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PubMed1999

Iscoms with different quillaja saponin components differ in their immunomodulating activities.

In this study we demonstrate that iscoms made with different defined fractions of quillaja saponins (fractions A and C) exhibit strikingly different immunomodulatory activities. Fraction A has a potent immunomodulatory activity by enhancing antigen specific proliferation and production of IL-2 and IFN-gamma, interestingly, this is not reflected by increased levels of IgG2a. The C-fraction on the other hand strongly enhance antibody production and has the ability to modulate the IgG subclass pattern towards IgG2a, in spite of the fact that C-iscoms induce only low levels of IFN-gamma. Iscoms containing both fractions A and C (Iscoprep703) induced higher serum antibody responses than iscoms made of either of the fractions alone and showed an enhanced ability to modulate the serum subclass pattern towards IgG2a compared to C-iscoms.

Adjuvants, Immunologic↗
PubMed1997

Induction of protective immunity against influenza virus in a macaque model: comparison of conventional and iscom vaccines.

Cynomolgus macaque monkeys (Macaca fascicularis) were immunized twice intramuscularly, either with a conventional non-adjuvanted subunit vaccine or with a candidate immune-stimulating complex (iscom) vaccine, each containing 10 micrograms envelope glycoprotein of a recent human influenza A(H3N2) virus (A/Netherlands/18/94). In contrast to the macaques vaccinated with the classical subunit vaccine, those immunized with the iscom vaccine developed high titres of specific IgM, IgA and IgG serum antibodies, as well as high titres of haemagglutination-inhibiting and virus-neutralizing serum antibodies. Also, specific proliferative T cell responses were only found in the iscom-vaccinated monkeys and their levels were similar to those found in monkeys experimentally infected with the homologous virus. Upon intratracheal challenge with the homologous virus, the iscom-vaccinated monkeys were completely protected from detectable virus replication in lungs, pharynx and nose, whereas those vaccinated with the classical subunit vaccines were not, or were only partially protected. The kinetics of specific serum antibody development in the iscom-vaccinated monkeys after challenge were quite similar to those of monkeys after secondary infection with the same virus. In contrast, the post-challenge kinetics of serum antibody development in the monkeys vaccinated with the classical subunit vaccines resembled those of naive monkeys, confirming that these vaccines only provided limited protection in such animals.

Adjuvants, Immunologic↗
PubMed1992

Involvement of interleukin-2 and interferon-gamma in the immune response induced by influenza virus iscoms.

Splenocytes from mice primed with influenza virus envelope proteins incorporated in iscoms, as micelles or as infectious virus, were restimulated in vitro with the same antigen. Interleukin-2 (IL-2) and interferon-gamma (IFN-gamma) were assayed in the supernatants of such cultures. Influenza virus iscoms induced IL-2 and IFN-gamma responses in restimulation experiments that were antigen specific and significantly higher than those induced by micelles or infectious virus. Serum samples collected at the end of the experiments were analysed for the antibody response and profile. The antibody titres induced by iscoms were of a similar order of magnitude as those induced by infectious virus, and were about 18 times higher than the titres induced by micelles. In mice immunized with iscoms or infectious virus the most abundant antibodies were of the IgG1 and IgG2a isotype, and the IgE response was low. We conclude that immunization with iscoms stimulates the Th1-like subtype of murine T lymphocytes.

Animals↗
PubMed2005

ISCOM-based vaccines: the second decade.

The immunostimulating complex or 'iscom' was first described 20 years ago as an antigen delivery system with powerful immunostimulating activity. Iscoms are cage-like structures, typically 40 nm in diameter, that are comprised of antigen, cholesterol, phospholipid and saponin. ISCOM-based vaccines have been shown to promote both antibody and cellular immune responses in a variety of experimental animal models. This review focuses on the evaluation of ISCOM-based vaccines in animals over the past 10 years, as well as examining the progress that has been achieved in the development of human vaccines based on ISCOM adjuvant technology.

Animals↗
PubMed2001

Characterization of hepatitis C virus core-specific immune responses primed in rhesus macaques by a nonclassical ISCOM vaccine.

Current therapies for the treatment of hepatitis C virus (HCV) infection are only effective in a restricted number of patients. Cellular immune responses, particularly those mediated by CD8(+) CTLs, are thought to play a role in the control of infection and the response to antiviral therapies. Because the Core protein is the most conserved HCV protein among genotypes, we evaluated the ability of a Core prototype vaccine to prime cellular immune responses in rhesus macaques. Since there are serious concerns about using a genetic vaccine encoding for Core, this vaccine was a nonclassical ISCOM formulation in which the Core protein was adsorbed onto (not entrapped within) the ISCOMATRIX, resulting in approximately 1-microm particulates (as opposed to 40 nm for classical ISCOM formulations). We report that this Core-ISCOM prototype vaccine primed strong CD4(+) and CD8(+) T cell responses. Using intracellular staining for cytokines, we show that in immunized animals 0.30-0.71 and 0.32-2.21% of the circulating CD8(+) and CD4(+) T cells, respectively, were specific for naturally processed HCV Core peptides. Furthermore, this vaccine elicited a Th0-type response and induced a high titer of Abs against Core and long-lived cellular immune responses. Finally, we provide evidence that Core-ISCOM could serve as an adjuvant for the HCV envelope protein E1E2. Thus, these data provide evidence that Core-ISCOM is effective at inducing cellular and humoral immune responses in nonhuman primates.

Adjuvants, Immunologic↗
PubMed1996

Immunogenicity of infectious bovine rhinotracheitis virus (BHV-1) proteins integrated into ISCOMs or liposomes.

Dynamics and persistence of antibody responses to immunization and reimmunization of rabbits with BHV-1 ISCOMs or BHV-1 liposomes were investigated for 20 weeks and compared with those induced by a commercial vaccine against infectious bovine rhinotracheitis (IBR) or free BHV-1 protein subunits. Comparable levels of antibodies to BHV-1, determined by ELISA, were found throughout the observation period in rabbits treated with BHV-1 ISCOMs or the commercial vaccine. The immunogenicity of BHV-1 liposomes was higher than that of the free virus proteins, but lower than those of BHV-1 ISCOMs or the commercial vaccine. Virus neutralization test confirmed the best immunostimulatory effect of BHV-1 ISCOMs as far as the levels and the persistence of antibodies were concerned. The reactivities of the specific virus protein subunits with anti-BHV-1 antibodies elicited in rabbits immunized with BHV-1 ISCOMs or the commercial vaccine were compared by Western blotting. The patterns of the bands were similar, but some differences were found in their numbers and intensities.

Animals↗
PubMed1989

Inflammatory response and antigen localization following immunization with influenza virus ISCOMs.

The inflammatory response, antigen retention, and antigen localization was studied in mice after immunization with influenza virus glycoproteins presented in two physically defined forms--micelles and ISCOMS (immunostimulating complexes). Two hours after intraperitoneal injection, the proportion of polymorphonuclear leukocytes (PMNs) in peritoneal lavage cells increased from less than 1% to 82% in ISCOM-treated mice and from less than 1% to 41% of the total cell count in micelle-treated mice. For both treatment groups, the proportion of PMNs returned to around zero 24 h postimmunization. Total recovery of radioactive antigen was significantly greater (P less than 0.05) in ISCOM-treated than in micelle-treated mice at one, two, and eight days postinjection. At all times tested, animals given ISCOMs had significantly more radioactive antigen in their spleens than animals given micelles. By electron microscopy ISCOMs were found to attach externally to the plasma membrane or within phagosomes of macrophages in close association with the membranes.

Animals↗
PubMed1988

Influenza virus ISCOMs: antibody response in animals.

A monovalent experimental ISCOM vaccine has been prepared with the envelope glycoproteins haemagglutinin and neuraminidase of the equine virus strain A/Solvalla/79 (H3N8). In vaccination trials on BALB/c mice the ISCOM vaccine induced more than ten times higher serum antibody titres measured in ELISA than a corresponding experimental micelle vaccine. Similarly, in guinea-pigs the ISCOMs induced about tenfold higher haemagglutination inhibition (HI) and neuraminidase inhibition (NI) titres than a micelle vaccine or a conventional killed influenza whole virus vaccine. Horses vaccinated with a divalent experimental ISCOM vaccine, containing the equine strains A/Prague/56 (H7N7) and A/Solvalla/79 (H3N8), responded with ELISA antibody titres against haemagglutinin which were higher and lasted considerably longer than those in horses vaccinated with conventional whole virus vaccine. ISCOMs induced complete immunoprotection in mice vaccinated with a dose of 1 microgram envelope glycoproteins of the mouse pathogenic strain A/PR/8/34 (H1N1).

Adjuvants, Immunologic↗
PubMed1988

Humoral immune response elicited in rats by measles viral membrane antigens presented in liposomes and ISCOMs.

The immunogenicity of measles virus glycoproteins presented associated to liposomes or ISCOMs was compared with that of whole virus and solubilized membrane proteins in W/Fu rats. The rats were immunized three times at ten-day intervals with syngeneic peritoneal exudate cells fed in vitro with the various antigen preparations. A strong and persisting antibody response with haemagglutinin inhibitory and neutralization activity was observed in rats immunized with liposomes, ISCOMs, or virus. The responses were very similar despite the lower dose of protein received by rats immunized with ISCOMs (1 microgram protein) or with liposomes (20 micrograms protein). By contrast, injection of peritoneal exudate cells previously fed in vitro with soluble H and F glycoproteins resulted in only a poor and transient response. The sera from rats immunized with virus, liposomes or ISCOMs contained antibodies immunoprecipitating mainly H and F glycoproteins. Despite a strong enrichment in F polypeptides during the preparation of ISCOMs, they induced an equal anti-H and anti-F antibody response.

Adjuvants, Immunologic↗
PubMed1989

Immune response to immunostimulatory complexes (ISCOMs) prepared from human immunodeficiency virus type 1 (HIV-1) or the HIV-1 external envelope glycoprotein (gp120).

In mice, immunostimulatory complexes (ISCOMs) prepared from HIV-1 B external envelope glycoprotein (gp120) induced 10-fold higher antibody titres than gp120 emulsified in depot adjuvant, as measured by enzyme-linked immunosorbent assay (ELISA). Rhesus monkeys immunized with gp120 ISCOMs produced precipitating and virus neutralizing antibody titres equivalent to those seen in HIV-infected chimpanzees and humans. After multiple immunizations with HIV-1 B gp120 ISCOMs, a rhesus monkey developed a neutralizing response to the HIV-1 isolates RF and MN, but not to the CC isolate. Antisera from ISCOM-immunized rhesus monkeys recognized gp120 on the membranes of HIV-1 B-infected H9 cells, indicating the preservation of epitope structure in the ISCOMs matrix.

Adjuvants, Immunologic↗
PubMed1992

An immune stimulating complex (ISCOM) subunit rabies vaccine protects dogs and mice against street rabies challenge.

Dogs and mice were immunized with either a rabies glycoprotein subunit vaccine incorporated into an immune stimulating complex (ISCOM) or a commercial human diploid cell vaccine (HDCV) prepared from a Pitman Moore (PM) rabies vaccine strain. Pre-exposure vaccination of mice with two intraperitoneal (i.p.) doses of 360 ng ISCOM or 0.5 ml HDCV protected 95% (38/40) and 90% (36/40) of mice, respectively, against a lethal intracerebral (i.c.) dose with challenge virus strain (CVS). One 360 ng i.p. dose of ISCOM protected 87.5% (35/40) of mice against i.c. challenge with CVS. Three groups of five dogs were vaccinated intramuscularly (i.m.) with 730 ng of rabies ISCOM prepared from either the PM or the CVS rabies strains, and they resisted lethal street rabies challenge. Postexposure treatment of mice with three or four 120 ng i.m. doses of ISCOM protected 90% (27/30) and 94% (45/48), respectively, of mice inoculated in the footpad with street rabies virus, but three doses of HDCV conferred no protection. When four doses of HDCV were administered postexposure, 78% (32/41) of the mice died of anaphylactic shock; 21% (11/52) of mice had already died of rabies 4 days after the third vaccine dose was administered.

Animals↗
PubMed1990

Iscoms.

The common problem for defined purified antigens or antigen determinants has been to make them immunogenic regardless of whether they are produced conventionally, produced as cloned genetechnology products or chemically synthesized. The first problem is to get the protective antigen into a submicroscopic particle where the antigen is presented in several copies, i.e. as a multimer. For some antigens it seems also necessary to enhance the immunogenicity with an adjuvant. The immunostimulating complex (iscom) was created to fulfil these criteria by assembling antigens in a multimeric form on a matrix with built-in adjuvant to form a particle. The components are held together by hydrophobic interactions. The iscom has turned out to be highly immunogenic, inducing high antibody mediated and cell-mediated immunity including cytotoxic T cell response to influenza virus. In a mouse model iscoms containing influenza virus envelope proteins induced protective immunity by one intranasal administration. Protective immunity was also induced to a retrovirus--feline leukemia virus. In a monkey model system iscoms containing gp360 of Epstein-Barr virus induced protection to induction of tumours. Iscoms have also been used as carriers for small molecules such as oligopeptides, which combination appeared to be highly immunogenic.

Adjuvants, Immunologic↗
PubMed1998

Uptake and adjuvant activity of orally delivered saponin and ISCOM vaccines.

Saponins are a highly heterogenous group of glycosides which are common in plants and have been known to have adjuvant properties since the 1920s. The immunostimulating complex or ISCOM is a particulate adjuvant/antigen delivery system. ISCOMs are open cage-like complexes typically with a diameter of about 40 nm which are built up by cholesterol, lipid, immunogen and saponins from the bark of Quillaia saponaria Molina (soap bark tree). ISCOMs and saponins are used as adjuvants in some commercial veterinary vaccines and have been examined as adjuvants in a large number of human experimental vaccines. This review describes the current status and potential of saponin and ISCOMs as adjuvants for orally-administered vaccines with special reference to the induction of local and systemic immune responses and interactions with the intestinal epithelium. The structure and composition of saponins and ISCOMs will also be reviewed.

Journal Article↗
PubMed1998

Characterization of Neospora caninum iscom antigens using monoclonal antibodies.

Neospora caninum is a cyst-forming coccidian parasite which in cattle can cause abortion and birth of feeble calves. For the serological diagnosis of neosporosis, antibodies directed to the parasite can be demonstrated by ELISA, utilizing N. caninum proteins incorporated into iscoms (immunostimulating complexes) as antigen. Electrophoretic and immunoblotting studies had earlier revealed that N. caninum iscoms contained a restricted number of proteins compared with soluble parasite extracts, but the cellular origin of the incorporated proteins has not yet been determined. In the present study, monoclonal antibodies were raised against N. caninum iscoms. Six of these, named Ncmab-4, 7, 10, 13, 17 and 24, were used to characterize the N. caninum iscom antigen. The nature of the reactive epitopes and their localization within N. caninum tachyzoites were determined by means of immunological methods, including immunoblot, IFAT and immunogold electron microscopy. The apparent molecular weights of the dominant iscom antigens were found to be 18, 30, 32, 41 and 61 kDa. While the 61 kDa antigen was located intracellularly, the others were found on the parasite surface as well as within distinct intracellular compartments.

Animals↗
PubMed1994

Neospora caninum in dogs: detection of antibodies by ELISA using an iscom antigen.

An indirect enzyme linked immunsorbent assay (ELISA) for detection of antibodies to Neospora caninum in serum from dogs is described. Extracted tachyzoite proteins incorporated into immunostimulating complexes (iscoms) were used as coating antigen. A mixture of a monoclonal antibody to dog immunoglobulin G and a horse radish peroxidase conjugated antibody to mouse Ig was used to detect bound antibody. When the iscom preparation was analysed by means of sodium dodecyl sulphate polyacrylamide gel electrophoresis it appeared to consist of a restricted number of proteins compared with whole parasite homogenates. In immunoblot analysis, using N. caninum positive sera from rabbits and dogs as probes, the major antigens recognized had approximate molecular weights between 30 and 45 and 17 to 19 kDa. Compared with an ELISA using a crude solubilized tachyzoite antigen, the iscom ELISA substantially improved the sensitivity and specificity (to 97.6% and 95.6%, respectively, against an immunofluorescence test, IFAT, as indicator of true status). There was a statistically significant positive correlation between IFAT titres and iscom ELISA OD450 values. The iscom ELISA absorbances (and the IFAT titres) of dogs with proven clinical infections were not higher than those from nonclinically affected, putatively infected dogs.

Animals↗
PubMed1991

ISCOM of BHV-1 envelope glycoproteins protected calves against both disease and infection.

A subunit vaccine in the form of immunostimulating complex (iscom) was prepared to contain the envelope glycoproteins of bovine herpesvirus type 1 (BHV-1). This iscom preparation was tested in a vaccination experiment on 4-month-old calves seronegative to BHV-1. In this experiment, four groups with three animals per group were used. Two groups were vaccinated with the iscom preparation twice, four weeks apart, one group with 50 micrograms and the other with 100 micrograms per calf. The third group received a commercial inactivated whole-virus vaccine applying the same vaccination program. The fourth group served as control. Two weeks after the second vaccination, all the animals were challenge-infected intranasally with a virulent BHV-1 strain and four days later with a virulent Pasteurella multocida--this in order to mimic hard field conditions. When exposed to challenge infection, all the animals vaccinated with the iscom were fully protected, i.e., no virus could be recovered from their nasal secretions and no clinical symptoms were recorded. In contrast, the animals vaccinated with the commercial vaccine, responded to challenge with moderate fever and loss of appetite, and virus was isolated from the nasal secretions. The animals in the control group developed severe clinical symptoms. In the sera of iscom-vaccinated animals, the virus neutralization titers reached levels of 1/3500 or higher.

Adjuvants, Immunologic↗
PubMed1988

The requirement of lipids for the formation of immunostimulating complexes (iscoms).

The iscom--immunostimulating complex--is a highly immunogenic formulation of microbial membrane antigens. The biochemically analyzed components of the iscom are the protein and the glycoside Quil A. Continued analysis of the iscom showed that the protein moiety--the antigen--does not contribute to the iscom as a construct. Instead, cholesterol and Quil A are the essential structural components assembled together into a typical cage-like structure. A more "fluid" lipid, such as phosphatidylcholine, is needed to facilitate the incorporation of amphipathic poly- or oligopeptides into the iscom matrix.

1,2-Dipalmitoylphosphatidylcholine↗
PubMed1997

Iscoms containing purified Quillaja saponins upregulate both Th1-like and Th2-like immune responses.

The immune stimulating complex (iscom) is built up by antigen, cholesterol, phospholipids, and adjuvant active Quillaja saponins. Previous studies have shown that iscoms containing Quil A (a semipurified preparation of saponins) efficiently induce antibody and cell-mediated immune responses. In this study, we demonstrate that iscoms containing a mixture of two purified low toxicity Quillaja saponin fractions (ISCOPREP 703) are able to upregulate both Th1-like and Th2-like immune responses. Thus, ovalbumin (OVA) iscoms induced higher levels of antigen-specific IgG1 and IgG2a antibodies and increased the production of both IFN-gamma and IL-4 compared with OVA administered without adjuvant. In contrast, OVA formulated in Al(OH)3 elicited IgG1 and IgE antibodies and primed spleen cells producing IL-4 and IL-10, suggesting the activation of primarily Th2-like cells. These findings underline that adjuvants are able to alter the character of immune responses and may be used to generate responses with desired properties.

Animals↗