Tick-borne encephalitis : prognosis, immunization and virus strain characterization

The aims were to investigate the morbidity associated with tick-borne encephalitis (TBE) both in the acute phase and at long-term follow-up, to develop a rapid neutralization test for confirmation of TBEV-specific antibody response and to study the serological response after TBE-vaccination and, finally, to characterize Swedish human TBEV isolates.

The morbidity was studied in one retrospective follow-up study of consecutive TBE-patients, treated during a 10-year period (Paper 1) and in one prospective study of TBE-patients with aseptic meningoencephalitis of non-TBE etiology as a reference group (Paper II).

The retrospective study with applied neuropsychiatric questionnaire comprised 114/143 individuals followed for 47 months (20-133 months). Two elderly men were dead due to TBE. Of the remaining 112 individuals 40 (36%) were left with residual TBE related symptoms, in 31 classified as moderate or severe. The most common complaints were cognitive/neuropsychiatric symptoms, balance/coordination disturbances, headache and hearing loss/tinnitus. Three patients had permanent paralysis. A vast majority of the TBE patients had contracted the infection during leisure time and were permanent residents or visited endemic regions on regular basis. Half of them were aware of other TBE-cases in their environment.

The prospective follow-up study in 85/108 TBE-patients and 64/488 non-TBE patients confirmed the existence of a post-encephalitic syndrome after TBE. 40% of TBE patients and 20% of the non-TBE patients (p=0.006) were left with residual symptoms after one year e.g. various cognitive dysfunctions, ataxia/tremor, dysphasia and headache. Nine TBE patients developed paresis, of which 5 cases persisted after one year (tetraparesis and bilateral shoulder paresis). The TBE patients had longer hospitalization-time and sick-leave, more intense blood-CSF-barrier damage and more pronounced intrathecal IgG-production compared to patients in the reference group. No CSF parameter was found useful as a prognostic marker.

A rapid neutralization test (RFFIT) was developed and found sensitive and specific for confirmation of TBEV-specific antibody response (Paper III). The assay had high performance stability and took just one day to perform, in contrast to PRNT which was unstable and time-consuming. The test is useful in seroprevalence studies for confirmation of TBE-specific activity in ELISA reactive samples, for evaluation of TBE immunity and for the diagnosis of TBE patients previously exposed to other flaviviruses.

The RFFIT with a Swedish human TBEV-isolate proved to be more sensitive than ELISA or HI to measure the antibody response to TBE-vaccination (FSME-ImmunTM Inject, Baxter) in 535 randomly selected adult persons (Paper IV). The emphasis of the study was laid on long-term follow-up from the 3rd until 3 years after the 5th, dose. At the time of the 3rd dose, 77% of the vaccinees had neutralizing antibody activity and at the time of the 4th-6th doses in 89-95%. The corresponding figures after the 3rd dose was >90%, and after doses 4 and 5 >98%. Based on our data and previous experience of vaccine failures after two doses, a more condensed three-dose primary vaccination schedule may be advantageous. Judging from antibody persistence, it seems justified to initiate studies of antibody persistence after the 4th dose for periods beyond the recommended three-year booster interval.

Swedish TBEV strains have previously not been characterized. 17 human strains were studied, isolated from acute phase serum of TBE patients, three from 1958-1966 and 14 from 1991-1994 (Paper V). Serological characterization using a panel of E-specific mouse MAbs and cross-neutralization indicated that the strains belonged to the Western TBEV subtype which includes the Austrian vaccine strain Neudoerfl. Genetic analysis of a partial E-sequence confirmed the close relationship: all Swedish strains belonged to the Western TBEV lineage. When comparing the almost complete sequence of the E-gene of two Swedish strains with the Neudoerfl strain only one conservative amino acid substitution was found. This close similarity and the neutralizing activity to a local strain evoked by the vaccine indicate that the vaccine available in Sweden ought to induce a proper protection. A correlation between the phylogenetic relationships and the geographical origin of the strains was indicated, but genetic data or geographic origin did not correlate to severity of disease.

List of scientific papers

I. Haglund M, Forsgren M, Lindh G, Lindquist L (1996). "A 10-year follow-up study of tick-borne encephalitis in the Stockholm area and a review of the literature: need for a vaccination strategy. " Scand J Infect Dis 28(3): 217-24
https://pubmed.ncbi.nlm.nih.gov/8863349

II. Gunther G, Haglund M, Lindquist L, Forsgren M, Skoldenberg B (1997). "Tick-bone encephalitis in Sweden in relation to aseptic meningo-encephalitis of other etiology: a prospective study of clinical course and outcome. " J Neurol 244(4): 230-8
https://pubmed.ncbi.nlm.nih.gov/9112591

III. Vene S, Haglund M, Vapalahti O, Lundkvist A (1998). "A rapid fluorescent focus inhibition test for detection of neutralizing antibodies to tick-borne encephalitis virus. " J Virol Methods 73(1): 71-5
https://pubmed.ncbi.nlm.nih.gov/9705177

IV. Haglund M, Vene S, Lundkvist A, Lindquist L, Forsgren M (2000). "Study of the serological response after caccination against Tick-borne encephalitis in Sweden." (Manuscript)

V. Haglund M, Vene S, Forsgren M, Gunther G, Johansson B, Niedrig M, Plyusnin A, Lindquist L, Lundkvist A (2000). "Characterization of human Tick-borne encephalitis virus from Sweden." (Manuscript)