Molecular Basis of the Divergent Immunogenicity of Two Pediatric Tick-Borne Encephalitis Virus Vaccines

Abstract

Studies evaluating the immunogenicity of two pediatric tick-borne encephalitis virus (TBEV) vaccines have reported contradictory results. These vaccines are based on two different strains of the European TBEV subtype: FSME-Immun Junior is based on the Neudörfl (Nd) strain, whereas Encepur Children is based on the Karlsruhe (K23) strain. The antibody (Ab) response induced by these two vaccines might be influenced by antigenic differences in the envelope (E) protein, which is the major target of neutralizing antibodies. We used an established hybrid virus assay platform to compare the levels of induction of neutralizing antibodies against the two vaccine virus strains in children aged 1 to 11 years who received two immunizations with FSME-Immun Junior or Encepur Children. The influence of amino acid differences between the E proteins of the Nd and K23 vaccine strains was investigated by mutational analyses and three-dimensional computer modeling. FSME-Immun Junior induced 100% seropositivity and similar neutralizing antibody titers against hybrid viruses containing the TBEV E protein of the two vaccine strains. Encepur Children induced 100% seropositivity only against the hybrid virus containing the E protein of the homologous K23 vaccine strain. Antibody responses induced by Encepur Children to the hybrid virus containing the E protein of the heterologous Nd strain were substantially and significantly (P < 0.001) lower than those to the K23 vaccine strain hybrid virus. Structure-based mutational analyses of the TBEV E protein indicated that this is due to a mutation in the DI-DII hinge region of the K23 vaccine strain E protein which may have occurred during production of the vaccine seed virus and which is not present in any wild-type TBE viruses.IMPORTANCE Our data suggest that there are major differences in the abilities of two European subtype pediatric TBEV vaccines to induce antibodies capable of neutralizing heterologous TBEV strains. This is a result of a mutation in the DI-DII hinge region of the E protein of the K23 vaccine virus strain used to manufacture Encepur Children which is not present in the Nd strain used to manufacture FSME-Immun Junior or in any other known naturally occurring TBEVs.

The envelope protein of tick-borne encephalitis virus influences neuron entry, pathogenicity, and vaccine protection

“…This amino acid is found in the K23 vaccine strain (GenBank accession no. AM600965.1) [44]; however, this is the only TBEV strain found in the database (GenBank) sequenced that contains this amino acid in that position (www.viprbrc. org).…”

The Envelope Protein of Tick-Borne Encephalitis Virus Influence Neuron Entry, Pathogenicity and Vaccine Protection

“…Interestingly, FSME-IMMUN® was shown to the neutralize Swedish strains better compared to Encepur®, where some sera showed borderline neutralizing titers after Encepur vaccination and one serum did not neutralize 93/783 at all. A previous study found that the amino acid K52 is very important for efficient neutralization by Encepur®, this amino acid is found in the K23 vaccine strain [53], however, this is the only TBEV strain found in the gene bank database sequenced that contains this amino acid in that position (www.viprbrc.org). This could also explain why the Swedish isolates which lacks the K52 are not neutralized as efficiently by Encepur®.…”

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

“…Interestingly, one mutation in the EDI/EDII hinge region in the K23 vaccine seed virus (used for manufacturing of Encepur) was identified to be responsible for reduced VN antibody titers against heterologous Neudoerfl virus (vaccine strain used for manufacturing of FSME-IMMUN) of sera received from children vaccinated with Encepur Children. In contrast, sera of children immunized with FSME-IMMUN Junior showed comparable high levels of VN antibodies against both TBEV strains [ 136 ].…”