Immunotherapy With a Ragweed-Toll-Like Receptor 9 Agonist Vaccine for Allergic Rhinitis

BACKGROUND Conjugating immunostimulatory sequences of DNA to specific allergens offers a new approach to allergen immunotherapy that reduces acute allergic responses. METHODS We conducted a randomized, double-blind, placebo-controlled phase 2 trial of a vaccine consisting of Amb a 1, a ragweed-pollen antigen, conjugated to a phosphorothioate oligodeoxyribonucleotide immunostimulatory sequence of DNA (AIC) in 25 adults who were allergic to ragweed. Patients received six weekly injections of the AIC or placebo vaccine before the first ragweed season and were monitored during the next two ragweed seasons. RESULTS There was no pattern of vaccine-associated systemic reactions or clinically significant laboratory abnormalities. AIC did not alter the primary end point, the vascular permeability response (measured by the albumin level in nasal-lavage fluid) to nasal provocation. During the first ragweed season, the AIC group had better peak-season rhinitis scores on the visual-analogue scale (P=0.006), peak-season daily nasal symptom diary scores (P=0.02), and midseason overall quality-of-life scores (P=0.05) than the placebo group. AIC induced a transient increase in Amb a 1-specific IgG antibody but suppressed the seasonal increase in Amb a 1-specific IgE antibody. A reduction in the number of interleukin-4-positive basophils in AIC-treated patients correlated with lower rhinitis visual-analogue scores (r=0.49, P=0.03). Clinical benefits of AIC were again observed in the subsequent ragweed season, with improvements over placebo in peak-season rhinitis visual-analogue scores (P=0.02) and peak-season daily nasal symptom diary scores (P=0.02). The seasonal specific IgE antibody response was again suppressed, with no significant change in IgE antibody titer during the ragweed season (P=0.19). CONCLUSIONS In this pilot study, a 6-week regimen of the AIC vaccine appeared to offer long-term clinical efficacy in the treatment of ragweed allergic rhinitis. (ClinicalTrials.gov number, NCT00346086 [ClinicalTrials.gov] .).

[1]  R. Lockey,et al.  Adverse effects and fatalities associated with subcutaneous allergen immunotherapy. , 2008, Clinical allergy and immunology.

[2]  S. Durham,et al.  Grass Pollen Immunotherapy Induces Mucosal and Peripheral IL-10 Responses and Blocking IgG Activity1 , 2004, The Journal of Immunology.

[3]  S. Durham,et al.  Inhibition of allergen-IgE binding to B cells by IgG antibodies after grass pollen immunotherapy. , 2003, The Journal of allergy and clinical immunology.

[4]  A. Frew.  25. Immunotherapy of allergic disease. , 2003, The Journal of allergy and clinical immunology.

[5]  P. Eng,et al.  Long‐term efficacy of preseasonal grass pollen immunotherapy in children , 2002, Allergy.

[6]  Noel R. Rose,et al.  Manual of clinical laboratory immunology , 2002 .

[7]  Thomas D. Schmittgen,et al.  Analysis of relative gene expression data using real-time quantitative PCR and the 2(-Delta Delta C(T)) Method. , 2001, Methods.

[8]  A. Kagey‐Sobotka,et al.  Immunostimulatory sequence DNA linked to the Amb a 1 allergen promotes T(H)1 cytokine expression while downregulating T(H)2 cytokine expression in PBMCs from human patients with ragweed allergy. , 2001, The Journal of allergy and clinical immunology.

[9]  S. Durham,et al.  Grass pollen immunotherapy for seasonal rhinitis and asthma: a randomized, controlled trial. , 2001, The Journal of allergy and clinical immunology.

[10]  J. Schroeder,et al.  IL-4 production by human basophils found in the lung following segmental allergen challenge. , 2001, The Journal of allergy and clinical immunology.

[11]  J. Corbeil,et al.  Conjugation of protein to immunostimulatory DNA results in a rapid, long‐lasting and potent induction of cell‐mediated and humoral immunity , 2000 .

[12]  E. Raz,et al.  Conjugation of immunostimulatory DNA to the short ragweed allergen amb a 1 enhances its immunogenicity and reduces its allergenicity. , 2000, The Journal of allergy and clinical immunology.

[13]  S. Durham,et al.  Allergen immunotherapy: does it work and, if so, how and for how long? , 2000, Thorax.

[14]  E. Juniper,et al.  Validation of the standardized version of the Rhinoconjunctivitis Quality of Life Questionnaire. , 1999, The Journal of allergy and clinical immunology.

[15]  K. B. Hafner,et al.  Treatment of cat allergy with T-cell reactive peptides. , 1996, American journal of respiratory and critical care medicine.

[16]  W. Busse,et al.  Ragweed immunotherapy in adult asthma. , 1996, The New England journal of medicine.

[17]  D. Metcalfe,et al.  Detection of intracytoplasmic cytokine using flow cytometry and directly conjugated anti-cytokine antibodies. , 1995, Journal of immunological methods.

[18]  M. Jacobson,et al.  Grass pollen immunotherapy: efficacy and safety during a 4‐year follow‐up study , 1995, Allergy.

[19]  D. Tinkelman,et al.  Compliance with an allergen immunotherapy regime. , 1995, Annals of allergy, asthma & immunology : official publication of the American College of Allergy, Asthma, & Immunology.

[20]  B. Whisman,et al.  The effect of immunotherapy on the cutaneous late phase response to antigen. , 1994, The Journal of allergy and clinical immunology.

[21]  J. Janosky,et al.  Compliance with allergen immunotherapy. , 1993, Annals of allergy.

[22]  A. Sheffer,et al.  SPECIAL PROBLEMS REGARDING ALLERGEN IMMUNOTHERAPY , 1992, Immunology and Allergy Clinics of North America.

[23]  P. Creticos.  IMMUNOLOGIC CHANGES ASSOCIATED WITH IMMUNOTHERAPY , 1992, Immunology and Allergy Clinics of North America.

[24]  J. Bousquet,et al.  Immunotherapy with a standardized Dermatophagoides pteronyssinus extract. IV. Systemic reactions according to the immunotherapy schedule. , 1990, The Journal of allergy and clinical immunology.

[25]  B. Whisman,et al.  The relationships between late cutaneous responses and specific antibody responses with outcome of immunotherapy for seasonal allergic rhinitis. , 1989, The Journal of allergy and clinical immunology.

[26]  R. Lockey,et al.  Fatalities from immunotherapy (IT) and skin testing (ST) , 1987, The Journal of allergy and clinical immunology.

[27]  P. Norman,et al.  Immunotherapy with allergens. , 1987, JAMA.

[28]  L. Lichtenstein,et al.  Suppression of late-phase skin reactions by immunotherapy with ragweed extract. , 1985, The Journal of allergy and clinical immunology.

[29]  A. Togias,et al.  Influx of kininogens into nasal secretions after antigen challenge of allergic individuals. , 1985, The Journal of clinical investigation.

[30]  M. Mardiney,et al.  Dose response of IgE and IgG antibodies during ragweed immunotherapy. , 1984, The Journal of allergy and clinical immunology.

[31]  G. Gleich,et al.  Effect of immunotherapy on immunoglobulin E and immunoglobulin G antibodies to ragweed antigens: a six-year prospective study. , 1982, The Journal of allergy and clinical immunology.

[32]  A. Kagey‐Sobotka,et al.  A comparison of immunotherapy schedules for injection treatment of ragweed pollen hay fever. , 1982, The Journal of allergy and clinical immunology.

[33]  L. Lichtenstein,et al.  IgE antibody measurements in ragweed hay fever. Relationship to clinical severity and the results of immunotherapy. , 1973, The Journal of clinical investigation.

[34]  L. Lichtenstein,et al.  A single year of immunotherapy for ragweed hay fever. Immunologic and clinical studies. , 1971, Annals of internal medicine.

[35]  L. Lichtenstein,et al.  Immunotherapy of hay fever with ragweed antigen E: comparisons with whole pollen extract and placebos. , 1968, The Journal of allergy.

[36]  A. G. Osler,et al.  In vitro studies of human ragweed allergy: changes in cellular and humoral activity associated with specific desensitization. , 1966, The Journal of clinical investigation.

[37]  F. C. Lowell,et al.  A double-blind study of the effectiveness and specificity of injecton therapy in ragweed hay fever. , 1965, The New England journal of medicine.

[38]  F. C. Lowell,et al.  A “double blind” study of treatment with aqueous allergenic extracts in cases of allergic rhinitis , 1963 .

[39]  L. Noon.  Prophylactic inoculation against hay fever. , 1911, International archives of allergy and applied immunology.