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PubMed2001

Heterosubtypic immunity against human influenza A viruses, including recently emerged avian H5 and H9 viruses, induced by FLU-ISCOM vaccine in mice requires both cytotoxic T-lymphocyte and macrophage function.

Induction of heterosubtypic immunity to influenza viral antigens is of paramount importance to the prevention of epidemics and potential pandemics. The 1997 incidence of avian influenza infections in humans in Hong Kong heightened the need for pandemic preparedness and a search for vaccines and vaccine delivery systems that can confer broad protection. In this report, we demonstrate that the delivery of H1N1 subtype influenza viral antigens as immunostimulating complexes (ISCOM) induces broad cross-protection in mice against challenge with various influenza virus subtypes, including the avian H9 and the H5 strains that were recently responsible for deaths in humans. The ISCOM delivery system induced high and long-lived serum antiviral antibodies and class I-restricted cytotoxic T-lymphocytes (CTL). Studies with perforin, IFN-gamma, and mu-chain gene knock-out mice demonstrated that the heterosubtypic protection required cross-reactive, functional cytotoxic T cells and nonhemagglutination inhibiting serum antibodies. Interferon-gamma, a major player in viral clearance by nonlytic mechanisms, did not appear to play a role in heterosubtypic immunity. Nonformulated H1N1 influenza antigens failed to induce significant CTL or long-lasting antibody responses or to protect mice against challenge with heterosubtypic viruses. Furthermore, while influenza virus infection induced a dominant nucleoprotein (NP)-specific CTL response in H2 mice, the ISCOM delivery system induced a dominant hemagglutinin-specific CTL response. Moreover, non-neutralizing but cross-reactive antibodies played a role in reducing viral titers by macrophages. These results suggest that exogenous delivery of influenza antigens as ISCOM can influence their antigen processing and presentation, their ability to induce/recall CTL specificities, and their capacity to mediate broad cross-protection against influenza virus variants.

Animals↗
PubMed1992

Acute and latent infection of mice immunised with HSV-1 ISCOM vaccine.

The effect of immunisation with an HSV-1 antigen preparation (containing at least 6 viral glycoproteins) on primary infection with HSV and the establishment of latency, was assessed in two mouse models (involving either skin or corneal challenge with virus). The vaccine preparation, given either with Freund's complete adjuvant or aluminium hydroxide gel or in the form of immunostimulating complexes (ISCOMS), induced high ELISA antibody responses (highest with HSV as the ISCOM preparation) and low levels of neutralising antibody. In both models, immunisation with the HSV ISCOM preparation significantly reduced the incidence of zosteriform spread of virus and the severity of disease and, in some cases, the incidence of latent infection in sensory ganglia. In the eye model it was possible to show that immunisation with the HSV ISCOMS restricted the establishment of latency almost entirely to the ophthalmic part of the trigeminal ganglion. Protection from establishment of latency correlated with prechallenge antibody levels.

Acute Disease↗
PubMed1995

Immunogenicity of influenza and HSV-1 mixed antigen ISCOMs in mice.

Immunostimulating complexes (ISCOMs) were prepared with mixtures of antigens from influenza A virus (A/PR/8/34 or A/Sichuan/2/87) and herpes simplex virus type 1 (HSV-1), and were characterised by enzyme linked immunosorbent assay (ELISA) and electron microscopy using double-labelling immunogold techniques employing monoclonal antibodies to influenza or HSV-1 glycoproteins. The immunogenicity of the mixed antigen ISCOMs was evaluated in mice, following administration by the subcutaneous route, by measuring the total and subclass IgG antibody responses. Protection of these animals against challenge with live influenza A/Sichuan virus or live HSV-1, was compared with that induced by immunization with aqueous mixed antigen preparations. It was found that relatively high humoral responses to both influenza and HSV antigens, and increased levels of protection to both influenza and HSV viruses were elicited in mice receiving the mixed antigen ISCOM preparation compared to those observed in animals receiving the mixed aqueous subunit preparation. The findings also indicate that antigens from more than one virus can be used in an ISCOM formulation to produce immunity and protection.

Animals↗
PubMed2000

Inducing protective antibodies against ring-infected erythrocyte surface peptide antigen of Plasmodium falciparum using immunostimulating complex (ISCOMs) delivery.

In the present study, synthetic peptides (EENVEHDA)2 [(oc)2] and (DDEHVEEPTVA)2 [(un)2] of ring-infected erythrocyte surface antigen (RESA) of Plasmodlium filciparum were linked with palmitic acid and entrapped in immunostimulating complexes (ISCOMs). The immunogenicity of the peptide(s) and mixture of peptides were studied in mice with different genetic background. Peptide(s) entrapped in ISCOMs using a low-dose immunization strategy generated high-titer as well as high-affinity antibodies. Interestingly, no genetic restriction of the immune response was observed in any of the strains studied. The IgG subclass pattern with the peptide(s) showed predominately IgG2a/2b isotypes, while with the mixed peptide formulation, (un)2-specific IgG isotype pattern showed induction of both IgG1 and IgG2a/2b isotypes. These cytophilic antibodies inhibited the ring as well as schizont stage and total parasite growth during in vitro merozoite reinvasion inhibition study. In the mixed peptide preparation, the same pattern of immune response was achieved as that of individual peptide(s) using ISCOMs delivery. Therefore, the entrapment of otherwise poorly immunogenic synthetic peptides in ISCOMs resulted in increased immunogenicity followed by strong secondary response and can be adopted for developing subunit immunogen formulation against malarial parasite.

Alum Compounds↗
PubMed1993

Immunopotentiation of synthetic oligopeptides by chemical conjugation to iscoms.

A method has been devised for coupling cysteine-containing peptides to pre-formed immune stimulating complexes (iscoms). Four different peptides were used and the peptide-iscom conjugates were evaluated as immunogens in mice. It was demonstrated that highly immunogenic peptide-iscom conjugates can be prepared provided that the peptides are successfully linked to the carrier iscoms.

Adjuvants, Immunologic↗
PubMed1996

Priming in vivo and quantification in vitro of class I MHC-restricted cytotoxic T cells to human papilloma virus type 11 early proteins (E6 and E7) using immunostimulating complexes (ISCOMs).

Immunostimulating complexes (ISCOMs) efficiently deliver soluble antigen into both the cytosolic (endogenous) and endosomal (exogenous) pathways of antigen processing. Cytosolic delivery to antigen-presenting cells (APCs) may therefore be useful for the stimulation and assay of class I major histocompatibility complex (MHC)-restricted cytotoxic T lymphocytes (CTL) in vitro. In this study, mice were immunized with ISCOMs containing fusion proteins of the E6 or E7 early proteins of human papilloma virus type 11 (HPV 11) to elicit CTL. These CTL were then restimulated in vitro using APCs pulsed with the same ISCOMs, prior to cytotoxicity assay using syngeneic target cells infected with recombinant vaccinia viruses. In this way, antigen-specific, MHC-restricted lysis by CD8+ cells was detected. However, this was dependent on the use of low density splenocytes as APCs for restimulation in vitro. Limiting dilution analyses showed a direct correlation between the CTL responder frequency and the number of times the animals were immunized in vivo. We conclude that in lieu of infectious virus, the use of ISCOMs to mediate antigen delivery to APCs in vitro can be used to quantitate CTL activity. This may have applications in monitoring vaccine efficacy, particularly to viruses such as HPV, which cannot be presently obtained as infectious virus in sufficient quantity for CTL propagation and assay.

Animals↗
PubMed1996

Protective immunity induced in chicken by a single immunization with Mycoplasma gallisepticum immunostimulating complexes (ISCOMS).

An experimental immunostimulating complex vaccine has been prepared from detergent (Mega-10) solubilized Mycoplasma gallisepticum (MG) antigens. Sucrose gradient centrifugation, SDS-PAGE and immunoblotting studies demonstrated that the ISCOM vaccine contained virtually all of the immunodominant MG membrane proteins, including p64 and p56. Protective immunity generated by the experimental MG ISCOM vaccine was demonstrated in challenge experiments. Chickens immunized with a single dose containing between 1 and 50 micrograms of MG ISCOMs had significantly reduced lesion scores in the air sac after challenge. The reisolation of the challenge MG strain was significantly less frequent from the chickens in vaccinated groups than from the unvaccinated control group. Presence of humoral antibodies in chickens vaccinated with 1-25 micrograms MG ISCOMs was not detectable by blocking ELISA or haemagglutination-inhibition before challenge. Chickens vaccinated once or twice with a 50 micrograms dose were transitory positive by blocking ELISA and rapid plate agglutination before challenge.

Animals↗
PubMed2001

A comparison of oral and parenteral routes for therapeutic vaccination with HSV-2 ISCOMs in mice; cytokine profiles, antibody responses and protection.

It is likely that recurrent infections with HSV-2 (or HSV-1) are influenced by local levels of immunity at mucosal surfaces, when virus reactivated from the latent state is infecting mucosal epithelial cells. Increasing the levels of cellular and humoral immunity through immunisation and maintaining such increased levels, may reduce establishment and spread of reactivated virus at the local site, thereby ameliorating recurrent disease symptoms. The use of HSV-2 antigens incorporated into immunostimulating complexes (ISCOMs) for immunisation of mice previously infected with HSV-2 was investigated in the present study. Prophylactic administration of HSV-2 ISCOM vaccine to mice elicits local antibody detectable in nasal washings, serum antibody and the presence of cytokines IL-2, IFN-gamma and IL-4 in supernatants from spleen cell cultures stimulated in vitro with HSV-2 antigens. Use of the same vaccine in mice infected previously with HSV-2, results in increased levels of total and subclass serum ELISA antibody and also increased levels of serum neutralising antibody. Treatment of HSV-2 infected mice with the HSV-2 ISCOM vaccine also induces higher levels of the cytokines IL-2, IFN-gamma and IL-4, in in vitro stimulated spleen cell cultures. Challenge with a lethal dose of HSV-1 showed that mice previously infected with HSV-2 and subsequently given two doses of HSV-2 ISCOMs vaccine were protected.

Animals↗
PubMed1998

Studies on experimental adjuvanted influenza vaccines: comparison of immune stimulating complexes (Iscoms) and oil-in-water vaccines.

Detergent-disrupted influenza virus vaccines, formulated as Iscoms, or oil-in-water (o/w) emulsions, were administered parenterally to mice and evaluated for immunogenicity and protective efficacy. Both formulations enhanced both primary and secondary serum antibody responses. The magnitude of these responses with o/w emulsions was further enhanced by the addition of the non-ionic block copolymer L121 in the emulsion. Four weeks after primary immunization, mice were challenged by exposure to an aerosol containing infectious virus. Resistance to challenge in terms of survival rate and weight change correlated well with serum antibody titre for all formulations. Two major differences were observed between the adjuvant formulations. Iscom vaccines, formulated with Quil-A or the less toxic Quillaia saponin preparation Iscoprep 703, induced specific cytotoxic T-lymphocyte responses, whereas the o/w-based vaccines did not. In addition, dose-site reactivity studies in sheep showed that Iscom vaccines were less reactive than o/w-based vaccines, the degree of reactivity of the latter increasing sharply with increasing L121 concentration. On the basis of these studies, Iscoms were chosen for development as a potential adjuvant for human influenza vaccines.

Adjuvants, Immunologic↗
PubMed2000

Antibody responses, cytokine levels and protection of mice immunised with HSV-2 antigens formulated into NISV or ISCOM delivery systems.

The immunogenicity of a type 2 herpes simplex virus (HSV-2) antigen preparation following its formulation into immunostimulating complexes (ISCOMs) or non-ionic surfactant vesicles (NISV) was investigated in a murine model. The immune responses induced by each formulation were characterised by antigen specific total and subclass serum responses, and by lymphocyte proliferation and cytokine (interleukin-2 (IL-2), interleukin-4 (IL-4) and interferon-gamma (IFN-gamma)) production by in vitro restimulated spleen cells. The degree of protection afforded to mice by these various HSV-2 vaccine preparations against homologous (HSV-2) and heterologous (HSV-1) challenge infection was also determined. The findings suggest that formulation of the HSV-2 glycoprotein antigens with ISCOM or NISV delivery vehicles, and the methods used to prepare these formulations, influenced the immunogenicity of the final preparation. Higher IgG2a and neutralising antibody levels, IL-2 and IFN-gamma levels and lymphoproliferative responses were noted in mice immunised with the HSV-2 ISCOM formulated vaccine preparation. Furthermore, although HSV-2 antigens formulated in dehydration-rehydration NISV, or entrapped in NISV by freeze-thawing at 30 degrees C (HSV-2 NISV 30), also elicited relatively high antibody, IL-2 and IFN-gamma levels and relatively high lymphoproliferative responses, formulation of HSV-2 antigens by freeze-thawing with NISV at 60 degrees C (HSV-2 NISV 60) did not. There were no differences between any of the HSV-2 vaccine formulations in terms of IL-4 induction in in vitro stimulated spleen cell cultures. Almost complete protection against HSV-2 challenge was afforded by the HSV-2 ISCOM preparation, while partial protection against challenge infection was afforded by the HSV-2 NISV 30 vaccine formulation. The findings are discussed in relation to the nature of the immune mechanisms, particularly Th1- or Th2-like responses, that may be elicited by HSV-2 antigen preparations formulated into various delivery systems and the relevance of these immune responses to protection against HSV infection in the murine model.

Administration, Oral↗
PubMed2000

Impaired immunogenicity of immunostimulating complexes (iscoms) by administration in slow-release formulations.

This study was performed to explore the possible benefits of formulations and administration regimens that allow a protracted release of iscoms from the injection site. Three forms of slow release of immunostimulating complexes (iscoms) were therefore tested; encapsulation in sodium alginate gel, emulsification in Freund's incomplete adjuvant (FIA) or pulsed-release mimicked by weekly administrations. The administration of iscoms in a depot (alginate or FIA) or in pulses resulted in an antibody response of similar magnitude to that of a traditional two-dose scheme. The character of the immune response was on the other hand affected, i.e. the proportion of specific IgG2a and the IFN-gamma production was decreased by a protracted or repeated release of iscoms, either by a depot or by weekly administrations.

Alginates↗
PubMed1996

ISCOMs (immunostimulating complexes): the first decade.

A little over a decade ago, novel immunostimulating complexes (ISCOMs) were described. This review examines the position and progress that ISCOM technology has achieved in the fields of vaccine research and medicine over this period. Much of the work on ISCOMs has remained in the area of vaccine research where there is still an urgent need for improved adjuvants to help combat important diseases such as AIDS, malaria and influenza. Currently the only widely licensed adjuvants for human use are the aluminium salts, but with the trend towards highly purified subunit vaccines, which are inherently less immunogenic than some of the older vaccines, potent adjuvants capable of promoting specific immune responses are required. ISCOMs are one such technology that offers many of these requirements and as their use in vaccines enters its second decade clinical trials are commencing that will establish whether these submicron, non-living particles composed of saponin, cholesterol, phospholipid and in many cases protein, are useful components for a range of human vaccines.

Adjuvants, Immunologic↗
PubMed1998

Preservation of mucosal and systemic adjuvant properties of ISCOMS in the absence of functional interleukin-4 or interferon-gamma.

Adjuvants are a critical component of non-viable vaccine vectors, particularly for those to be used via mucosal routes. Although most adjuvants act by inducing local inflammatory responses, the molecular basis of many of these effects is unclear. Here we have investigated whether interleukin-4 (IL-4) and interferon-gamma (IFN-gamma) are required for the induction of local and systemic immune responses by oral and parenteral administration of ovalbumin (OVA) in immune stimulating complexes (ISCOMS), a potent mucosal adjuvant vector. Our results show that after oral or systemic immunization with OVA ISCOMS, IL-4 knockout (IL4KO) and IFN-gamma receptor knockout (IFN-gamma RKO) mice develop an entirely normal range of immune responses including delayed-type hypersensitivity (DTH), serum immunoglobulin G (IgG) antibodies, T-cell proliferation and cytokine production, class I major histocompatibility complex (MHC)-restricted cytotoxic T lymphocyte (CTL) activity and intestinal IgA antibodies. These responses were of a similar magnitude to those found in the wild-type mice, indicating that the immunogenicity of ISCOMS is not influenced by the presence of IL-4 or IFN-gamma and emphasizing the potential of ISCOMS as widely applicable mucosal adjuvants.

Adjuvants, Immunologic↗
PubMed1992

Comparison of protection afforded by whole virus ISCOM versus MDP adjuvanted formalin-inactivated SIV vaccines from IV cell-free or cell-associated homologous challenge.

A SIV-ISCOM and a SIV-MDP adjuvanted vaccine were tested for their potential to induce protection from intravenous cell-free or cell-associated homologous SIV challenge in rhesus monkeys (Macaca mulatta). Seven monkeys vaccinated four times over a four-month period with either the SIV-ISCOM or the SIV-MDP vaccine were challenged intravenously with approximately 10 MID50 cell-free SIVmac251 (32H). They all were protected from developing viremia during a three-month observation period. Two other groups of four monkeys were vaccinated essentially in the same way with either of these vaccines. They were challenged intravenously with approximately 10 MID50 of infected PBMC of a rhesus monkey that had been infected with SIVmac251 (32H) 11 months earlier (stock prepared by J. Heeney). Two monkeys of each of these two groups proved to be protected from developing viremia during a two-month observation period. For both the cell-free and the cell-associated SIV challenge, monkeys vaccinated with measles virus ISCOMS or MDP adjuvanted measles virus antigen, served as controls. They all became viremic within two weeks after SIV challenge. This is the first demonstration that vaccinated previously unchallenged nonhuman primates can be protected from infection with lentivirus-infected PBMC from another animal. Serological analysis indicated that SIV-specific serum antibody titers were considerably higher in SIV-ISCOM vaccinated animals than in the SIV-MDP vaccinated animals. The serology also confirmed the protection data, by showing the absence of increase in SIV-specific serum antibodies in apparently protected animals after challenge.

Acetylmuramyl-Alanyl-Isoglutamine↗
PubMed1995

Comparative antibody responses and protection in mice immunised by oral or parenteral routes with influenza virus subunit antigens in aqueous form or incorporated into ISCOMs.

The total and subclass antibody responses of mice and protection of these animals against live influenza A/Sichuan/2/87 virus challenge infection were determined after immunisation with homologous A/Sichuan/87 aqueous or ISCOM-formulated surface glycoprotein subunit antigens administered by either the oral or intramuscular routes. The results show that the greatest systemic and local antibody responses were elicited in mice immunised with A/Sichuan ISCOMs by the intramuscular route; protection against homologous virus challenge was also effective in these animals, particularly after two doses of the vaccine. However, relatively high immune responses and protection were also elicited by the A/Sichuan/87 ISCOM vaccine administered orally. Immunisation of mice by the intramuscular route resulted in levels of serum IgG2a subclass antibody significantly greater than those induced by the same preparation given by the oral route, or by the aqueous A/Sichuan/87 subunit antigen preparation administered by either route. The findings indicate that the ISCOM delivery system can be used for immunisation by the oral route, although in mice, under the conditions used, this strategy compares unfavourably with the intramuscular route in terms of both local and systemic immune responses and protection against homologous challenge virus infection.

Administration, Oral↗
PubMed1992

Interactions between immune-stimulating complexes (ISCOMs) and peritoneal mononuclear leucocytes.

Studies were undertaken in mice using immune-stimulating complexes (ISCOMs) or micelles prepared from envelope glycoproteins of human influenza virus (PR8) and matrix (i.e., ISCOM skeleton without incorporated antigen). Electron microscopic studies showed that ISCOMs, in contrast to micelles, have a remarkable affinity for cell membranes and seem to rapidly promote their own internalization by cells to which they adhere. PR8 ISCOMs, but not matrix nor micelles, significantly increased the expression of membrane Ia by peritoneal mononuclear leucocytes 24 hr after intraperitoneal immunization.

Animals↗
PubMed2000

Priming with Chlamydia trachomatis major outer membrane protein (MOMP) DNA followed by MOMP ISCOM boosting enhances protection and is associated with increased immunoglobulin A and Th1 cellular immune responses.

We previously reported that DNA vaccination was able to elicit cellular immune responses and partial protection against Chlamydia trachomatis infection. However, DNA immunization alone did not generate immune responses or protection as great as that induced by using live organisms. In this study, we evaluated the immunologic effects of a combinational vaccination approach using C. trachomatis mouse pneumonitis (MoPn) major outer membrane protein (MOMP) DNA priming followed by boosting with immune-stimulating complexes (ISCOM) of MOMP protein (MOMP ISCOM) for protection of BALB/c mice against MoPn lung infection. Substantially better protection to challenge infection was observed in mice given combinational vaccination compared with mice given MOMP ISCOM immunization alone, and the protection approximated that induced by live organisms. Enhanced protection was correlated with stronger delayed-type hypersensitivity, higher levels of gamma interferon production, and increased immunoglobulin A antibody responses in lung homogenates. The results indicate that DNA priming followed by ISCOM protein boosting may be useful in designing a fully protective chlamydial vaccine.

Animals↗
PubMed1995

Induction of systemic and mucosal immune responses following immunization with somatostatin-avidin complexes incorporated into ISCOMS.

Synthetic, biotinylated somatostatin-14 (Somatotropin Release-Inhibiting Factor; SRIF) was conjugated to avidin, and the resulting complex incorporated into immune-stimulating complexes (ISCOMS). The ISCOMS were used to study the systemic and mucosal immune responses induced by parenteral and gastrointestinal vaccination. Mice were immunized by intraperitoneal (IP) and intragastric (IG) routes and subsequently by either IP or IG secondary immunizations (groups-IP/IP; IP/IG; IG/IG). Antigen specific IgG and IgA antibody secreting cells (ASC) from the spleen, mesenteric lymph nodes (MLN) and Peyer's patches (PP's) were studied by an enzyme-linked immunospot assay (ELISPOT). Specific proliferative responses of spleen cells to avidin and to SRIF were measured. Immunization IP/IP evoked the highest serum IgG levels to avidin and to SRIF as well as the highest numbers of splenic IgG isotype ASC. The greatest IgA response in MLN and PP's was induced by IP/IG immunization. Only marginal mucosal immunity and no splenic cell specific proliferative responses were found by IG/IG immunization. These results indicate that ISCOMS are an effective delivery system for protein-peptide antigens. The ISCOMS system described elicited systemic and mucosal antibody immune responses, and primed specific proliferative response when administered IP/IG. This offers another approach for the design and delivery of mucosally administered peptide vaccines.

Administration, Oral↗