Tick-borne encephalitis vaccine (whole virus, inactivated)

Tick-borne encephalitis (TBE) is a viral infection caused by the TBE virus (TBEV) with an endemic range spreading throughout Europe and into Russia, China, and other parts of Asia. The three main subtypes are transmitted by two distinct species of Ixodes tick, with the European subtype (TBEV-Eu) transmitted by I. ricinus and both the Siberian (TBEV-Sib) and the Far Eastern (TBEV-FE) subtypes transmitted by I. persulcatus. All three subtypes are members of the Flavivirus genus within the Flaviviridae family, which also contains other clinically relevant flaviviruses including Zika, West Nile, and dengue.

Like other flaviviruses, TBEV particles are membrane/protein-bound, smooth spheres roughly 50 nm in diameter enclosing a single copy of the ~11 kb positive-strand RNA genome. This genome encodes three structural (envelope (E), membrane (M), and capsid (C) proteins) and seven non-structural (NNS1, NS2A, NS2B, NS3, NS4A, NS4B, and NS5) proteins required for the intracellular assembly of new TBEV particles. The particle consists of a nucleocapsid (the viral genome associated with multiple copies of the C protein) surrounded by a membrane in which E and M proteins are embedded to form an icosahedrally-symmetric protein coat. Extracellular TBEV particles interact with an as yet undefined receptor to achieve endocytic uptake; once inside the acidic environment of the endosome, the E protein is protonated and undergoes extensive rearrangement to reveal a "fusion loop" that mediates TBEV membrane fusion and the release of the nucleocapsid, which subsequently disassociates to release free viral RNA. Viral replication and particle assembly, involving both viral and host factors, occurs in the ER, followed by the trafficking of viral particles through the trans-Golgi network (TGN), further particle processing, and eventual extracellular release.

The ability of TBEV to cross the blood-brain barrier and cause neurological symptoms (neurovirulence) has been correlated with several factors, namely solvent-exposed residues within the E protein, which also represent the primary target for neutralizing antibodies. These likely work through inhibiting host cell receptor binding, inhibiting endosomal fusion, or through Fc-mediated clearance of infected cells. Non-neutralizing, though still protective, antibodies have also been described against the NS1 protein, which also likely mediate clearance of infected cells through antibody-dependent cell-mediated cytotoxicity or the complement system.

TBE vaccines contain inactivated whole virus, either of the Neudoerfl or Karlsruhe (K23) strains of the TBEV-Eu subtype, and induce a strong neutralizing antibody seroconversion rate in fully immunized individuals. Despite genetic differences between the subtypes, they are similar enough to produce effective cross-immunity for the TBEV-Sib and TBEV-FE subtypes in individuals vaccinated with a vaccine derived from the TBEV-Eu subtype.