In vitro assessment of tick-borne encephalitis vaccine: Suitable human cell platforms and potential biomarkers.

Aurora Signorazzi,Marilena Etna,Anke Huckriede,Eliana Coccia

doi:10.14573/altex.2010081

Abstract

Tick-borne encephalitis (TBE) virus causes a severe disease that can lead to permanent neurological complications. The whole inactivated TBE vaccine is highly effective, as proven by high seroconversion rates and near eradication of the disease in countries where vaccination programs have been implemented. TBE vaccine potency testing currently requires the use of in vivo methods that present issues of reproducibility as well as animal discomfort. As an alternative, public and private entities are currently exploring a batch-to-batch consistency approach that would demonstrate conformity of a newly produced vaccine batch with a batch of proven in vivo efficacy with respect to a range of measurable in vitro quality parameters. To identify a suitable cellular platform to be used in a panel of in vitro batch-to-batch assessments for the TBE vaccine, we exposed human cell-based systems, both of primary origin and cell line-derived, to vaccine formulations of high and low quality. Following stimulation, cell responses were evaluated by assessing the expression of selected genes by RT-qPCR. Our findings show that the expression of interferon-stimulated genes differed after treatment with non-adjuvanted vaccine batches of different quality in peripheral blood mononuclear cells (PBMCs) and in monocyte-derived dendritic cells, but not in monocyte-free PBMC suspensions nor in cell line-derived immune cells. These results indicate suitable platforms and potential biomarkers for a cell-based assay that, together with other immunochemical analyses, could serve for batch-to-batch assessment of the TBE vaccine, reducing, and eventually replacing, in vivo methods for potency testing.

Highlights

Tick-borne encephalitis virus (TBEV) is an arthropod-borne flavivirus endemic in forested areas across Europe and Asia and the etiological agent of a neuroinvasive illness that can lead to severe long-term sequelae (Haglund and Günther, 2003; Dörrbecker et al, 2010)
3.1 THP-1 cells do not show specific responses to TBE vaccine formulations To develop an in vitro system suitable for assessing the conformity of batches in the context of commercial TBE vaccine production, we initially turned to THP-1 cells, a human monocytic cell line extensively used to study monocyte or macrophage functions (Chanput et al, 2014)
We first determined the viability of THP-1 cells upon stimulation with TBE vaccine and non-adjuvanted vaccine (NAV), along with their respective negative controls, i.e., excipient and matrix (Fig. S11)

Summary

Introduction

Tick-borne encephalitis virus (TBEV) is an arthropod-borne flavivirus endemic in forested areas across Europe and Asia and the etiological agent of a neuroinvasive illness that can lead to severe long-term sequelae (Haglund and Günther, 2003; Dörrbecker et al, 2010). The incidence of the disease has increased by more than 300% in Europe and Russia in the last 30 years because of climate and socio-economical changes (Süss, 2011; Nah et al, 2020). Existing TBE vaccines are highly immunogenic and provide at least 10 years of antibody persistence (Beran et al, 2018) through the induction of envelope protein-directed antibodies and of TBEV-specific CD4+ T cells (Kubinski et al, 2020). Several licensed TBE vaccines are available across central Europe, Russia and Asia.

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