[Skip to Content]
Access to paid content on this site is currently suspended due to excessive activity being detected from your IP address Please contact the publisher to request reinstatement.
[Skip to Content Landing]

Effect of 2 Years of Treatment With Sublingual Grass Pollen Immunotherapy on Nasal Response to Allergen Challenge at 3 Years Among Patients With Moderate to Severe Seasonal Allergic RhinitisThe GRASS Randomized Clinical Trial

Educational Objective
To learn whether a shorter course of immunotherapy is effective for the treatment of allergic rhinitis.
1 Credit CME
Key Points

Question  Does 2 years of grass pollen sublingual immunotherapy reduce symptoms after nasal allergen challenge at 3-year follow-up (1 year after discontinuation of treatment)?

Findings  In this randomized clinical trial of 106 adults, 2 years of treatment with sublingual immunotherapy, compared with placebo, did not significantly reduce total nasal symptom scores after challenge at 3 years.

Meaning  Among patients with moderate to severe seasonal allergic rhinitis, 2 years of sublingual grass pollen immunotherapy was not significantly different than placebo in improving the nasal response to allergen challenge at 3-year follow-up.


Importance  Sublingual immunotherapy and subcutaneous immunotherapy are effective in seasonal allergic rhinitis. Three years of continuous treatment with subcutaneous immunotherapy and sublingual immunotherapy has been shown to improve symptoms for at least 2 years following discontinuation of treatment.

Objective  To assess whether 2 years of treatment with grass pollen sublingual immunotherapy, compared with placebo, provides improved nasal response to allergen challenge at 3-year follow-up.

Design, Setting, and Participants  A randomized double-blind, placebo-controlled, 3–parallel-group study performed in a single academic center, Imperial College London, of adult patients with moderate to severe seasonal allergic rhinitis (interfering with usual daily activities or sleep). First enrollment was March 2011, last follow-up was February 2015.

Interventions  Thirty-six participants received 2 years of sublingual immunotherapy (daily tablets containing 15 µg of major allergen Phleum p 5 and monthly placebo injections), 36 received subcutaneous immunotherapy (monthly injections containing 20 µg of Phleum p 5 and daily placebo tablets) and 34 received matched double-placebo. Nasal allergen challenge was performed before treatment, at 1 and 2 years of treatment, and at 3 years (1 year after treatment discontinuation).

Main Outcomes and Measures  Total nasal symptom scores (TNSS; range; 0 [best] to 12 [worst]) were recorded between 0 and 10 hours after challenge. The minimum clinically important difference for change in TNSS within an individual is 1.08. The primary outcome was TNSS comparing sublingual immunotherapy vs placebo at year 3. Subcutaneous immunotherapy was included as a positive control. The study was not powered to compare sublingual immunotherapy with subcutaneous immunotherapy.

Results  Among 106 randomized participants (mean age, 33.5 years; 34 women [32.1%]), 92 completed the study at 3 years. In the intent-to-treat population, mean TNSS score for the sublingual immunotherapy group was 6.36 (95% CI, 5.76 to 6.96) at pretreatment and 4.73 (95% CI, 3.97 to 5.48) at 3 years, and for the placebo group, the score was 6.06 (95% CI, 5.23 to 6.88) at pretreatment and 4.81 (95% CI, 3.97 to 5.65) at 3 years. The between-group difference (adjusted for baseline) was −0.18 (95% CI, −1.25 to 0.90; [P = .75]).

Conclusions and Relevance  Among patients with moderate to severe seasonal allergic rhinitis, 2 years of sublingual grass pollen immunotherapy was not significantly different from placebo in improving the nasal response to allergen challenge at 3-year follow-up.

Trial Registration  clinicaltrials.gov Identifier: NCT01335139; EudraCT Number: 2010-023536-16

Sign in to take quiz and track your certificates

Buy This Activity

JN Learning™ is the home for CME and MOC from the JAMA Network. Search by specialty or US state and earn AMA PRA Category 1 CME Credit™ from articles, audio, Clinical Challenges and more. Learn more about CME/MOC

Article Information

Corresponding Author: Stephen R. Durham, MD, Allergy and Clinical Immunology, Section of Inflammation, Repair, and Development, National Heart and Lung Institute, Imperial College London, Dovehouse St, London, UK SW3 6LY (s.durham@imperial.ac.uk).

Author Contributions: Drs Durham and Togias had full access to all of the data in the study and take responsibility for the integrity of the data and the accuracy of the data analysis. Drs Scadding, Calderon-Zapata, and Shamji contributed equally to the work.

Concept and design: Calderon-Zapata, Bahnson, Laurienzo Panza, Togias, Durham.

Acquisition, analysis, or interpretation of data: Scadding, Calderon-Zapata, Shamji, Eifan, Penagos, Dumitru, Sever, Bahnson, Lawson, Harris, Plough, Qin, Lim, Togias, Durham.

Drafting of the manuscript: Calderon-Zapata, Eifan, Penagos, Dumitru, Sever, Bahnson, Plough, Qin, Durham.

Critical revision of the manuscript for important intellectual content: Scadding, Calderon-Zapata, Shamji, Eifan, Dumitru, Sever, Bahnson, Lawson, Harris, Plough, Laurienzo Panza, Lim, Togias, Durham.

Statistical analysis: Sever, Bahnson, Lawson, Qin, Lim.

Administrative, technical, or material support: Scadding, Calderon-Zapata, Shamji, Eifan, Penagos, Dumitru, Sever, Bahnson, Plough, Laurienzo Panza.
Other - mechanistic assessments: Harris.

Conflict of Interest Disclosures: All authors have completed and submitted the ICMJE Form for Disclosure of Potential Conflicts of Interest. Dr Calderon reports receipt of personal fees for advisory board participation from ALK and Hal Allergy and for lectures from ALK, Merck, and Stallergenes-Greer. Dr Penagos reports receipt of grants from the US Department of Health and Human Services (HHS), the National Institutes of Health (NIH), the National Institute of Allergy and Infectious Diseases (NIAID), and the Immune Tolerance Network (ITN); nonfinancial support from ALK-Abello A/S Hørsholm during the conduct of the study; and personal fees for the development of educational presentations from ALK-Abello and Stallergenes outside the submitted work. Dr Dumitru reports receipt of grants to cover conference attendance from Allergy Therapeutics and Stallergenes outside the submitted work. Dr Durham reports receipt of grants from the ITN and NIAID, and nonfinancial support from ALK during the conduct of the study; and grants from Regeneron, Biotech Tools, ALK, personal fees from Anergis, Circassia, Biomay, Merck, Allergy Therapeutics, ALK, and med Update GmbH outside the submitted work. No other disclosures were reported.

GRASS Study Contributors: Andrea Goldstone, RN, MS, Fotini Rozakeas, RN, MS, and Rachel Yan, RN, MS, Imperial College Nursing Staff; Natalia Klimowska-Nassar, MA, and Mimi Poon, MSc, Imperial College Study Management and Administration; Delica Kit Cheung, MSc, Constance Ito, MSc, Janice Layhadi, PhD, Elisabeth Lemm, BSc, Ellen Macfarlane, BSc, Orla MacMahon, BSc, Tomokasu Matsuoka, MD, PhD, Rebecca Parkin, BSc, and Amy Switzer, MSc, Imperial College Laboratory Projects; Adam Asare, PhD (past), Eduard Chani, PhD, Judith Evind, Deborah Phippard PhD (past), Peter Sayre MD, PhD, Maureen Sharkey, MA (past), and Don Whitehouse, MS, ITN staff; Steven Adah, PhD (past), Theresa Allio, PhD, Christine Czarniecki, PhD, and Jui Shah, PhD (past), Division of Allergy, Immunology, and Transplantation, National Institute of Allergy and Infectious Diseases (DAIT-NIAID) Staff; and Travis Mason, BS, Ann Nguyen, BSN, Shayala Gibbs, MPH, and Spencer Childress, BS, Rho Federal Systems Staff.

Funding/Support: The trial was conducted by the ITN with financial support from the DAIT-NIAID, National Institutes of Health (NIH) under award numbers NO1-AI-15416, UM1AI109565, and UM2AI117870; the following DAIT-NIAID–funded groups: Statistical and Clinical Coordinating Centers (contract HHSN272200800029C and grant UM2AI117870), Clinical Site Monitoring Center (contract HHSN272201200004C), and Regulatory Management Center (contract HHSN272201200002C); ALK-Abello A/S Horsholm, Denmark supplied Alutard SQ Grass Pollen, and Grazax, and matching placebos used for the GRASS clinical trial to DAIT-NIAID without charge. Dr Durham served as the sponsor of the Medicines and Healthcare Products Regulatory Agency Clinical Trial Application.

Role of the Funder/Sponsor: The sponsor for the study was the ITN under a contract from the NIAID. The ITN clinical trial physician and administrative team and ITN scientists liaised closely concerning all aspects of the trial with the principal investigator (protocol chair) and the site team at Imperial College London. Similarly, the medical monitor from NIAID and the regulatory team at NIAID worked closely with ITN and the protocol chair and study team concerning all aspects of the study. ALK Denmark supplied the allergy vaccines, matched placebos, and allergen extracts for skin testing and nasal allergen provocation for the study free of charge. ALK had no input to the design and conduct of the study; collection, management, analysis, and interpretation of the data; preparation, review, or approval of the manuscript or decision to submit the manuscript for publication.

Disclaimer: The content of this article is solely the responsibility of the authors and does not necessarily represent the official views of the NIH.

Additional Contributions: We thank the patients for their participation in this study.

Meltzer  EO, Blaiss  MS, Derebery  MJ,  et al.  Burden of allergic rhinitis: results from the Pediatric Allergies in America survey.  J Allergy Clin Immunol. 2009;124(3)(suppl):S43-S70.PubMedGoogle ScholarCrossref
Salo  PM, Calatroni  A, Gergen  PJ,  et al Allergy-related outcomes in relation to serum IgE: results from the National Health and Nutrition Examination Survey 2005-2006.  J Allergy Clin Immunol. 2011;127(5):1226-1235 e1227.PubMedGoogle ScholarCrossref
Bousquet  J, Schünemann  HJ, Samolinski  B,  et al; World Health Organization Collaborating Center for Asthma and Rhinitis.  Allergic Rhinitis and its Impact on Asthma (ARIA): achievements in 10 years and future needs.  J Allergy Clin Immunol. 2012;130(5):1049-1062.PubMedGoogle ScholarCrossref
Wheatley  LM, Togias  A.  Clinical practice: allergic rhinitis.  N Engl J Med. 2015;372(5):456-463.PubMedGoogle ScholarCrossref
Cox  L, Nelson  H, Lockey  R,  et al.  Allergen immunotherapy: a practice parameter third update.  J Allergy Clin Immunol. 2011;127(1)(suppl):S1-S55.PubMedGoogle ScholarCrossref
Jutel  M, Agache  I, Bonini  S,  et al.  International consensus on allergy immunotherapy.  J Allergy Clin Immunol. 2015;136(3):556-568.PubMedGoogle ScholarCrossref
Canonica  GW, Cox  L, Pawankar  R,  et al.  Sublingual immunotherapy: World Allergy Organization position paper 2013 update.  World Allergy Organ J. 2014;7(1):6.PubMedGoogle ScholarCrossref
Lin  SY, Erekosima  N, Kim  JM,  et al.  Sublingual immunotherapy for the treatment of allergic rhinoconjunctivitis and asthma: a systematic review.  JAMA. 2013;309(12):1278-1288.PubMedGoogle ScholarCrossref
Didier  A, Malling  HJ, Worm  M, Horak  F, Sussman  GL.  Prolonged efficacy of the 300IR 5-grass pollen tablet up to 2 years after treatment cessation, as measured by a recommended daily combined score.  Clin Transl Allergy. 2015;5:12.PubMedGoogle ScholarCrossref
Durham  SR, Emminger  W, Kapp  A,  et al.  SQ-standardized sublingual grass immunotherapy: confirmation of disease modification 2 years after 3 years of treatment in a randomized trial.  J Allergy Clin Immunol. 2012;129(3):717-725.e5.PubMedGoogle ScholarCrossref
Durham  SR, Walker  SM, Varga  EM,  et al.  Long-term clinical efficacy of grass-pollen immunotherapy.  N Engl J Med. 1999;341(7):468-475.PubMedGoogle ScholarCrossref
Scadding  GW, Calderon  MA, Bellido  V,  et al.  Optimisation of grass pollen nasal allergen challenge for assessment of clinical and immunological outcomes.  J Immunol Methods. 2012;384(1-2):25-32.PubMedGoogle ScholarCrossref
Scadding  GW, Eifan  AO, Lao-Araya  M,  et al.  Effect of grass pollen immunotherapy on clinical and local immune response to nasal allergen challenge.  Allergy. 2015;70(6):689-696.PubMedGoogle ScholarCrossref
Bousquet  PJ, Combescure  C, Klossek  JM, Daurès  JP, Bousquet  J.  Change in visual analog scale score in a pragmatic randomized cluster trial of allergic rhinitis.  J Allergy Clin Immunol. 2009;123(6):1349-1354.PubMedGoogle ScholarCrossref
Juniper  EF, Thompson  AK, Ferrie  PJ, Roberts  JN.  Development and validation of the mini Rhinoconjunctivitis Quality of Life Questionnaire.  Clin Exp Allergy. 2000;30(1):132-140.PubMedGoogle ScholarCrossref
Francis  JN, James  LK, Paraskevopoulos  G,  et al Grass pollen immunotherapy: IL-10 induction and suppression of late responses precedes IgG4 inhibitory antibody activity.  J Allergy Clin Immunol. 2008;121(5):1120-1125 e1122.PubMedGoogle ScholarCrossref
Revicki  D, Hays  RD, Cella  D, Sloan  J.  Recommended methods for determining responsiveness and minimally important differences for patient-reported outcomes.  J Clin Epidemiol. 2008;61(2):102-109.PubMedGoogle ScholarCrossref
Frew  AJ, Powell  RJ, Corrigan  CJ, Durham  SR; UK Immunotherapy Study Group.  Efficacy and safety of specific immunotherapy with SQ allergen extract in treatment-resistant seasonal allergic rhinoconjunctivitis.  J Allergy Clin Immunol. 2006;117(2):319-325.PubMedGoogle ScholarCrossref
Shamji  MH, Ljørring  C, Francis  JN,  et al.  Functional rather than immunoreactive levels of IgG4 correlate closely with clinical response to grass pollen immunotherapy.  Allergy. 2012;67(2):217-226.PubMedGoogle ScholarCrossref
Medical Dictionary for Regulatory Activities (MedDRA). 2011; http://www.meddra.org. Accessed October 17, 2016.
Cox  L, Larenas-Linnemann  D, Lockey  RF, Passalacqua  G.  Speaking the same language: the World Allergy Organization Subcutaneous Immunotherapy Systemic Reaction Grading System.  J Allergy Clin Immunol. 2010;125(3):569-574.PubMedGoogle ScholarCrossref
Passalacqua  G, Baena-Cagnani  CE, Bousquet  J,  et al.  Grading local side effects of sublingual immunotherapy for respiratory allergy: speaking the same language.  J Allergy Clin Immunol. 2013;132(1):93-98.PubMedGoogle ScholarCrossref
Immune Tolerance Network.  Clinical trials research portal. https://www.itntrialshare.org/GRASS_Primary.url. Accessed Month, date, year.
Reinsch  CH.  Smoothing by spline functions.  Numer Math. 1967;10(3):177-183. doi:10.1007/BF02162161Google ScholarCrossref
Bousquet  J, Lockey  R, Malling  HJ.  Allergen immunotherapy: therapeutic vaccines for allergic diseases: a WHO position paper.  J Allergy Clin Immunol. 1998;102(4 pt 1):558-562.PubMedGoogle ScholarCrossref
Walker  SM, Durham  SR, Till  SJ,  et al.  Immunotherapy for allergic rhinitis.  Clin Exp Allergy. 2011;41(9):1177-1200.PubMedGoogle ScholarCrossref
Canonica  GW, Baena-Cagnani  CE, Bousquet  J,  et al.  Recommendations for standardization of clinical trials with allergen specific immunotherapy for respiratory allergy: A statement of a World Allergy Organization (WAO) taskforce.  Allergy. 2007;62(3):317-324.PubMedGoogle ScholarCrossref
Ott  H, Sieber  J, Brehler  R,  et al.  Efficacy of grass pollen sublingual immunotherapy for three consecutive seasons and after cessation of treatment: the ECRIT study.  Allergy. 2009;64(9):1394-1401.PubMedGoogle ScholarCrossref
Di Bona  D, Plaia  A, Leto-Barone  MS, La Piana  S, Di Lorenzo  G.  Efficacy of grass pollen allergen sublingual immunotherapy tablets for seasonal allergic rhinoconjunctivitis: a systematic review and meta-analysis.  JAMA Intern Med. 2015;175(8):1301-1309.PubMedGoogle ScholarCrossref
Durham  SR, Penagos  M.  Sublingual or subcutaneous immunotherapy for allergic rhinitis?  J Allergy Clin Immunol. 2016;137(2):339-349.e10.PubMedGoogle ScholarCrossref
Lin  S, Erekosima  N, Suarez-Cuervo  C,  et al.  Allergen-Specific Immunotherapy for the Treatment of Allergic Rhinoconjunctivitis and/or Asthma: Comparative Effectiveness Review. Rockville, MD: Agency for Healthcare Research and Quality; 2013.
Khinchi  MS, Poulsen  LK, Carat  F, André  C, Hansen  AB, Malling  HJ.  Clinical efficacy of sublingual and subcutaneous birch pollen allergen-specific immunotherapy: a randomized, placebo-controlled, double-blind, double-dummy study.  Allergy. 2004;59(1):45-53.PubMedGoogle ScholarCrossref
Gleich  GJ, Zimmermann  EM, Henderson  LL, Yunginger  JW.  Effect of immunotherapy on immunoglobulin E and immunoglobulin G antibodies to ragweed antigens: a six-year prospective study.  J Allergy Clin Immunol. 1982;70(4):261-271.PubMedGoogle ScholarCrossref
Lima  MT, Wilson  D, Pitkin  L,  et al Grass pollen sublingual immunotherapy for seasonal rhinoconjunctivitis: a randomized controlled trial.  Clin Exp Allergy. 2002;32(4):507-514.PubMedGoogle ScholarCrossref
Maloney  J, Bernstein  DI, Nelson  H,  et al.  Efficacy and safety of grass sublingual immunotherapy tablet, MK-7243: a large randomized controlled trial.  Ann Allergy Asthma Immunol. 2014;112(2):146-153.e2.PubMedGoogle ScholarCrossref
Maloney  J, Prenner  BM, Bernstein  DI,  et al.  Safety of house dust mite sublingual immunotherapy standardized quality tablet in children allergic to house dust mites.  Ann Allergy Asthma Immunol. 2016;116(1):59-65.PubMedGoogle ScholarCrossref
If you are not a JN Learning subscriber, you can either:
Subscribe to JN Learning for one year
Buy this activity
If you are not a JN Learning subscriber, you can either:
Subscribe to JN Learning for one year
Buy this activity
With a personal account, you can:
  • Access free activities and track your credits
  • Personalize content alerts
  • Customize your interests
  • Fully personalize your learning experience
Education Center Collection Sign In Modal Right

Name Your Search

Save Search
With a personal account, you can:
  • Track your credits
  • Personalize content alerts
  • Customize your interests
  • Fully personalize your learning experience

Lookup An Activity


My Saved Searches

You currently have no searches saved.

With a personal account, you can:
  • Access free activities and track your credits
  • Personalize content alerts
  • Customize your interests
  • Fully personalize your learning experience
Education Center Collection Sign In Modal Right
State Requirements