Adjuvants Enhance the Induction of Germinal Center and Antibody Secreting Cells in Spleen and Their Persistence in Bone Marrow of Neonatal Mice

Publisher's version (útgefin grein). The Supplementary Material for this article can be found online at: https://www.frontiersin.org/articles/10.3389/fimmu.2019.02214/full#supplementary-materialImmaturity of the immune system contributes to poor vaccine responses in early life. Germinal center (GC) activation is limited due to poorly developed follicular dendritic cells (FDC), causing generation of few antibody-secreting cells (ASCs) with limited survival and transient antibody responses. Herein, we compared the potential of five adjuvants, namely LT-K63, mmCT, MF59, IC31, and alum to overcome limitations of the neonatal immune system and to enhance and prolong responses of neonatal mice to a pneumococcal conjugate vaccine Pnc1-TT. The adjuvants LT-K63, mmCT, MF59, and IC31 significantly enhanced GC formation and FDC maturation in neonatal mice when co-administered with Pnc1-TT. This enhanced GC induction correlated with significantly enhanced vaccine-specific ASCs by LT-K63, mmCT, and MF59 in spleen 14 days after immunization. Furthermore, mmCT, MF59, and IC31 prolonged the induction of vaccine-specific ASCs in spleen and increased their persistence in bone marrow up to 9 weeks after immunization, as previously shown for LT-K63. Accordingly, serum Abs persisted above protective levels against pneumococcal bacteremia and pneumonia. In contrast, alum only enhanced the primary induction of vaccine-specific IgG Abs, which was transient. Our comparative study demonstrated that, in contrast to alum, LT-K63, mmCT, MF59, and IC31 can overcome limitations of the neonatal immune system and enhance both induction and persistence of protective immune response when administered with Pnc1-TT. These adjuvants are promising candidates for early life vaccination.AA was a recipient of a doctoral study grant from the University of Iceland Research Fund (2015-18). This study was financially supported by grants from the Icelandic Research Fund (130675051-53), The University of Iceland Research Fund (2014-17) and the Landspitali Science Fund (A-2015-084, A-2016-067). AH was supported by European Commission under the VASA, SHIGETECVAX and LeiShield-MATI RISE consortia, the Innovative Medicines Initiative, European Commission under the VSV-EBOPLUS consortium, and The University of British Columbia, Canada. We thank the late Dr. Emanuelle Trannoy, Sanofi Pasteur, France, for providing the pneumococcal conjugate vaccine and Dr. Thorunn Asta Olafsdottir, deCODE genetics for critical reading of the manuscript. Part of the work presented in this paper was presented as a poster at the European Congress of Immunology, Amsterdam, The Netherlands, 2.-5. September 2018 (abstract no. P.D3.01.03).Peer Reviewe