Abstract

Antibody production following vaccination can provide protective immunity to subsequent infection by pathogens such as influenza viruses. However, circumstances where antibody formation is impaired after vaccination, such as in older people, require us to better understand the cellular and molecular mechanisms that underpin successful vaccination in order to improve vaccine design for at-risk groups. Here, by studying the breadth of anti-haemagglutinin (HA) IgG, serum cytokines, and B and T cell responses by flow cytometry before and after influenza vaccination, we show that formation of circulating T follicular helper (cTfh) cells was associated with high-titre antibody responses. Using Major Histocompatability Complex (MHC) class II tetramers, we demonstrate that HA-specific cTfh cells can derive from pre-existing memory CD4+ T cells and have a diverse T cell receptor (TCR) repertoire. In older people, the differentiation of HA-specific cells into cTfh cells was impaired. This age-dependent defect in cTfh cell formation was not due to a contraction of the TCR repertoire, but rather was linked with an increased inflammatory gene signature in cTfh cells. Together, this suggests that strategies that temporarily dampen inflammation at the time of vaccination may be a viable strategy to boost optimal antibody generation upon immunisation of older people.

Highlights

  • Vaccination is an excellent intervention to limit the morbidity and mortality caused by infectious disease

  • The increase in anti-HA antibody titre was coupled with an increase in hemagglutination inhibitory antibodies to A.Cali09, the one influenza A strain contained in the TIV that was shared across the two cohorts (Fig. 1C)

  • HA-specific circulating T follicular helper (cTfh) cell frequency was strongly correlated with anti-A.Cali09 antibodies six weeks after vaccination, and there was not a reproducible relationship between total HA-specific CD4+ T cells and antibody titre, highlighting the importance of antigen-specific Tfh cell differentiation to support humoral immunity

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Summary

Introduction

Vaccination is an excellent intervention to limit the morbidity and mortality caused by infectious disease Despite their success, most vaccines are not completely effective, and efficacy varies significantly between different vaccines. The seasonal influenza vaccine needs to be administered each year in order to provide protection against the most prevalent circulating influenza strains, but its efficacy typically ranges from 40-80% even when the vaccine is antigenically matched to circulating viruses. This inefficacy contributes to the millions of severe influenza cases and hundreds of thousands of deaths globally [1], which could be potentially prevented by a more effective vaccine. Antibodies against the influenza surface glycoprotein haemagglutinin (HA) are capable of limiting infection, and anti-HA antibody titres and inhibitory activity are the most commonly used correlate of protection [2]

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