title: 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.
  
  
  OBJECTIVE
  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.
authors.affiliation: Vaccine R&D, Baxter Bioscience, Orth an der Donau, Austria Pfizer Biotech, Dublin, Ireland.
authors.forename: Yvonne
authors.initials: Y
authors.lastname: Beck
authors.affiliation: Vaccine R&D, Baxter Bioscience, Orth an der Donau, Austria.
authors.forename: Richard
authors.initials: R
authors.lastname: Fritz
authors.affiliation: Vaccine R&D, Baxter Bioscience, Orth an der Donau, Austria.
authors.forename: Klaus
authors.initials: K
authors.lastname: Orlinger
authors.affiliation: Vaccine R&D, Baxter Bioscience, Orth an der Donau, Austria Pfizer Manufacturing Austria, Orth an der Donau, Austria.
authors.forename: Stefan
authors.initials: S
authors.lastname: Kiermayr
authors.affiliation: Global Quality, Baxter Bioscience, Orth an der Donau, Austria.
authors.forename: Reinhard
authors.initials: R
authors.lastname: Ilk
authors.affiliation: Vaccine R&D, Baxter Bioscience, Orth an der Donau, Austria.
authors.forename: Daniel
authors.initials: D
authors.lastname: Portsmouth
authors.affiliation: Vaccine R&D, Baxter Bioscience, Vienna, Austria.
authors.forename: Eva-Maria
authors.initials: EM
authors.lastname: Pöllabauer
authors.affiliation: Vaccine R&D, Baxter Bioscience, Vienna, Austria.
authors.forename: Alexandra
authors.initials: A
authors.lastname: Löw-Baselli
authors.affiliation: Pfizer Biotech, Dublin, Ireland.
authors.forename: Annett
authors.initials: A
authors.lastname: Hessel
authors.affiliation: Pfizer Biotech, Dublin, Ireland.
authors.forename: Doris
authors.initials: D
authors.lastname: Kölch
authors.affiliation: Vaccine R&D, Baxter Bioscience, Orth an der Donau, Austria Pfizer Biotech, Dublin, Ireland.
authors.forename: M Keith
authors.initials: MK
authors.lastname: Howard
authors.affiliation: Vaccine R&D, Baxter Bioscience, Orth an der Donau, Austria.
authors.forename: P Noel
authors.initials: PN
authors.lastname: Barrett
authors.affiliation: Vaccine R&D, Baxter Bioscience, Vienna, Austria thomas.kreil@baxalta.com.
authors.forename: Thomas R
authors.initials: TR
authors.lastname: Kreil
mesh_terms: D057134:Antibodies, Neutralizing / Q000097:blood*; D000914:Antibodies, Viral / Q000097:blood*; D002648:Child; D002675:Child, Preschool; D004252:DNA Mutational Analysis; D004355:Drug Stability; D004669:Encephalitis Viruses, Tick-Borne / Q000276:immunology*; D005260:Female; D042822:Genomic Instability; D006801:Humans; D007223:Infant; D008297:Male; D008958:Models, Molecular; D020125:Mutation, Missense; D011487:Protein Conformation; D013678:Technology, Pharmaceutical; D014759:Viral Envelope Proteins / Q000737:chemistry / Q000235:genetics / Q000276:immunology; D014765:Viral Vaccines / Q000008:administration & dosage / Q000276:immunology*
chemical_list: D057134:Antibodies, Neutralizing; D000914:Antibodies, Viral; D014759:Viral Envelope Proteins; D014765:Viral Vaccines