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Chapter 2b: The molecular and antigenic structure of TBEV

viruses only, a feature observed especially with Pairwise comparisons of individual strains from
dengue viruses. 35, 103 different subtypes show that the differences are
relatively small (Figure 5B). Variation observed
Antigenic relationships of TBEV with within the subtypes is even smaller, and does
other flaviviruses not exceed 1.8% for the European subtype.

Even the most distantly related flaviviruses have The low degree of antigenic variation is an
approximately 40% identical amino acids in important aspect of vaccine usage. Experiments
their E proteins (Figure 5A). Most of these with serum samples obtained after vaccination
residues, however, are located inside the with a European subtype TBE vaccine revealed
protein whereas most of the surface-exposed no differences in the neutralization of
and antigenically relevant residues differ among European, Siberian or Far Eastern TBEV subtype
flaviviruses from different serocomplexes. This strains, whereas neutralization of the closely
is visualized in a comparison of such residues in related OHF virus (Figure 5A), was somewhat
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E of TBEV versus that of dengue virus serotype 2 reduced. In a related study, a high degree of
(Figure 5B, panel I) which shows that almost the cross-protection between TBEV subtypes was
whole surface is different, explaining the lack of also observed in mouse challenge experiments
cross-neutralization between TBEV and flavi- after immunization with vaccines based on
105,108
viruses of other serocomplexes (Figure 5A). The European or Far-Eastern subtype strains. It
only patch of conservation includes the fusion was therefore concluded that a single vaccine
loop, which is cryptic in TBEV and therefore will protect against all TBEV strains circulating in
inaccessible for antibodies (see above). nature, similar to the situation with vaccines
against other flaviviruses such as JEV and YFV.
Cross-neutralization is, however observed
within the TBEV serocomplex (Figure 5A), which Overall, the degree of cross-neutralization by
also includes Louping Ill, Langat, Omsk polyclonal sera within the TBEV serocomplex
hemorrhagic fever, Kyasanur Forest disease, (and other flavivirus serocomplexes) seems to
and Powassan viruses. These viruses display a follow the degree of amino acid conservation in
higher degree of conserved patches of amino E (Figure 5A). Observations made with some
acids at their surface that is responsible for flaviruses, however, indicate that differences at
cross-neutralization. Powassan virus is the most single amino acids can lead to substantial
distant relative of TBEV in this serocomplex with differences in virus neutralization, presumably
approximately 20% sequence divergence in E due to influences of such mutations on virus
(Figure 5A). envelope dynamics and the accessibility of
certain epitopes. 109,110 A similar variation,
TBEV subtypes and strains related to a single amino acid difference in E,
was reported in a comparative study of vaccines
Comparison of virus strains from all areas of that use different strains as seed viruses for
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TBEV endemicity have revealed three major vaccine production. Differences were found
subtypes [European, Siberian, and Far in the induction of antibodies that neutralize
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Eastern ] which are sometimes also referred circulating strains of TBEV that could be related
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to as genotypes. Additional heterogeneity to a single amino acid difference (N52K) at the
may exist and two further genetic lineages have hinge region between DI and DII.
been described. 104,105 Overall, the amino acid
sequence divergence observed in the E proteins Fine specificities of antibody responses
of different TBEV subtypes does not exceed to TBEV
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6.9%. This is within the range of natural
variation observed with other human- The mapping of epitopes in the E protein of
pathogenic flaviviruses (e.g. YFV 5%; WNV 7%). TBEV and other flaviviruses with mAbs has
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