Tick-Borne Encephalitis Virus: A Quest for Better Vaccines against a Virus on the Rise

Abstract

Tick-borne encephalitis virus (TBEV), a member of the family Flaviviridae, is one of the most important tick-transmitted viruses in Europe and Asia. Being a neurotropic virus, TBEV causes infection of the central nervous system, leading to various (permanent) neurological disorders summarized as tick-borne encephalitis (TBE). The incidence of TBE cases has increased due to the expansion of TBEV and its vectors. Since antiviral treatment is lacking, vaccination against TBEV is the most important protective measure. However, vaccination coverage is relatively low and immunogenicity of the currently available vaccines is limited, which may account for the vaccine failures that are observed. Understanding the TBEV-specific correlates of protection is of pivotal importance for developing novel and improved TBEV vaccines. For affording robust protection against infection and development of TBE, vaccines should induce both humoral and cellular immunity. In this review, the adaptive immunity induced upon TBEV infection and vaccination as well as novel approaches to produce improved TBEV vaccines are discussed.

Keywords: CD4+ T cells; CD8+ T cells; TBEV; antibodies; flavivirus; immunity; tick-borne encephalitis virus; vaccination; vaccine.

Figure 1

The structure of the TBEV E protein (PDB-ID 5O6A [5]). (A) Side view of a single TBEV E protein monomer. Depicted are the four domains (DI: red, DII: yellow, DIII: blue, DIV (stem/anchor): gray) and the fusion loop (FL: orange). (B) Top view of a soluble TBEV E protein dimer. Color code same as in (A). Ribbon diagrams were prepared with UCSF Chimera [110].

Figure 2

TBEV-specific immunity upon immunization with virus-like particles (VLPs). The TBEV polyprotein with proteins inducing protective antibody responses (prM, E, NS1) is shown. Upon immunization with purified VLPs (1) or vector-based vaccines co-expressing prM and E (in situ production of VLPs, (2)), mainly humoral immune responses are induced. Inclusion of the NS1 protein in these vector-based vaccine approaches may improve the protective immunity. (3) Vector-based immunization leads to the synthesis of proteins of interest (POIs), which are processed on different pathways leading to humoral and/or cellular immune responses. (4) Humoral immune response: POIs are either secreted into the extracellular space (NS1) or assemble into novel VLPs (nVLPs; prM-E) which are subsequently released from the cell. The secreted proteins and de novo produced (nVLPs) or directly administered VLPs, respectively, induce the production of TBEV-specific B cells and antibodies. (5) Cellular immune response: The POIs or endocytosed VLPs, respectively, are degraded into peptides mainly by host proteases in endosomes leading to antigen presentation via MHC class II molecules to CD4⁺ T cells. (6) CD4⁺ T cells promote the activation and proliferation of TBEV-specific B cells driving efficient antibody responses with development of memory responses. Created with BioRender.com.

Figure 3

Inclusion of flavivirus non-structural proteins to enhance vaccine-induced immunity. The TBEV polyprotein with proteins inducing CD4⁺ (C, E, NS1) and CD8⁺ (NS2A, NS3, NS4B, NS5) T cell responses is shown. Upon immunization with live attenuated flaviviruses (1) or non-infectious, replicating TBEV RNA (2), structural as well as non-structural proteins are included, promoting a humoral but also an efficient cellular immunity. (3) Immunization leads to the synthesis of proteins of interest (POIs), which are processed on different pathways leading to humoral and/or cellular immune responses. (4) Humoral immune response: POIs are either secreted into the extracellular space (NS1) or assemble into novel VLPs (nVLPs) or virions (nVirus) which are subsequently released from the cell. Thus, TBEV-specific B cells and antibodies are induced. (5) Cellular immune response: The POIs are degraded into peptides either by host proteases in endosomes or by proteasomes in the cytoplasm. By this process antigens are presented via MHC class II or I molecules to CD4⁺ or CD8⁺ T cells. CD4⁺ T cells promote the activation and proliferation of TBEV-specific B cells (6) and CD8⁺ T cells (7) with the development of memory responses. Created with BioRender.com.