Eléna Gonçalves1, Olivia Bonduelle1, Angèle Soria1,2, Pierre Loulergue3, Alexandra Rousseau4, Marine Cachanado4, Henri Bonnabau5, Rodolphe Thiebaut5, Nicolas Tchitchek6, Sylvie Behillil7,8, Sylvie van der Werf7,8, Annika Vogt1,9, Tabassome Simon4, Odile Launay3, Behazine Combadière1. 1. Sorbonne Université, Centre d'Immunologie et des Maladies Infectieuses - Paris (Cimi-Paris), INSERM U1135, Paris, France. 2. Service de Dermatologie et Allergologie, Hôpital Tenon, Assistance Publique Hôpitaux de Paris (AP-HP), Paris, France. 3. Université Paris Descartes, Sorbonne Paris Cité, Centre d'Investigation Clinique Cochin Pasteur, INSERM CIC 1417, French Clinical Research Infrastructure Network, Innovative Clinical Research Network in Vaccinology, AP-HP, Hôpital Cochin, Paris, France. 4. Department of Clinical Pharmacology and Clinical Research Platform of East of Paris, Assistance Publique-Hôpitaux de Paris, Paris, France. Sorbonne Université, Paris, France. 5. INSERM U1219, INRIA SISTM, Université de Bordeaux, Bordeaux France. 6. CEA - Université Paris Sud 11 - INSERM U1184, Immunology of Viral Infections and Autoimmune Diseases, Institut de Biologie François Jacob, 92265 Fontenay-aux-Roses, France. 7. Institut Pasteur, CNR des Virus des Infections Respiratoires, Département de Virologie and Centre National de Recherche Scientifique UMR CNRS 3569, Paris, France. 8. Université Paris Diderot, Sorbonne Paris Cité, Unité de Génétique Moléculaire des Virus à ARN, Paris, France. 9. Clinical Research Center for Hair and Skin Science, Department of Dermatology and Allergy, Charité-Universitätsmedizin Berlin, Berlin, Germany.
Abstract
BACKGROUND: Systems vaccinology allows cutting-edge analysis of innate biomarkers of vaccine efficacy. We have been exploring novel strategies to shape the adaptive immune response, by targeting innate immune cells through novel immunization routes. METHODS: This randomized phase I/II clinical study (n=60 healthy subjects aged 18-45 years old) used transcriptomic analysis to discover early biomarkers of immune response quality after transcutaneous (t.c.), intradermal (i.d.), and intramuscular (i.m.) administration of a trivalent influenza vaccine (TIV season 2012-2013) (1:1:1 ratio). Safety and immunogenicity (hemagglutinin inhibition (HI), microneutralization (MN) antibodies and CD4, CD8 effector T cells) were measured at baseline Day (D)0 and at D21. Blood transcriptome was analyzed at D0 and D1. RESULTS:TIV-specific CD8+GranzymeB+(GRZ) T cells appeared in more individuals immunized by the t.c. and i.d. routes, while immunization by the i.d. and i.m. routes prompted high levels of HI antibody titers and MN against A/H1N1 and A/H3N2 influenza viral strains. The early innate gene signature anticipated immunological outcome by discriminating two clusters of individuals with either distinct humoral or CD8 cytotoxic responses. Several pathways explained this dichotomy confirmed by nine genes and serum level of CXCL10 were correlated with either TIV-specific cytotoxic CD8+GRZ+ T-cell or antibody responses. A logistic regression analysis demonstrated that these nine genes and serum levels of CXCL10 (D1/D0) best foreseen TIV-specific CD8+GRZ+ T-cell and antibody responses at D21. CONCLUSION: This study provides new insight into the impact of immunization routes and innate signature in the quality of adaptive immune responses.
RCT Entities:
BACKGROUND: Systems vaccinology allows cutting-edge analysis of innate biomarkers of vaccine efficacy. We have been exploring novel strategies to shape the adaptive immune response, by targeting innate immune cells through novel immunization routes. METHODS: This randomized phase I/II clinical study (n=60 healthy subjects aged 18-45 years old) used transcriptomic analysis to discover early biomarkers of immune response quality after transcutaneous (t.c.), intradermal (i.d.), and intramuscular (i.m.) administration of a trivalent influenza vaccine (TIV season 2012-2013) (1:1:1 ratio). Safety and immunogenicity (hemagglutinin inhibition (HI), microneutralization (MN) antibodies and CD4, CD8 effector T cells) were measured at baseline Day (D)0 and at D21. Blood transcriptome was analyzed at D0 and D1. RESULTS: TIV-specific CD8+GranzymeB+(GRZ) T cells appeared in more individuals immunized by the t.c. and i.d. routes, while immunization by the i.d. and i.m. routes prompted high levels of HI antibody titers and MN against A/H1N1 and A/H3N2 influenza viral strains. The early innate gene signature anticipated immunological outcome by discriminating two clusters of individuals with either distinct humoral or CD8 cytotoxic responses. Several pathways explained this dichotomy confirmed by nine genes and serum level of CXCL10 were correlated with either TIV-specific cytotoxic CD8+GRZ+ T-cell or antibody responses. A logistic regression analysis demonstrated that these nine genes and serum levels of CXCL10 (D1/D0) best foreseen TIV-specific CD8+GRZ+ T-cell and antibody responses at D21. CONCLUSION: This study provides new insight into the impact of immunization routes and innate signature in the quality of adaptive immune responses.
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