Correspondence
Immunotherapy with a Ragweed Vaccine
N Engl J Med 2007; 356:86-87January 4, 2007
- Article
To the Editor:
Creticos et al. (Oct. 5 issue)1 describe the results of a study comparing a vaccine — consisting of an immunostimulatory DNA sequence conjugated to Amb a 1, a ragweed-pollen antigen — with saline placebo. The study showed improvement of several end points of nasal allergen challenge in the group receiving the Amb a 1–immunostimulatory oligodeoxyribonucleotide conjugate (AIC) vaccine, as compared with the placebo group. However, we question whether saline is the appropriate comparative agent.
Standardized allergen extracts are known to be effective as immunotherapy for allergic diseases. Dynavax Technologies is developing an inhaled immunostimulatory sequence without a linked allergen for the treatment of another allergic disease, asthma.2 Therefore, both the immunostimulatory sequence and the allergen (Amb a 1) could have activity against allergic diseases. Since immunotherapy is an established treatment for allergic diseases, it would be important to compare the efficacy of AIC with that of immunotherapy to determine whether the conjugated product offers any benefit over standard immunotherapy. Ideally, future clinical studies evaluating AIC would include a comparison group of patients receiving allergen immunotherapy.
Sally M. Seymour, M.D.
Badrul A. Chowdhury, M.D., Ph.D.
Food and Drug Administration, Silver Spring, MD 20993
sally.seymour@fda. hhs. gov The views expressed in this letter are those of the authors and do not necessarily reflect the views or policies of the Food and Drug Administration.
2 References1
Creticos PS ,Schroeder JT ,Hamilton RG , et al. Immunotherapy with a ragweed-toll-like receptor 9 agonist vaccine for allergic rhinitis. N Engl J Med 2006;355:1445-1455
Full Text | Web of Science | Medline2
Dynavax Technologies. Clinical development programs — asthma. (Accessed December 13, 2006, at http://www.dynavax.com.)
To the Editor:
Creticos et al. report improvement in the symptoms of allergic rhinitis, with concomitant changes in skin-test sensitivity and antibody titers. However, changes in cellular immune responses were not definitive.
In a randomized, blinded, phase 1 study involving 19 patients with ragweed allergy, we measured ragweed-specific recall responses in antigen-stimulated primary cultures before and 2 and 16 weeks after six subcutaneous injections of either an Amb a 1 immunostimulatory DNA vaccine or placebo. We found that in vivo ragweed-specific responses by type 2 helper T (Th2) cells were selectively redirected toward balanced responses in parallel with increased activity by type 1 helper T (Th1) cells.1 There were significant decreases in levels of interleukin-5 and CC chemokine ligands 17 and 22 (CCL17 and CCL22, respectively) at 2 and 16 weeks in vaccine-treated patients, accompanied by transient increases in levels of interferon-γ and CXC ligands 9 and 10 (CXCL9 and CXCL10, respectively). Unrelated (streptokinase) responses and global (phytohemagglutinin) responses were not altered.
1 ReferencesF. Estelle R. Simons, M.D., F.R.C.P.C.
Kent T. HayGlass, Ph.D.
University of Manitoba, Winnipeg, MB R3A 1R9, Canada
lmcniven@hsc.mb. ca 1
Simons FER ,Shikishima Y ,Van Nest G ,Eiden JJ ,HayGlass KT . Selective immune redirection in humans with ragweed allergy by injecting Amb a 1 linked to immunostimulatory DNA. J Allergy Clin Immunol 2004;113:1144-1151
CrossRef | Web of Science | Medline
Author/Editor Response
Seymour and Chowdhury question whether saline is the appropriate comparative agent in trials of allergen immunotherapy. Saline is a recognized control for clinical trials with standard immunotherapy, and it has been used in various clinical trials approved by the Food and Drug Administration's Center for Biologics Evaluation and Research.1,2
At the time we designed our study, it was important to show the efficacy of a study drug as compared with placebo and to provide proof-of-concept and to demonstrate safety. Now that a clear-cut therapeutic response has been shown with a six-injection regimen of AIC, a comparative trial may be justified. A proper study design will nevertheless be difficult to achieve. Standard immunotherapy cannot be safely escalated to the optimal therapeutic dose in six injections and, furthermore, must be continued for at least 3 years. A double-blind, double-dummy design — with one regimen of 6 injections and another regimen of 25 escalating injections with a known risk of anaphylactic reactions, followed by 3 years of maintenance injections — has inherent problems with maintaining proper blinding.
With regard to the comments of Simons and HayGlass concerning their study of AIC in patients with ragweed allergy: because of space constraints, some references and discussion were edited from our original article, including the results of their study3 and of a study by Tulic et al.4
4 ReferencesPeter S. Creticos, M.D.
John T. Schroeder, Ph.D.
Johns Hopkins University School of Medicine, Baltimore, MD 21224
pcretic@jhmi.edu David Broide, M.B., Ch.B.
University of California, San Diego, La Jolla, CA 920931
Norman PS ,Lichtenstein LM ,Kagey-Sobotka A ,Marsh DG . Controlled evaluation of allergoid in the immunotherapy of ragweed hay fever. J Allergy Clin Immunol 1982;70:248-260
CrossRef | Web of Science | Medline2
Norman PS ,Ohman JL Jr ,Long AA , et al. Treatment of cat allergy with T-cell reactive peptides. Am J Respir Crit Care Med 1996;154:1623-1628
Web of Science | Medline3
Simons FER ,Shikishima Y ,Van Nest G ,Eiden JJ ,HayGlass KT . Selective immune redirection in humans with ragweed allergy by injecting Amb a 1 linked to immunostimulatory DNA. J Allergy Clin Immunol 2004;113:1144-1151
CrossRef | Web of Science | Medline4
Tulic MK ,Fiset P ,Christodoulopoulos P , et al. Amb a 1 immunostimulatory oligodeoxynucleotide conjugate immunotherapy decreases the nasal inflammatory response. J Allergy Clin Immunol 2004;113:235-241
CrossRef | Web of Science | Medline
- Citing Articles (1)
Citing Articles
1
François Spertini, Christophe Reymond, Annette Leimgruber. (2009) Allergen-specific immunotherapy of allergy and asthma: current and future trends. Expert Review of Respiratory Medicine 3:1, 37-51
CrossRef
