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PubMed2026

A versatile reversed-phase liquid chromatography charged aerosol detection method for streamlined monitoring of QS-21 content and stability in liposomal adjuvant formulations.

Identifying and quantifying an active adjuvant along with its degradants in drug formulations is essential for ensuring the safety and efficacy of the drug product. QS-21 is a potent adjuvant that is being evaluated in several clinical trials and is currently formulated in licensed vaccines that protect against shingles, malaria, and RSV. In aqueous environments, QS-21 is subject to hydrolytic degradation that is influenced by pH and temperature, resulting in the formation of a degradant known as QS-21 Hydrolyzed Product, QS-21 HP, which can occur during manufacturing and/or prolonged storage. The intact QS-21 and QS-21 HP induce distinct immune response profiles, making it critical to monitor the degradation of QS-21 in vaccine adjuvant formulations. To date, there has been a paucity of reliable assays for QS-21, its isomers, and degradant QS-21 HP in liposomal adjuvant formulations available that can be transferred seamlessly in quality control (QC) environments. Herein, we introduce a simple and QC-friendly liquid chromatography coupled to a charged aerosol detector (LC-CAD) enabled by stationary phase screening combined with in silico method development optimization. The method exploits 2.7 μm fused-core phenyl hexyl particles, ensuring its versatility in standard and ultra-high pressure LC systems. This approach demonstrates a high correlation between predicted retention time (RT) and experimental outcomes with overall ∆RT < 4%. In addition, this assay shows great linearity, precision, specificity, and accuracy to advance process development characterization of new vaccine formulations.

Liposomes↗

PubMed1994

Phase 1 trial of immunological adjuvant QS-21 with a GM2 ganglioside-keyhole limpet haemocyanin conjugate vaccine in patients with malignant melanoma.

Increasing doses of saponin fraction QS-21 were administered as immunological adjuvant in a Phase 1 trial with a constant dose of the melanoma ganglioside GM2 covalently attached to keyhole limpet haemocyanin (KLH). Twenty-eight patients with AJCC Stage III or IV melanoma who were free from disease after surgery were treated with six vaccinations administered subcutaneously over a 5-month period. Local and systemic reactions were QS-21 dose-related. Doses of < or = 100 micrograms induced mild local tenderness and inflammation at vaccination sites lasting 2-4 days and occasional brief low-grade fever and malaise, but no significant incapacitation. The 200 micrograms dose induced low-grade fever and malaise after 30% of vaccinations and local reactions as large as 20 cm in diameter were seen in all patients, resulting in discomfort with usage of the injected extremity for 5-10 days. The titres of IgM and IgG antibodies against GM2, and IgG antibodies against KLH, were highest at the 100 and 200 micrograms QS-21 doses. No antibodies against QS-21 were detected. This trial identifies the 100 micrograms dose of QS-21 as the optimal well tolerated dose for induction of antibodies against both the melanoma ganglioside/GM2 and the protein KLH in melanoma patients.

Adjuvants, Immunologic↗

PubMed1995

GM2-KLH conjugate vaccine: increased immunogenicity in melanoma patients after administration with immunological adjuvant QS-21.

The cell surface gangliosides GM2, GD2, and GD3 are often overexpressed in malignant melanoma. We have shown previously that immunization of melanoma patients with GM2 and Bacillus Calmette-Guérin induced an IgM antibody response in most patients and that patients with high titer GM2 antibodies showed increased survival. As is commonly seen with carbohydrate antigens (which are T independent), the IgM response was short lived, and an IgG response was rarely observed. To increase immunogenicity, we conjugated GM2 covalently with keyhole limpet hemocyanin (KLH). GM2-KLH vaccine was given to melanoma patients alone or with one of the three adjuvants: Bacillus Calmette-Guérin, DETOX, or QS-21. The most effective vaccine was GM2-KLH with QS-21. It induced a much higher titer, a longer-lasting IgM GM2 antibody response, and a consistent IgG response (isotype IgG1 and IgG3). It also induced the highest titer anti-KLH response. The results suggest that the conjugate GM2-KLH plus QS-21 vaccine elicited significant T-cell help. Because there was no serious toxicity, this vaccine approach is attractive for augmenting the immunogenicity of other gangliosides, such as GD2 and GD3, and to determine the effects of ganglioside antibodies on the course of melanoma. In addition, the finding that QS-21 significantly increased the immunogenicity of GM2-KLH suggests that it may do the same for other conjugate vaccines, many of which are currently used without adjuvant.

Adjuvants, Immunologic↗

PubMed1995

Adjuvant activity of QS-21 for experimental E. coli 018 polysaccharide vaccines.

Three types of experimental vaccines containing O-side-chain polysaccharide from the enterotoxigenic strain Escherichia coli 018 were evaluated. The immunogenicity of free O-polysaccharide (PS), a polysaccharide-diphtheria toxoid conjugate (PS-conj), and detoxified lipopolysaccharide (dLPS) was tested in female ICR mice, either alone or in combination with QS-21, a purified saponin adjuvant derived from the bark of the tree Quillaja saponaria Molina. Both the number of individual mice responding and the titres of O-polysaccharide specific antibodies in pools of sera were increased by the addition of QS-21. The immune response to both O-specific polysaccharide and carrier was primarily IgM and IgG1. The addition of QS-21 not only increased the level of IgG1, but also had a significant adjuvant effect on antigen-specific IgG2a, IgG2b and IgG3.

Adjuvants, Immunologic↗

PubMed1995

Formulation of the purified fusion protein of respiratory syncytial virus with the saponin QS-21 induces protective immune responses in Balb/c mice that are similar to those generated by experimental infection.

The feasibility of employing a vaccine composed of the purified fraction 21 of Quillaja saponaria (QS-21) and the fusion (F) protein of respiratory syncytial virus (RSV) to induce protective immune responses in the lower respiratory tract of Balb/c mice was examined. Our goal was to compare local and systemic immune responses with those induced following immunization with the protein adsorbed to aluminium hydroxide (F/ALOH) adjuvant or by experimental infection. Sera from mice vaccinated with the QS-21 formulation (F/QS-21) contained elevated anti-F protein IgG antibody titres that were dependent on the dose of QS-21 employed. Similar to the immune responses generated by experimental infection, the sera from mice vaccinated with F/QS-21 possessed greater capacity to neutralize virus infectivity that was associated with the generation of heightened complement-fixing IgG2a antibody titres. In contrast, vaccination with F/ALOH elicited systemic immune responses that were characterized by a predominance of protein-specific antibodies of the IgG1 subclass and lower neutralizing antibody titres. The capacity of F/QS-21 to facilitate local pulmonary immune responses was also examined and found to be similar to those induced by experimental infection. After virus challenge, a 90-fold increase in the number of F protein-specific antibody-secreting cells was observed and associated with the clearance of virus from the infected lungs. Moreover, elevated levels of antigen-dependent killer cell activity were detected and appeared to be mediated by class I major histocompatibility complex restricted CD8+ T cells. Additional characterization of the pulmonary immune response was performed on the cellular infiltrates obtained after bronchoalveolar lavage and on formalin-fixed lung tissue. The local protective immune responses induced after challenge of the groups immunized with F/QS-21 or infectious virus were significantly different from those elicited in naive control mice injected with adjuvant alone, or in mice immunized with F/ALOH. The cellularity of the lavage fluids from the former groups was characterized by a significantly greater percentage of lymphocytes and less neutrophils. In similar fashion histological evaluation of the lungs from mice immunized with F/QS-21 or infectious virus revealed significantly elevated local immune responses after challenge. In conclusion, the results suggest that formulation with F/QS-21 alters the qualitative and quantitative nature of the immune response to the F glycoprotein when compared with the traditional aluminium-based adjuvants.

Adjuvants, Immunologic↗

PubMed1995

Structural and immunological characterization of the vaccine adjuvant QS-21.

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Adjuvants, Immunologic↗

PubMed1992

Saponin adjuvant enhancement of antigen-specific immune responses to an experimental HIV-1 vaccine.

The adjuvant activity of a single highly purified saponin from the soap bark tree Quillaja saponaria was evaluated by using it as a component in an experimental vaccine containing rHIV-1 envelope protein (HIV-1 160D) adsorbed to alum. BALB/c mice immunized with experimental vaccine formulations containing the saponin adjuvant QS-21 produced significantly higher titers of antibodies than mice vaccinated with only the alum-adsorbed HIV-1 160D. Potent amnestic antibody responses to HIV-1 viral proteins were also induced. Ag-specific proliferative responses to recombinant proteins and to three variants of HIV-1 were significantly increased using QS-21 as an adjuvant. Alum-adsorbed HIV-1 160D failed to induce measurable proliferative responses to inactivated HIV-1 viruses, but group-specific proliferative responses were raised when the QS-21 adjuvant was used in the vaccine formulation. MHC class I restricted CTL specific for the immunodominant V-3 loop were induced but only when the QS-21 adjuvant was included in the vaccine formulation. The production of serine esterase by Ag-activated splenic mononuclear cells, indicating the maturation of precursor CTL, was used as a secondary measure of CTL activity, and this response was also increased. The specificity of antibody responses was not significantly broadened using QS-21; the adjuvant increased the immune recognition of epitopes throughout the HIV-1 glycoprotein 160. However, the specificity of the proliferation and serine esterase responses was broadened, suggesting that the QS-21 augmented cell-mediated immune responses specific for epitopes outside of the V-3 loop. Additionally, the QS-21 adjuvant appeared to induce recognition of weakly immunogenic epitopes that were not recognized using only alum-adsorbed HIV-1 160D. The ability of QS-21 to augment both antibody and cell-mediated immune responses suggests that this adjuvant could be a valuable component in subunit vaccines.

AIDS Vaccines↗

PubMed1995

Effect of adjuvants on immunogenicity of MN recombinant glycoprotein 120 in guinea pigs.

The immunogenicity of recombinant gp120 from the MN strain of HIV-1, a candidate HIV-1 vaccine, was evaluated in guinea pigs using adjuvant formulations with different physical and chemical properties. The adjuvants tested included Freund's adjuvant (FA), alum, and the novel adjuvant QS-21. These studies demonstrated that QS-21 provides a number of advantages compared to the two other adjuvants tested. QS-21 formulations accelerated the production of antibodies to MN rgp120 and elicited complete seroconversion after a single immunization. QS-21 shifted the antigen dose-response curve for antibody production by as much as three orders of magnitude, enabling a more economical use of antigen. Antibody titers to MN rgp120 and to the principal neutralizing determinant in the V3 domain were higher in animals receiving QS-21 formulations than in animals immunized with the other adjuvants, and correlated well with higher virus neutralization titers in an in vitro assay. These results support the testing of QS-21 in future clinical trials of candidate HIV-1 vaccines.

AIDS Vaccines↗

PubMed1992

Immunogenicity and toxicity testing of an experimental HIV-1 vaccine in nonhuman primates.

A highly purified saponin from Q. saponaria (QS-21) was tested in juvenile rhesus macaques for adjuvant activity and toxicity. The QS-21 was tested alone or as part of an experimental subunit HIV-1 vaccine containing a truncated recombinant HIV-1 envelope protein (gp160D) adsorbed to alum. Antibody responses were measured using ELISA and cell-mediated immunity was measured using cellular proliferation assays. Potential toxicity was monitored by standard clinical pathology testing using peripheral blood and urine samples. No toxic effects were observed, even after the administration of the experimental vaccines three times at monthly intervals. The QS-21 saponin adjuvant enhanced total antibody production levels by greater than 100-fold and broadened the specificity of the response so that additional epitopes were recognized, when compared with alum-adsorbed HIV-1 gp160D formulation. Low-level, antigen-specific proliferative responses to HIV-1 recombinant gp160 were induced by either vaccine formulation. Proliferative responses were induced by a sham challenge with soluble recombinant HIV-1 gp160 for all of the animals that had been vaccinated. However, those that received the HIV-complete vaccine formulation containing QS-21 responded significantly better. These data demonstrated that the QS-21 adjuvant augmented both antibody responses and cell-mediated immunity and established immunological memory. The potent adjuvant activity and lack of toxicity suggest that this adjuvant should be safe and effective for use in HIV-1 vaccines.

AIDS Vaccines↗

PubMed1995

Approaches to augmenting the immunogenicity of melanoma gangliosides: from whole melanoma cells to ganglioside-KLH conjugate vaccines.

Gangliosides are neuraminic acid containing glycosphingolipids that are anchored into the lipid bilayer of the plasma membrane by their lipophilic ceramide moiety. They are overexpressed on tissues of neuroectodermal origin, particularly in tumors such as melanomas, sarcomas, neuroblastomas and astrocytomas. With the ganglioside-KLH plus immunological adjuvant QS-21 conjugate vaccine, GM2 and GD2 have been shown to be consistently immunogenic, inducing cytotoxic IgM antibodies in most patients. The immunogenicity of other gangliosides also expressed on melanoma cells such as 9-0-acetyl GD3 and GD3 lactone is currently being tested with this conjugate vaccine approach. From the initiation of our adjuvant vaccine trials in 1975 to the present, the immunogenicity of ganglioside vaccines has increased significantly as vaccine development has progressed. For instance, GM2 antibody responses increased from low titer IgM antibodies induced in occasional patients after whole cell vaccines, to moderate titer IgM antibodies in 86% of patients after GM2/BCG vaccines, to higher titer IgM antibodies in 100% of patients treated with the GM2-KLH plus QS-21 vaccine. These antibodies are capable of mediating complement mediated cytotoxicity of GM2 expressing melanoma cells in the majority of patients and such antibodies, whether naturally produced or vaccine induced, have been associated with a significantly improved disease-free and overall survival. An initial double-blind randomized trial in AJCC Stage III melanoma patients comparing GM2/BCG with BCG alone, demonstrated a 14% improvement in disease-free interval at 4 years and an 11% improvement in overall survival, though neither result achieved statistical significance. Based on these encouraging clinical results and the clearly improved immunogenicity of the GM2-KLH plus QS-21 vaccine compared to the previous GM2/BCG vaccine, the following two large clinical trials are anticipated to begin in 1995-1996. The GM2-KLH plus QS-21 vaccine will be tested in the intergroup setting by ECOG in 450 patients with AJCC Stage II or III melanoma who are free of disease after surgery. Also to be tested in a multicenter trial is a GM2-KLH plus GD2-KLH plus QS-21 vaccine in patients with high risk AJCC Stage II-IV sarcoma after surgical excision of all known disease.

Adjuvants, Immunologic↗

PubMed1992

Saponin adjuvant induction of ovalbumin-specific CD8+ cytotoxic T lymphocyte responses.

The ability of a saponin adjuvant, QS-21, to induce OVA-specific, class I MHC Ag-restricted CTL was investigated using different forms of soluble OVA and OVA adsorbed onto alum as immunogens. C57BL/6 mice were immunized with soluble native or denatured OVA in formulations that contained increasing quantities of QS-21, and CTL responses were measured using EL4 and E.G7-OVA cells as targets and splenic mononuclear cells as effectors. Ag-specific CTL responses were produced but only if the QS-21 adjuvant was used. Similar responses were induced using alum-adsorbed OVA when mixed with the QS-21 adjuvant but not when used alone. The CTL were specific for an epitope present on the OVA258-276 synthetic peptide, which contains the dominant CTL epitope recognized by C57BL/6 mice. The CD8+ subpopulation of lymphocytes in immune mice was not increased in spleens but increased significantly in vitro after culture with soluble OVA. The CTL activity of splenic mononuclear cell preparations was totally destroyed by treatment with mAb specific to the CD8 Ag plus complement. The ability of the QS-21 adjuvant to induce class I MHC Ag-restricted CTL after immunization with soluble proteins is a characteristic unique to saponin adjuvants.

Adjuvants, Immunologic↗

PubMed1991

A purified saponin acts as an adjuvant for a T-independent antigen.

Three strains of mice were injected with a T-independent antigen, Escherichia coli 055:B5 polysaccharide (PS) combined with purified saponin, QS-21, isolated from Quillaja saponaria bank. PS was prepared by hydrolysis of lipopolysaccharide (LPS). Nine week old mice were injected intradermally with 60 micrograms PS, as determined by an anthrone assay, with or without 15 micrograms QS-21 on days 0 and 14. On day 22 sera were assayed by EIA for PS specific antibodies. Titers were 11-fold higher in CD-1 mice with QS-21. C3H/HeJ (Ipsd) and C3H/HeSnJ (Ipsr) mice also showed an adjuvant associated increase in titer with saponin. Therefore, LPS responsiveness was not required for the adjuvant effect. PS vaccinated C3H and CD-1 mice with and without QS-21 had similar antibody isotype profiles. IgG2b titers accounted for more than half of the total Ig response. IgG2a was next highest followed by IgG3, IgM, IgG1, and IgA. In comparison, CD-1 mice injected with 0.1 microgram intact LPS had a different LPS specific isotype profile. IgG3 was the highest followed by IgG1, IgG2b, IgM, IgG2a, and IgA.

Adjuvants, Immunologic↗

PubMed1995

Influence of interleukin 12 on p53 peptide vaccination against established Meth A sarcoma.

BALB/c murine sarcoma Meth A is known to have three missense point mutations in p53. We previously reported that a nonamer peptide containing the codon 234 mutational product (designated 234CM) elicited 234CM-specific cytotoxic T cells and that immunization with 234CM in adjuvant before tumor challenge inhibited Meth A growth. Because interleukin 12 (IL-12) has been shown to have antitumor activity against established tumors and immuno-modulatory activities, we analyzed its effect on p53 peptide immunization and Meth A growth. Multiple injections of IL-12 alone (4 times a week for 2 weeks) caused regression of established Meth A sarcoma, and this effect was dose dependent. IL-12 treatment prior to Meth A challenge had little or no antitumor activity. To evaluate the effect of IL-12 on the generation of 234CM-specific cytotoxic T lymphocytes, spleen cells from BALB/c mice immunized with 234CM in adjuvant and injected with various doses of IL-12 were sensitized with 234CM in vitro. Multiple injections of 1 ng of IL-12 induced the highest cytotoxicity against target cells pulsed with 234CM. Higher doses of IL-12 suppressed 234CM-specific cytotoxic T-cell generation. Mice immunized with 234CM in QS-21 adjuvant and treated with 1 ng of IL-12 rejected established Meth A sarcoma. Mice comparably treated with 1 ng of IL-12 but immunized with 234CW peptide (the wild-type counterpart to 234CM) in QS-21 or with QS-21 alone showed progressive tumor growth.

Amino Acid Sequence↗

PubMed1991

Separation and characterization of saponins with adjuvant activity from Quillaja saponaria Molina cortex.

Saponins were purified from Quillaja saponaria Molina bark by silica and reverse phase chromatography. The resulting purified saponins were tested for adjuvant activity in mice. Several distinct saponins, designated QS-7, QS-17, QS-18, and QS-21, were demonstrated to boost antibody levels by 100-fold or more when used in mouse immunizations with the Ag BSA and beef liver cytochrome b5. These purified saponins increased titers in all major IgG subclasses. To determine optimal dose in mice for adjuvant response, QS-7 and QS-21 were tested in a dose-response study in intradermal immunization with BSA in mice; for both of these purified saponins, adjuvant response (determined by stimulation of ELISA titers to BSA) neared maximum at doses of 5 micrograms and was shown to plateau up to the highest dose tested, 80 micrograms. These purified saponins vary considerably in their toxicity, as assessed by lethality in mice; the main component, QS-18, being the most toxic. Saponins QS-7 and QS-21 showed no or very low toxicity in mice, respectively. None of these saponins stimulated production of reaginic antibodies. The monosaccharide composition of these saponins showed similar but distinct compositions with all four containing fucose, xylose, galactose and glucuronic acid. Predominant differences were observed in the quantities of rhamnose, arabinose, and glucose. Monomer m.w. (determined by size exclusion HPLC) were determined to range from 1800 to 2200.

Adjuvants, Immunologic↗

PubMed1995

Immunogenicity of synthetic TF-KLH (keyhole limpet hemocyanin) and sTn-KLH conjugates in colorectal carcinoma patients.

Mucins of colorectal carcinomas overexpress the cancer-associated disaccharides Thomsen-Friedenreich antigen (TF) and sialyl-Tn antigen (sTn), making these antigens suitable for active specific immunotherapy. Patients at high risk for recurrent colon cancer, but free from disease after surgical resection, were immunized with synthetic TF and sTn covalently attached by a two-carbon crotyl linker to keyhole limpet hemocyanin (KLH). Four groups of patients were treated with TF-KLH without adjuvant, TF-KLH plus the immunological adjuvant Detox, sTn-KLH plus Detox, or sTn-KLH plus the immunological adjuvant QS-21, and the serological response was monitored. Enzyme-linked immunosorbent assay (ELISA), dot-blot immunostains, and inhibition assays were used to identify antibody responses against synthetic TF and sTn epitopes and against natural antigens, including asialoglycophorin expressing TF antigen, and ovine submaxillary mucin and the human colon cancer line LS-C expressing sTn antigen. Our results demonstrate that vaccines containing TF or sTn-KLH conjugates plus immunological adjuvants Detox and especially QS-21 induced high IgM and IgG antibody titers against the respective synthetic disaccharide epitopes. However, when tested against natural antigens expressing these disaccharide epitopes, IgM antibodies showed weak to moderate reactivity, while IgG antibodies were almost totally unreactive. On the basis of these results we are continuing to test modifications of synthetic TF and sTn epitopes to identify those that induce IgM and IgG antibodies that are more reactive with these antigens as they are expressed on tumor mucins.

Antibodies, Neoplasm↗

PubMed1995

Formulation of an immunogenic human cytomegalovirus vaccine: responses in mice.

The immunogenicity of a vaccine formulation consisting of recombinant-derived human cytomegalovirus (HCMV) glycoprotein B (UL55) combined with a chemically defined adjuvant derived from saponin, QS-21, was evaluated in mice. The immune responses of mice given the gB/QS-21 formulation were compared with those induced by gB combined with either Freund's adjuvant or aluminum hydroxide. The gB/QS-21 combination induced higher levels of virus-binding antibodies and significantly higher levels of virus-neutralizing antibodies than gB combined with either Freund's adjuvant or aluminum hydroxide. Animals given gB/QS-21 exhibited IgG subclass switching and produced significant titers of virus-specific IgG2a antibodies. Furthermore, animals given gB/QS-21 produced antigen-specific cytotoxic spleen cells. Because of its immunogenicity, a subunit vaccine containing HCMV gB and QS-21 offers a potential approach to the immunoprophylaxis of HCMV disease.

Adjuvants, Immunologic↗

PubMed1991

Development of a genetically engineered vaccine against feline leukemia virus infection.

A genetically engineered subunit vaccine against FeLV infection was developed. The protective immunogen in the vaccine was a purified recombinant protein containing the entire amino acid sequence of FeLV subgroup A gp70 envelope protein. The optimal adjuvant was determined to be a highly purified saponin, QS-21, derived from Quillaja saponaria Molina. A vaccine formulation containing the recombinant protein, QS-21, and aluminum hydroxide was tested in specific-pathogen-free kittens and was shown to induce neutralizing antibodies as well as appreciable antibody responses to native gp70 by enzyme immunoassay and protein (western) immunoblot analysis and of whole virus preparations.

Adjuvants, Immunologic↗

PubMed1995

Serological response patterns of melanoma patients immunized with a GM2 ganglioside conjugate vaccine.

Gangliosides, such as GM2, GD2, GD3, and 9-O-acetyl GD3, are receiving attention as targets for antibody-based and vaccine-based therapies of melanoma. GM2 appears to be a particularly immunogenic ganglioside in humans, as indicated by the presence of naturally occurring IgM anti-GM2 antibodies in approximately 5% of humans and the fact that immunization with irradiated GM2-expressing melanoma cells or purified GM2 adherent to bacillus Calmette-Guérin elicits GM2 antibodies of low to moderate titers in a high proportion of vaccinated patients. To develop vaccines that consistently induce high titers of IgM as well as IgG anti-GM2 antibodies, vaccines containing GM2 conjugated to keyhole limpet hemocyanin as the carrier protein and QS-21 as the adjuvant have been constructed. The serological response of vaccinated patients was monitored by ELISA using purified GM2 ganglioside for IgM and IgG anti-GM2 antibodies and for GM2 cell surface-reactive antibodies by immune adherence assays and cytotoxic tests (IgM antibodies) and mixed hemadsorption assays (IgG antibodies). The majority of vaccinated patients developed IgM and IgG antibodies detectable by ELISA. In most cases, the results of IgM ELISA correlated with assays for cell surface-reactive IgM antibodies. This was not true for IgG anti-GM2 antibodies, where strong discrepancies were seen between high titers in ELISA and little or no reactivity in mixed hemadsorption tests for cell surface-reactive antibodies. These IgG antibodies (and the less frequent IgM antibodies that show similar discrepancies) may be directed against GM2 determinants that are buried, hidden, or not present on GM2-expressing target cells. With regard to a major objective of ganglioside vaccines--i.e., generation of cytotoxic antibodies--the GM2-keyhole limpet hemocyanin/QS-21 vaccine is clearly superior to the previously tested GM2/bacillus Calmette-Guérin vaccine. However, variability in patient response and lack of persistence of high-titered IgM cytotoxic antibodies in many patients are problems that remain to be solved.

Adjuvants, Immunologic↗