lipid-a and Rhinitis--Allergic--Seasonal

Pollinex Quattro is a novel, ultra short-course vaccine for treatment of seasonal allergic rhinitis from grass, tree or ragweed pollen allergy. Its unique formulation combines chemically modified allergens adsorbed onto a L-tyrosine depot to enhance tolerability with the novel adjuvant, monophosphoryl lipid A, to improve efficacy. Controlled clinical studies indicate that four preseasonal injections with grass or tree formulations significantly reduce rhinoconjunctivitis symptoms and medication use, as well as elevate allergen-specific immunoglobulin G and blunt elevation of immunoglobulin E upon allergen exposure. Postmarketing surveillance studies indicate similar clinical outcomes. In all cases, the allergy vaccine was well tolerated with minimal local reactions, while systemic reactions were rare and mild. Results from recent investigational trials with grass and ragweed formulations are consistent with previous efficacy and safety outcomes, and will be used toward product registration in North America.

Topics: Adjuvants, Immunologic; Adolescent; Adult; Chemistry, Pharmaceutical; Child; Desensitization, Immunologic; Humans; Immunization Schedule; Lipid A; Product Surveillance, Postmarketing; Randomized Controlled Trials as Topic; Rhinitis, Allergic, Seasonal; Tyrosine; Vaccines

Allergy vaccination (AV) consists of injecting increasing amounts of offending allergens into sensitive patients with the intention of reducing their level of sensitivity to allergens. This form of therapy was first used over one hundred years ago and until recently had not changed in principle. The vaccines themselves are now far better characterised and standardised, according to new regulatory requirements. The therapy is believed to exert its effects by a combination of means: by the induction of blocking antibodies; a switch from a T helper (Th)2 to a more Th1 allergen-specific immune response; and induction of anergy, probably via the development of allergen-specific regulatory T cells. New allergen forms and formulations are being designed with these targets in mind. Allergoids (allergens chemically modified to reduce allergenicity, but to retain immunogenicity) are becoming employed more frequently. More modern depot forms, such as those containing tyrosine or calcium phosphate, are replacing aqueous extracts and older depot adjuvants such as alum. T cell-reactive peptides and recombinant allergens or their muteins are also being studied as replacements for whole extracts and have shown some potential. Immunomodulators, such as monophosphoryl lipid A (MPL), designed with defined targets in mind are now included in some vaccines and help to accelerate the process. All these measures have led to a reduction in the need for the traditional long injection schedules. The authors are very familiar in particular with the background to the use of MPL as an adjuvant. They have been personally involved in the development of this approach, which has led to a product being available for use on a regular basis in some European countries. Hence, this work is reported in considerable detail. Other similar immunomodulators, such as CpG motifs, are in development, while new targets, such as the Notch protein/receptor interaction, are exciting new developments that may eventually bear fruit. The excellent safety profile of the sublingual route of administration of allergy vaccines could lead to the wider use of AV, and locally active immunomodulators could make AV a therapy of choice for many more patients than at present.

Topics: Adjuvants, Immunologic; Allergens; Chemistry, Pharmaceutical; Clinical Trials as Topic; CpG Islands; Delayed-Action Preparations; Desensitization, Immunologic; Humans; Hypersensitivity; Immunologic Factors; Lipid A; Membrane Proteins; Receptors, Notch; Rhinitis, Allergic, Seasonal; Th1 Cells; Th2 Cells

Specific immunotherapy acts to modify the underlying cause of allergic rhinoconjunctivitis. Addition of adjuvants, such as monophosphoryl lipid A (MPL), might allow for efficacious and safe treatment with only 4 injections administered preseasonally, which is in contrast to most available schedules requiring long injection courses.. The primary objective was to assess the clinical efficacy of Ragweed MATA MPL (short ragweed pollen allergoid adsorbed to L-Tyrosine + MPL) versus placebo in reducing allergic rhinoconjunctivitis symptoms caused by ragweed pollen in an environmental exposure chamber (EEC) 3 weeks after treatment.. This was a randomized, double-blind, placebo-controlled phase IIb study to evaluate the clinical efficacy and safety of Ragweed MATA MPL compared with placebo by using controlled ragweed pollen exposure in an EEC. Two hundred twenty-eight patients with a history of ragweed allergy and positive skin prick test responses to ragweed were randomized and received 4 weekly injections of active treatment or placebo. Total nasal and nonnasal symptom scores were obtained in the EEC before and after treatment.. Mean improvement in total symptom scores in the Ragweed MATA MPL group was statistically significantly greater than in the placebo group (relative mean improvement of active vs placebo, 48%; P < .05; median improvement, 82%). The majority of adverse events (AEs) experienced by subjects were mild injection-site reactions. No severe systemic AEs or serious AEs occurred during the study.. This study demonstrated that an ultrashort course of Ragweed MATA MPL is efficacious in reducing allergy symptoms in patients with seasonal allergic rhinitis and that it is well tolerated.

Topics: Adolescent; Adult; Aged; Allergens; Ambrosia; Antigens, Plant; Clinical Protocols; Conjunctivitis, Allergic; Desensitization, Immunologic; Environmental Exposure; Female; Humans; Hypersensitivity, Immediate; Lipid A; Male; Middle Aged; Plant Extracts; Rhinitis, Allergic, Seasonal; Treatment Outcome; Young Adult

Sublingual immunotherapy (SLIT) allergy vaccines have an excellent safety profile, but opinions vary on their efficacy, and treatment regimens are often lengthy. This study assessed the effects of the Toll-like receptor 4 agonist monophosphoryl lipid A (MPL®) on safety/tolerability and clinical and immunological efficacy when combined with grass pollen SLIT formulations in treating patients with seasonal allergic rhinitis. This is the first reported study of adjuvanted SLIT.. In this double-blind placebo-controlled phase I/IIa study, 80 grass pollen-sensitive subjects were randomized into 4 groups of 20 subjects to receive daily treatment for 8 weeks. Sixteen patients per group received SLIT and 4 received placebo. The formulation given to each group varied with respect to grass pollen extract and MPL content. Grass allergen nasal challenge tests (NCTs) were performed prior to dosing and in weeks 4 and 10. Grass pollen-specific immunoglobulin G (IgG) and IgE antibodies were measured at baseline and prior to dosing in weeks 2, 3, 4, 5 and 10.. Local and systemic adverse events were generally comparable for patients who received active treatment and placebo. Patients in the 2 groups given SLIT containing the highest amount of MPL experienced the highest proportion of negative NCTs after 10 weeks (47 and 44%, vs. 20% with placebo). These patients also showed earlier median increases in specific IgG and smaller increases in IgE levels than those receiving other formulations.. These results suggest that SLIT preparations containing MPL are well tolerated and alter the immunological response to grass antigens after 3 weeks of exposure, with an associated suppression of nasal challenge responses.

Topics: Adjuvants, Immunologic; Administration, Sublingual; Allergens; Antigens, Plant; Desensitization, Immunologic; Humans; Lipid A; Middle Aged; Nasal Provocation Tests; Poaceae; Pollen; Rhinitis, Allergic, Seasonal

Specific immunotherapy (SIT) is a well-established and clinically effective treatment for allergic diseases. A pollen allergoid formulated with the T helper type 1 (Th1)-inducing adjuvant monophosphoryl lipid A (MPL) facilitates short-term SIT. Little is known about mechanisms of tolerance induction in this setting. In a prospective study, 34 patients allergic to grass pollen (25 male, nine female, median age 10.2 years) received a total of 44 SIT courses (20 in the first, 24 in the second) with MPL-adjuvanted pollen allergoids. Immunogenicity was measured by levels of specific immunoglobulin G (IgG(grass)) and IgG4(grass) by antibody blocking properties on basophil activation, and by induction of CD4(+), CD25(+) and forkhead box P3 (FoxP3(+)) regulatory T cells (T(reg)). Specific IgG and IgG4 levels increased only slightly in the first year of SIT. In the second year these changes reached significance (P < 0.0001). In keeping with these findings, we were able to show an increase of T(reg) cells and a decreased release of leukotrienes after the second year of treatment. In the first year of treatment we found little evidence for immunological changes. A significant antibody induction was seen only after the second course of SIT. Short-course immunotherapy with pollen allergoids formulated with the Th1-inducing adjuvant MPL needs at least two courses to establish tolerance.

Topics: Adjuvants, Immunologic; Adolescent; Allergoids; Antibody Formation; Child; Female; Humans; Immune Tolerance; Immunoglobulin G; Immunotherapy; Lipid A; Male; Plant Extracts; Pollen; Prospective Studies; Rhinitis, Allergic, Seasonal; T-Lymphocytes, Regulatory; Th1 Cells; Time Factors

CRX-675 is an aqueous formulation of a toll-like receptor 4 agonist and an inducer of TH1 responses. Studies in allergic dogs showed that pretreatment with CRX-675 reduced nasal congestion induced by allergen challenge.. To study the safety of intranasal CRX-675 treatment in patients with seasonal allergic rhinitis.. We conducted a single-center, randomized, double-blind, placebo-controlled, dose-escalating safety trial of single doses of CRX-675 given intranasally before intranasal ragweed challenges. Patients with ragweed-induced seasonal allergic rhinitis received increasing concentrations of ragweed to determine the dose that would result in a 30% reduction in nasal volume (PD30) during screening. Two weeks later, each patient was rechallenged with their assigned PD30 ragweed dose. Fourteen days later, patients were treated with either placebo (n = 16) or CRX-675 (2, 20, 100, or 200 microg intranasally, n = 12 per arm) 24 hours before a subsequent PD30 ragweed challenge. Patients were rechallenged with ragweed 14 days thereafter.. No serious or severe adverse events were reported. Most adverse events were mild (grade 1) and either were considered unrelated to CRX-675 or resolved without intervention. The adverse event profile of CRX-675-treated patients was similar to that of placebo-treated patients, and no dose-related toxic effects were observed. There was no clear trend in the ability of CRX-675 to inhibit nasal allergen challenge responses, but improvement in nasal symptom scores was observed at 100 microg.. This preliminary trial suggests that intranasally applied CRX-675 is safe at the doses tested. Appropriate dosing and timing will ultimately define its potential therapeutic role for allergies.

Topics: Administration, Intranasal; Dose-Response Relationship, Drug; Drug-Related Side Effects and Adverse Reactions; Humans; Immunotherapy, Active; Lipid A; Rhinitis, Allergic, Seasonal; Toll-Like Receptor 4

The effects of immunotherapy (IT) on the activation and functions of B cells are not well described yet. We therefore measured the expression of several surface markers on peripheral B cells during short-term IT. Twelve patients with seasonal allergic rhinoconjunctivitis, sensitized to hazel, alder, and birch pollen proven by positive history, skin test, sIgE, and nasal provocation test, were included in the study. Eight patients received short-term IT with TA tree pollen and the immunoadjuvant monophosphoryl Lipid A; 4 patients received a placebo suspension containing 2% tyrosine. After separation of PBMCs, the expression of surface molecules on peripheral B cells were analyzed by flow cytometry before the start of IT, before the 3rd injection, at the end of IT, and after the pollen season. The expression of CD23, CD54, and HLA-DR-II on CD19+ B cells decreased during IT and then increased again after the pollen season. In the placebo group, the expression of CD23, CD54, and HLA-DR-II remained unchanged during the first three measurements. After the season, the expression of CD23, CD54 and HLA-DR-II increased in both groups. CD86 expression was decreased during treatment in both groups. Although CD86 expression increased in both groups after the season, the increase was more pronounced in the placebo group. No changes in the expression of CD32, CD40, and HLA-ABC-I were registered during the study. The results show that expression of CD23, CD54, and HLA-DR-II on peripheral B cells decreases during IT, which indicates reduced B-cell activation. Whether these effects are a result of direct allergen action on the B cells or whether they are mediated by T cells and their clinical relevance remains to be elucidated.

Topics: Adjuvants, Immunologic; Adult; Allergens; Allergoids; Antigens, Differentiation, B-Lymphocyte; B-Lymphocytes; Desensitization, Immunologic; Double-Blind Method; Down-Regulation; Female; Flow Cytometry; Follow-Up Studies; Humans; Immunotherapy; Lipid A; Lymphocyte Activation; Male; Middle Aged; Patch Tests; Plant Extracts; Probability; Receptors, IgE; Rhinitis, Allergic, Seasonal; Statistics, Nonparametric; Time Factors; Treatment Outcome

Topics: Allergens; Animals; Antigens, Plant; Cells, Cultured; Cryptomeria; Disease Models, Animal; Glucosides; Humans; Immunotherapy; Japan; Leukocytes, Mononuclear; Lipid A; Mice; Mice, Inbred BALB C; Plant Proteins; Pollen; Rhinitis, Allergic, Seasonal; Toll-Like Receptor 4; Treatment Outcome

PQ Birch represents an allergen-specific immunotherapy for the treatment of birch pollinosis. It consists of native birch pollen extract chemically modified with glutaldehyde adsorbed to L-tyrosine in its microcrystalline form with addition of the adjuvant Monophosphoryl Lipid A (MPL®). A nonclinical safety testing strategy was designed based upon interpretation of current legislation and regulatory intelligence and comprised genotoxicity studies (bacterial reverse mutation and Chinese hamster ovary micronucleus assays), a rat repeat dose toxicology study and a rabbit local tolerance study. No safety findings of concern were found. Thus, no evidence of genotoxicity was found. Relatively minor, immunostimulatory effects were seen following repeated subcutaneous dosing (once every 2 weeks for 13 weeks) as reversible increased white cell count (notably neutrophils), increased globulin level (resulting in decreased albumin/globulin [A/G] ratio) and increased fibrinogen, as well as minor dose site reaction in the form of inflammatory cell infiltrate. These findings are likely due to the immunostimulatory nature of MPL® and/or the presence of L-tyrosine within the adjuvanted vaccine. Similar dose site inflammatory changes to the injected formulation were also noted in the rabbit local tolerance study.

Topics: Adjuvants, Immunologic; Animals; Betula; CHO Cells; Cricetulus; Female; Immunotherapy; Lipid A; Male; Mutagenicity Tests; Pollen; Rabbits; Rats, Wistar; Rhinitis, Allergic, Seasonal; Salmonella typhimurium; Skin; Tyrosine

Topics: Adjuvants, Immunologic; Adolescent; Adult; Aged; Asthma; Child; Child, Preschool; Female; Humans; Hypersensitivity; Italy; Lipid A; Male; Middle Aged; Prevalence; Prospective Studies; Rhinitis, Allergic, Seasonal; Risk Factors; Treatment Outcome; Young Adult

Ultra-short course pollen immunotherapy adjuvanted with monophosphoryl lipid A (MPL) is attractive to conventional allergen-specific immunotherapy (AIT). Long term efficacy of MPL-AIT has not been evaluated.. 68 patients (age 16.75 ± 5.3 years) with allergic rhinitis to grass pollen were investigated. Group 1: 21 controls; Group 2: 19 after complete AIT, and Group 3: 28 with AIT and treatment cessation: 4 years range 3-6 years ago.. The clinical symptoms (running nose, sneezing, conjunctivitis and the weekly overall score) were significantly reduced in patients group 2 and 3 compared with controls without AIT p < 0.0001. T-regulatory cells and TH1/TH2 cytokine pattern did not differ between patient groups.. The patients in our trial with grass pollen allergy exhibited significant and long-lasting improvements after MPL-AIT, however larger trials are needed to support this finding.

Topics: Adjuvants, Immunologic; Adolescent; Adult; Allergens; Antigens, Plant; Child; Conjunctivitis, Allergic; Desensitization, Immunologic; Female; Humans; Lipid A; Male; Poaceae; Pollen; Rhinitis, Allergic, Seasonal; Treatment Outcome; Young Adult

The clinical efficacy and safety of allergoid immunotherapy have been demonstrated in clinical trials. However, simultaneous monitoring of the immunological changes by allergoids versus allergens in the cells of the same individual has not been extensively performed, and the impact of concurrent Toll-like receptor 4 (TLR4) ligation has not been specified.. Three types of birch allergen were utilized: glutaraldehyde-treated allergoid (extract A), the same allergoid plus monophosphoryl lipid A (MPL), i.e., TLR4 ligand (extract A*), and native allergen (extract B). Antigen-specific responses after the in vitro stimulation of blood cells with the extracts were assessed by studying costimulatory receptors on the B cell surface by flow cytometry, cytokine responses by ELISA, and CD63 and CD203c upregulation (basophil activation test) in allergic versus nonallergic subjects.. HLA-DR selectively increased upon allergen or allergoid treatment in the allergic group only. The extract types elicited similar cytokine responses, with IL-6 and IL-10 production detected only in certain atopic subjects. The allergoids revealed a strong reduction (100- to <10,000-fold) in basophil activation versus native allergen. Reactivity was undetectable in the basophils from nonallergic subjects.. The allergenicity of the allergoid employed was sharply reduced when compared to the native allergen, while its immunogenicity was largely retained, especially in the presence of MPL. We also provide further evidence that allergic and nonallergic individuals show preexisting differences in their immune repertoires.

Topics: Adjuvants, Immunologic; Allergens; Allergoids; Basophils; Betula; Cells, Cultured; Desensitization, Immunologic; Enzyme-Linked Immunosorbent Assay; HLA-DR Antigens; Humans; Immunotherapy; Interleukin-10; Interleukin-6; Lipid A; Phosphoric Diester Hydrolases; Plant Extracts; Pollen; Pyrophosphatases; Rhinitis, Allergic, Seasonal; Tetraspanin 30; Toll-Like Receptor 4

The prevalence of seasonal allergic rhinitis in the western world is high and increasing. Besides considerably affecting physical and psychosocial aspects of patients' lives, allergic rhinitis is often associated with allergic asthma and may aggravate this condition over time. Specific immunotherapy is currently the only approved therapy that can modify the underlying disease process and induce long-term tolerance to allergens. Pollinex Quattro is a subcutaneous four injections immunotherapy consisting of tyrosine-absorbed specific allergoids and enhanced with the adjuvant monophosphoryl lipid A (MPL(®)). MPL(®) induces a significant Th 1-type immune response, characterized by an increase of allergen-specific IgG antibody levels and dampening of the IgE response during allergen exposure. Due to this dual action of stimulating the immune system, Pollinex Quattro is clinically effective after only four injections given pre-seasonally. A large clinical program has demonstrated efficacy and tolerability of Pollinex Quattro in children, adolescents and adults with grass and tree pollen allergy. A health economics study concluded that an immunotherapy with only 4 injections might be more cost-beneficial than other application forms of immunotherapy.

Topics: Adjuvants, Immunologic; Allergens; Desensitization, Immunologic; Humans; Immunoglobulin E; Immunoglobulin G; Immunotherapy; Lipid A; Poaceae; Pollen; Rhinitis, Allergic, Seasonal; Toll-Like Receptors; Vaccines

This novel ultra-short-course seasonal allergy vaccine, containing glutaraldehyde-modified allergens and the adjuvants 3-deacylated monophosphoryl lipid A (MPL) and L-tyrosine, requires a preseasonal course of only four injections to be effective in the treatment of seasonal allergic rhinitis. In patients with seasonal allergic rhinitis and/or allergic asthma, a four-injection vaccination course with either the grass pollen or tree pollen allergy vaccine significantly reduced skin prick sensitivity reactions, significantly elevated allergen-specific IgG levels and significantly reduced the seasonally induced boost of IgE. Preseasonal vaccination of adult patients with either grass pollen or tree pollen allergy vaccine significantly reduced the median combined symptom/medication score compared with placebo. Similarly, preseasonal vaccination of children and adolescents with allergies to grass pollen or tree pollen significantly reduced the global symptom and medication use scores compared with the previous pollen season. Postmarketing surveillance indicated that after a course of vaccination, 82% of patients experienced reduced symptoms and 62% reduced their rescue medication use compared with the previous season. The allergy vaccine was generally well tolerated. Local reactions, mainly injection-site redness and swelling, were more common than systemic reactions. There were no serious adverse events.

Topics: Adjuvants, Immunologic; Allergens; Antigens, Plant; Asthma; Clinical Trials as Topic; Conjunctivitis, Allergic; Desensitization, Immunologic; Humans; Lipid A; Plant Extracts; Rhinitis, Allergic, Seasonal; Treatment Outcome; Vaccines

Topics: Adjuvants, Immunologic; Allergens; Antigens, Plant; Asthma; Desensitization, Immunologic; Humans; Lipid A; Plant Extracts; Reproducibility of Results; Rhinitis, Allergic, Seasonal; Vaccines

Monophosphoryl lipid A (MPL) is a nontoxic derivative of the lipopolysaccharide (LPS) of Salmonella minnesota R595. MPL has been used as an adjuvant in grass and tree pollen vaccines for the treatment of seasonal allergic rhinitis. Little is known about the influence of MPL on cellular responses to allergens in man. We therefore studied the effects of MPL in vitro on peripheral blood mononuclear cells (PBMC) obtained from patients with grass pollen hay fever.. The PBMCs from 13 subjects were cultured with grass pollen Phleum pratense extract (0, 2 and 20 microg/ml) and MPL (0 and 10 microg/ml; defined as an optimal concentration in preliminary studies) and after 6 days proliferative responses were measured by thymidine incorporation and cytokine production by enzyme-linked immunosorbent assay (ELISA).. Proliferative responses were unaffected by the presence of MPL whereas MPL induced a significant increase in allergen-induced interferon (IFN)-gamma production [allergen alone, 645 +/- 466 pg/ml (mean +/- SE) vs allergen + MPL, 3232 +/- 818 pg/ml; P < 0.001]. In addition, there was a significant decrease in interleukin (IL)-5 production (4307 +/- 1030 pg/ml vs 2997 +/- 826 pg/ml; P < 0.01). Although MPL alone could induce modest increases in IL-10 production, MPL did not influence the production of this cytokine in allergen-stimulated cultures. Addition of neutralizing antibody against IL-12 resulted in 95% inhibition of MPL-induced IFN-gamma production. Depletion of monocytes from the culture system abrogated the effects of MPL on elevated cytokine production.. In summary, use of MPL with grass pollen extract results in immune deviation of allergen-induced peripheral Th2-cell responses in favour of 'protective' Th1 responses in an IL-12 and monocyte-dependent fashion.

Topics: Adjuvants, Immunologic; Adult; Allergens; Antibodies; Cell Division; Cells, Cultured; Cytokines; Female; Humans; Intercellular Adhesion Molecule-1; Interleukin-12; Lipid A; Male; Monocytes; Poaceae; Pollen; Rhinitis, Allergic, Seasonal; Th1 Cells