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Front. Immunol. | doi: 10.3389/fimmu.2018.00381

Overcoming the Neonatal Limitations of Inducing Germinal Centers through Liposome-based Adjuvants including C-type Lectin Agonists Trehalose Dibehenate or Curdlan

  • 1WHO Collaborative Center for Vaccine Immunology, Departments of Pathology- Immunology and Pediatrics, Université de Genève, Switzerland
  • 2Vaccine Adjuvant Research, Department of Infectious Disease Immunology, State Serum Institute (SSI), Denmark
  • 3Department of Microbiology and Molecular Medicine, Université de Genève, Switzerland
  • 4Infectious Disease Research Institute, United States
  • 5Campus Vienna Biocenter 3, Valneva (Austria), Austria

Neonates and infants are more vulnerable to infections and show reduced responses to vaccination. Consequently, repeated immunizations are required to induce protection and early life vaccines against major pathogens such as influenza are yet unavailable. Formulating antigens with potent adjuvants, including immunostimulators and delivery systems, is a demonstrated approach to enhance vaccine efficacy. Yet, adjuvants effective in adults may not meet the specific requirements for activating the early life immune system. Here, we assessed the neonatal adjuvanticity of three novel adjuvants including TLR4 (GLA-SE), TLR9 (IC31®) and Mincle (CAF01) agonists, which all induce germinal centers and potent antibody responses to influenza hemagglutinin (HA) in adult mice. In neonates, a single dose of HA formulated into each adjuvant induced T follicular helper (TFH) cells. However, only HA/CAF01 elicited significantly higher and sustained antibody responses, engaging neonatal B cells to differentiate into germinal centers already after a single dose. Although antibody titers remained lower than in adults, HA-specific responses induced by a single neonatal dose of HA/CAF01 were sufficient to confer protection against influenza viral challenge. Postulating that the neonatal adjuvanticity of CAF01 may result from the functionality of the C-type Lectin Receptor (CLR) Mincle in early life we asked whether others C-type lectin agonists would show a similar neonatal adjuvanticity. Replacing the Mincle agonist TDB by Curdlan, which binds to Dectin-1, enhanced antibody responses through the induction of similar levels of TFH, germinal centers and bone marrow high-affinity plasma cells. Thus, specific requirements of early life B cells may already be met after a single vaccine dose using CLR-activating agonists, identified here as promising B cell immunostimulators for early life vaccines when included into cationic liposomes.

Keywords: T follicular helper cells, germinal centers, neonates, Vaccines, adjuvants

Received: 23 Nov 2017; Accepted: 12 Feb 2018.

Edited by:

Fabio Bagnoli, GlaxoSmithKline (Italy), Italy

Reviewed by:

Katie L. Flanagan, RMIT University, Australia
Michael Schotsaert, Icahn School of Medicine at Mount Sinai, United States  

Copyright: © 2018 Vono, Eberhardt, Mohr, Auderset, Christensen, Schmolke, Coler, Meinke, Andersen, Lambert, Mastelic-Gavillet and Siegrist. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.

* Correspondence: Prof. Claire-Anne Siegrist, Université de Genève, WHO Collaborative Center for Vaccine Immunology, Departments of Pathology- Immunology and Pediatrics, Geneva, Switzerland,