Enhanced germinal center reaction by targeting vaccine antigen to major histocompatibility complex class II molecules

Tor Kristian Andersen,Anders A Tveita,Gunnveig Grødeland,Marte Fauskanger,Johanne T Jacobsen,Ramakrishna P Gopalakrishnan,Peter C Huszthy,Bjarne Bogen

doi:10.1038/s41541-019-0101-0

Abstract

Enhancing the germinal center (GC) reaction is a prime objective in vaccine development. Targeting of antigen to MHCII on APCs has previously been shown to increase antibody responses, but the underlying mechanism has been unclear. We have here investigated the GC reaction after targeting antigen to MHCII in (i) a defined model with T and B cells of known specificity using adjuvant-free vaccine proteins, and (ii) an infectious disease model using a DNA vaccine. MHCII-targeting enhanced presentation of peptide: MHCII on APCs, and increased the numbers of GC B cells, TFH, and plasma cells. Antibodies appeared earlier and levels were increased. BCR of GC B cells and serum antibodies had increased avidity for antigen. The improved responses required cross-linking of BCR and MHCII in either cis or trans. The enhanced GC reaction induced by MHCII-targeting of antigen has clear implications for design of more efficient subunit vaccines.

Highlights

Most successful vaccines owe their efficacy to induction of protective antibodies;[1] levels of antibodies represent a correlate of protection against most infectious diseases
The pId315:I-Ed complex is recognized by Id-specific CD4+ T cells from TCRtransgenic mice,[21] but can be physically detected by a TCR mimetic (TCRm), a scFv generated by phage display technology recently developed in our lab (Fig. 1c)
Enhancing the germinal center (GC) reaction is a prime objective in vaccine development against infectious diseases

Summary

Introduction

Most successful vaccines owe their efficacy to induction of protective antibodies;[1] levels of antibodies represent a correlate of protection against most infectious diseases. A key step in development of potent antibodies is the affinity maturation that occurs during the germinal center (GC) reaction. The GC reaction is initiated when activated B cells move into the B-cell follicles.[2] GC B cells hypermutate the variable (V) region of their B-cell receptor (BCR) through the action of activation-induced cytidine deaminase (AID). Cells with high-affinity BCRs are selected for clonal expansion through interactions with follicular DCs and follicular T-helper cells (TFH).[3] High-affinity B cells develop into long-lived memory B cells and antibody-secreting plasma cells.[4] For these reasons, increasing GC B-cell responses should be a prime goal in vaccine development

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Results

Conclusion