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

Audur Anna Aradottir Pind,Jan Holmgren,Andreas Meinke,Stefania P Bjarnarson,Ali M Harandi,Sigrun Thorsdottir,Ingileif Jonsdottir,Magdalena Dubik,Giuseppe Del Giudice

doi:10.3389/fimmu.2019.02214

Abstract

Immaturity 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.

Highlights

Vaccines against infectious diseases have a major impact on human health, preventing each year 2–3 millions deaths worldwide [1]
We screened for potential effects of the adjuvants mmCT, MF59, IC31, and CTB-CpG on the neonatal immune response compared to the previously established effects of LT-K63 [9] on the induction of Germinal center (GC) reaction and enhanced Ab response in neonates
LT-K63, mmCT, MF59, and IC31 all enhanced GC induction after neonatal immunization with Pnc1-TT, shown by PNA staining of spleen sections

Summary

Introduction

Vaccines against infectious diseases have a major impact on human health, preventing each year 2–3 millions deaths worldwide [1]. Infectious diseases caused a large part of these deaths, many of which are vaccinepreventable [2]. These numbers emphasize the need for effective approaches to limit infections and preventable deaths in early life. The neonatal immune system is immature resulting in increased vulnerability to infections and poor vaccine-induced immune responses in early life. Protective vaccines against many pathogens are available, the vaccine-induced antibody (Ab) responses wane after 6–9 months, and multiple vaccinations are essential to maintain protection and immunological memory [3]

Methods

Results

Conclusion