Background: Interferons modulate the innate and adaptive immune response to viruses and vaccines. Transplant recipients respond poorly to influenza vaccine. The contribution of IFNΛ and B-cells in the response to influenza vaccine in transplantation is unknown.
Methods: SOT recipients were enrolled in a randomized trial of trivalent influenza vaccine. Sera were obtained pre- and post-vaccination to determine vaccine response. All patients were genotyped for single nucleotide polymorphisms in the IFNΛ3-promoter (rs8099917/rs12979860). Genotypes were correlated with vaccine seroconversion. In addition, the impact of IFNΛ3 on interferon-stimulated-gene (ISG) expression, B-cell proliferation, antibody-production, and cytokine-profile (41 cytokines) in H1N1-stimulated PBMCs was examined.
Results: We analyzed 196 patients. Patients with minor-allele genotypes (CT/TT and/or GT/GG) were more likely to seroconvert to at least one vaccine antigen (p=0.028). Seroconversion rates were poor in the subset of patients receiving high-dose MMF. In this subgroup, the minor-allele genotype (rs8099917) was a strong predictor of vaccine response (70% in minor allele vs. 25% in major; p<0.001). We further investigated the molecular mechanisms underlying this clinical finding. In healthy controls with minor allele genotypes, PBMCs stimulated with influenza A/H1N1 strain expressed >4000-fold lower IFNΛ3. Further, stimulation of B cells with IFNΛ3 resulted in reduced B cell activation as evidenced by significantly lower Th-2 cytokines (IL4/IL5/IL9/IL13, all p<0.05), antigen-presentation (HLA-DR), and co-stimulatory markers (eg, CD40 ligand). In response to influenza stimulation and with IFNΛ3, B-cell proliferation and IgG-production were reduced (80%, 3-fold respectively, p<0.05). Using computer and molecular modelling, we then developed peptides that were antagonists of the IFNΛ receptor. When added to B cells, these had a vaccine adjuvant-like effect and restored H1N1-induced IgG production.
Conclusions: Post transplant, IFNΛ3 may act as a key-regulator of vaccine-responses by reducing Th2-cytokines and B-cell proliferation. Genotyping of IFNΛ3 could differentiate between vaccine responders and nonresponders leading to personalized vaccination strategies in transplant recipients. Antagonistic-peptides that modulate IFNΛ have the potential to be novel vaccine adjuvants.
To cite this abstract in AMA style:Egli A, Santer D, O'Shea D, Baluch A, Joyce M, Lisboa L, Tyrrell L, Houghton M, Humar A, Kumar D. Clinical and Mechanistic Study of How Innate Immunity Gene Polymorphisms Can Affect Influenza Vaccine Responses Post-Transplant, A [abstract]. Am J Transplant. 2013; 13 (suppl 5). https://atcmeetingabstracts.com/abstract/clinical-and-mechanistic-study-of-how-innate-immunity-gene-polymorphisms-can-affect-influenza-vaccine-responses-post-transplant-a/. Accessed September 18, 2021.
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