Transcriptome analysis and safety profile of the early-phase clinical response to an adjuvanted grass allergoid immunotherapy

• Published in: The World Allergy Organization journal Vol. 12; no. 11; p. 100087
• Main Authors: Starchenka, Sviatlana, Heath, Matthew D., Lineberry, Alyson, Higenbottam, Tim, Skinner, Murray A.
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 01.11.2019; Elsevier BV; World Allergy Organization; Elsevier
• Subjects: Adjuvants; Allergen immunotherapy; Allergens; Allergies; Allergoid; Biomarkers; Gene expression; Grass pollen; Grasses; Immunology; Immunotherapy; Injections; Lipids; Phenols; Pollen; Rhinitis; Safety; Transcriptome; United Kingdom > UK; United States > US; SAR; URA; Transcriptome; MPL; mRNA; SD; ADRs; Safety; TLR; Allergoid; EAACI; MATA; SU; AE; AIT; ARC; FVC; TSS; FEV; Grass pollen; SAEs; IPA; Allergen immunotherapy; TEAEs; DC; MCT; SIT; TSS, total symptom score; DC, dendritic cell; ARC, adverse reaction complex; SAR, seasonal allergic rhinoconjunctivitis; FVC, forced vital capacity; SD, standard deviation; TEAEs, treatment-emergent adverse events; EAACI, European Academy of Allergy and Clinical Immunology; mRNA, messenger ribosomal nucleic acid; ADRs, adverse drug reactions; TLR, toll-like receptor; AE, adverse events; MATA, modified allergen tyrosine adsorbate; MCT, microcrystalline tyrosine; SIT, specific immunotherapy; IPA, Ingenuity Pathway Analysis; SAEs, serious adverse events; MPL, monophosphoryl lipid A; AIT, allergen mmunotherapy; SU, standardized units; FEV, forced expiratory volume; URA, Upstream Regulator Analysis
• ISSN: 1939-4551; 1939-4551
• DOI: 10.1016/j.waojou.2019.100087

Specific immunotherapy is the only type of disease-modifying treatment, which induces rapid desensitization and long-term sustained unresponsiveness in patients with seasonal allergic rhinoconjunctivitis. The safety and tolerability of a new cumulative dose regimen of 35600 SU Grass MATA MPL for subcutaneous immunotherapy were assessed in pre-seasonal, single-blind, placebo controlled Phase I clinical study. Underlying immunological mechanisms were explored using transcriptome analysis of peripheral blood mononuclear cells. Study subjects with a history of moderate to severe seasonal allergic rhinitis and/or conjunctivitis (SAR) due to grass (Pooideae) pollen exposure were randomized on a 1:1 ratio to receive either six 1.0 mL injections of cumulative dose regimen 35600 SU of Grass MATA MPL or placebo. The study consisted of three periods: screening, randomization and treatment and End of Study period. Blood samples were taken for clinical safety laboratory assessments and for the assessment of gene expression analysis during screening visit and End of Study visit. The safety statistics was calculated using Fisher's exact test. Delta Delta Ct method analysis of RT2 Profiler PCR Array gene expression results was used to calculate changes in gene expression level. Genes with the absolute value of log2 fold change greater than ±1.1 and p-value less than 0.05 were identified as differentially expressed and underwent IPA data analysis. The results of the study indicated that the higher cumulative dose regimen of the immunotherapy was well-tolerated. Changes in gene expression profile were associated with early immune responses implicating innate and adaptive immune mechanisms. Pathways and mechanistic network analysis via IPA mapped differentially expressed genes onto canonical pathways related to T cell differentiation, cytokine signalling and Th1/Th2 activation pathways. The transcriptome findings of the study could be further verified in large-scale field studies in order to explore their potential as predictive markers of successful immunotherapy. The higher dose cumulative regime 35600 SU of Grass MATA MPL vaccine was well tolerated and safe. Molecular markers IL-27, IL-10, IL-4, TNF, IFNγ, TGFβ and TLR4 were the main predicted molecular drivers of the observed gene expression changes following early stages of SIT with Grass MATA MPL immunotherapy.