. Immunization experiments in mice reflected the antigen content of the iscoms. High antibody response was induced to HLA-DR in non-depleted iscoms. Major humoral responses were observed to the viral structural proteins MA p17, CA p24, p55, and also to TM gp41. A low or negligible antibody response to SU gp120 was induced by the HIV-iscoms. The negligible response was, however, overcome by the addition of recombinant gp160 to the virus lysate prior to formation of iscoms, resulting in a preparation evoking a clear serum antibody to gp160.

Animals↗
PubMed2006

On the dilution behaviour of immuno-stimulating complexes (ISCOMs).

Immunostimulating complexes (ISCOMs) are used as potent vaccine delivery systems. However, the mechanisms by which ISCOMs work are mostly unknown. The immunological potency of ISCOMs has often been associated with their characteristic cage-like structure. Since ISCOMs can be regarded as composite mixed micelles that contain Quillaja saponin as the surfactant, we postulated a micelle to vesicle transition of the particles upon dilution with aqueous solutions. The dilution behaviour of ISCOMs is not only an important preparative aspect, but may also be of high relevance for both cell culture and in vivo applications in which dilutions occur. Crude and purified preparations of ISCOM matrices were prepared by dialysis. Methods used to analyse the micelle to vesicle transitions were transmission electron microscopy and dynamic light scattering. Significant morphological changes occurred upon dilution with TRIS buffered saline and non-buffered saline, and a step-wise transition from the typical cage-like structure via both less well defined ISCOM-like structures and helical micelles to small lipidic particles was observed. Aggregation of the resulting small lipidic particles was noted. The results obtained by dynamic light scattering complemented these findings. With increasing dilution factors, increase in particle size and polydispersity was observed. Zeta-potentials showed a trend towards less negative values upon dilution, indicating that saponins were not retained within the lipid matrix. The results indicated that at least partial separation of Quillaja saponins from the remaining colloidal species occurred upon dilution with aqueous solutions. The release of saponins upon dilution may be an important aspect of how ISCOMs work.

Adjuvants, Immunologic↗
PubMed1995

Adjuvanticity of ISCOMs incorporating a T cell-reactive lipoprotein of the facultative intracellular pathogen Francisella tularensis.

Immunostimulating complexes (ISCOMs) are known to be highly effective adjuvants for envelope antigens of viral agents, but have not been evaluated for use with antigens of intracellular bacteria. Balb/c mice were subcutaneously immunized with ISCOMs into which the T cell-reactive membrane protein TUL4 of Francisella tularensis had been incorporated. Spleen cells from the immunized mice responded in vitro to TUL4 and to heat-killed F. tularensis live vaccine strain (LVS) with proliferation and production of gamma-interferon, whereas spleen cells from control mice immunized with TUL4 only did not respond to the antigens. When mice immunized with TUL4 ISCOMs were challenged with F. tularensis LVS, bacterial counts in spleen and liver were lower than in non-immunized mice. Again, TUL4 had no effect when used without ISCOMs. When proteins of a total membrane preparation of F. tularensis LVS were incorporated in ISCOMs and used for immunization, a decrease in bacterial counts was obtained which was similar in magnitude to that of TUL4 ISCOMs. Generally, the adjuvant effects demonstrated did not compare with the excellent protective effect of live tularaemia vaccine. Nonetheless, ISCOMs provide a means whereby protective antigens of F. tularensis can be tested.

Adjuvants, Immunologic↗
PubMed2006

On the preparation, microscopic investigation and application of ISCOMs.

ISCOM matrices constitute colloidal structures formed from Quillaja saponins, cholesterol and phospholipid. Addition of protein antigens to these matrices leads to the formation of ISCOMs. In this review we report on microscopic investigations of ISCOM matrices and ISCOMs as well as related colloidal structures, such as helices, worm-like micelles, ring-like micelles, and lamellae structures. We briefly outline the immunologic basis for the use of ISCOMs as vaccine delivery systems, and describe the various methods to form ISCOMs. Negative staining transmission electron micrographs of all colloidal structures are presented and described. On the basis of our microscopic investigations, different formation mechanisms of ISCOMS are discussed.

Adjuvants, Immunologic↗