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To whom correspondence may be addressed. Emails: rino.r.rappuoli@gsk.com; bpulend@emory.edu; claire-anne.siegrist@unige.ch

Author contributions: G.D.G., R.R., V.C., A.J.P., B.P., and C.-A.S. designed research; H.I.N., E.C., D.K., L.W., M.C., S.E.B., N.B.P., D.E.Z., and T.D. performed research; A.A., G.D.G., R.R., V.C., A.J.P., B.P., and C.-A.S. analyzed data; and H.I.N., E.C., D.K., R.R., A.J.P., B.P., and C.-A.S. wrote the paper.

Reviewers: A.G.-S., Icahn School of Medicine at Mount Sinai; S.H.E.K., Max Planck Institute for Infection Biology; and F.S., Institute for Research in Biomedicine, Università della Svizzera Italiana.

H.I.N., E.C., D.K., and L.W. contributed equally to this work.

We thank Dr. Angus Goodson, Elizabeth Davies, Hannah Robinson, and Richard Sewell for assisting with the clinical trial; Amber Thompson, Jaclyn Bowman, Susan Ndimah, Karlijn De Nie, and Rebecca Sie for assisting with laboratory evaluation; and the families who participated in this study.

Conflict of interest statement: R.R. and G.D.G. are full-time employees at Glaxo-Smith-Kline Vaccines. C.-A.S. is a member of several advisory committees on vaccination and has received research grants from vaccine manufacturers for preclinical and clinical research, all unrelated to this work. A.J.P. chairs the United Kingdom Department of Health’s Joint Committee on Vaccination and Immunization and the European Medicines Agency scientific advisory group on vaccines. He has previously conducted clinical trials in behalf of Oxford University funded by vaccine manufacturers, including manufacturers of influenza vaccines, but no longer does so.

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Research Funding:

This study was supported in part by European Commission FP7 Grant “Advanced Immunisation Technologies”; the National Institute for Health Research Oxford Biomedical Research Centre; and the Medical Research Council (to the Human Immunology Unit). Work in B.P.’s laboratory was supported by National Institutes of Health Grants U19AI090023, R37AI48638, R37DK057665, U19AI057266, and AI100663-02. H.I.N. is the recipient of a CNPq research fellowship.

Keywords:

  • systems biology
  • influenza vaccine
  • MF59
  • adjuvant
  • children

Systems biology of immunity to MF59-adjuvanted versus nonadjuvanted trivalent seasonal influenza vaccines in early childhood

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Journal Title:

Proceedings of the National Academy of Sciences

Volume:

Volume 113, Number 7

Publisher:

, Pages 1853-1858

Type of Work:

Article | Final Publisher PDF

Abstract:

The dynamics and molecular mechanisms underlying vaccine immunity in early childhood remain poorly understood. Here we applied systems approaches to investigate the innate and adaptive responses to trivalent inactivated influenza vaccine (TIV) and MF59-adjuvanted TIV (ATIV) in 90 14- to 24-mo-old healthy children. MF59 enhanced the magnitude and kinetics of serum antibody titers following vaccination, and induced a greater frequency of vaccine specific, multicytokine-producing CD4+ T cells. Compared with transcriptional responses to TIV vaccination previously reported in adults, responses to TIV in infants were markedly attenuated, limited to genes regulating antiviral and antigen presentation pathways, and observed only in a subset of vaccinees. In contrast, transcriptional responses to ATIV boost were more homogenous and robust. Interestingly, a day 1 gene signature characteristic of the innate response (antiviral IFN genes, dendritic cell, and monocyte responses) correlated with hemagglutination at day 28. These findings demonstrate that MF59 enhances the magnitude, kinetics, and consistency of the innate and adaptive response to vaccination with the seasonal influenza vaccine during early childhood, and identify potential molecular correlates of antibody responses.

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Nakaya et al

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