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Epidemiological and Ecological Studies of Tick-borne Encephalitis Virus
Linköping University, Department of Clinical and Experimental Medicine, Division of Microbiology and Molecular Medicine. Linköping University, Faculty of Health Sciences.
2014 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

Ticks are blood-sucking parasites that are an inconvenience for both humans and animals. The tick by itself is normally harmless unless they attack in excessive numbers. The harm from ticks stems from them being excellent vectors for other parasites, in the form of bacteria and virus that via the ticks are provided a bridge to move across the blood streams of different animals, including humans.

One of the most pathogenic tick-borne disease for humans is caused by a flavivirus, the tick-borne encephalitis virus (TBEV). Each year approximately 10 000 individuals on the Eurasian continent develop neurological disease, in the form of meningitis, encephalitis, myelitis and radiculitis, following a bite by a TBEV infected tick.

To evaluate the risk of TBEV infection after a tick-bite, we have developed a study to investigate ticks that have bitten humans and to follow up the tick-bitten humans to investigate if they get infected, and if they develop symptoms, and further trace the virus back to the tick that is infected with TBEV. Ticks, blood samples, and questionnaires were collected in collaboration with 34 primary health care centers in Sweden and on the Åland Islands during 2008 and 2009.

Several demographical and biological factors were investigated regarding the interaction between ticks and humans. The main finding was that men removed the ticks later than women, and that both older men and older women removed the ticks later than younger individuals. This could in part explain why older individuals in general, and men in particular, are at greater risk of acquiring tick-borne encephalitis (TBE).

Furthermore, the prevalence of TBEV in ticks that have bitten humans were investigated, in order to correlate the copy number of TBEV in the tick and the tick feeding-time to the risk of developing symptomatic and asymptomatic infection. This entailed the development of new methodology for tick analysis and TBEV real-time PCR. The result showed a very low risk of TBEV infection in the studied areas, only 5 of 2167 investigated ticks contained TBEV. Three of the individuals bitten by TBEV infected ticks were vaccinated and did not develop symptoms of TBEV infection. One unvaccinated individual got bitten by a tick containing 1800 virus copies, with a feeding-time of 12-24h, and interestingly showed no signs of infection. Another unvaccinated individual got bitten by a tick containing 7.7 million virus copies, with a feedingtime of >60h. This individual developed symptoms consistent with a 1st phase of TBE, including fever and headache, but did not develop the 2nd neurological phase of TBEV infection. Despite only  finding 5 ticks infected with TBEV, a correlation between the virus load in the tick and the tick feeding-time was observed. In 2 other individuals, TBEV antibody seroconversion was detected during the 3 month study period, one without symptoms, while the other experienced symptoms consistent with the 1st phase of TBE. These observations support the hypothesis that a higher virus amount in the tick and a longer feeding time increases the risk of TBEV infection.

To further examine TBEV in ticks that have bitten humans and find factors that may predict the risk of human infection and development of TBE, we characterized several TBEV strains genetically. Including TBEV strains isolated from ticks that have bitten human, from questing field-collected ticks, and TBEV strains isolated from patients with TBE. In one of the ticks detached from a human after >60h of feeding, there was a heterogeneous population of TBEV quasispecies with varying poly(A) length in the 3’ untranslated region of the genome was observed. These variations might have implications for differences in virulence between TBEV strains, and the heterogeneous quasispecies population observed could be the virus adapting from replication in tick cells to mammalian cells.

We also investigated the response to TBEV vaccination in relation to 14 health-related factors in a population of older individuals on the Åland Islands. Blood samples, questionnaires, and vaccination records were collected from 533 individuals. Three different serological assays to characterize antibody response to TBEV vaccination were used. The main finding was that the number of vaccine doses in relation to age was the most important factor determining successful vaccination. The response to each vaccination dose declined linearly with age, and as much as 47%  of individuals 50 years or older that had taken 3 vaccine doses were seronegative, compared to 23% that had taken 4 doses and 6% with 5 doses. Comparison between the serological assays revealed that the cutoffs determining the balance between sensitivity and specificity differed, but not the overall accuracy.

Taken together, these results contribute to a better understanding of the TBEV epidemiology and can provide tools in the prevention of TBE.

Place, publisher, year, edition, pages
Linköping: Linköping University Electronic Press, 2014. , 72 p.
Series
Linköping University Medical Dissertations, ISSN 0345-0082 ; 1399
National Category
Medical and Health Sciences
Identifiers
URN: urn:nbn:se:liu:diva-105921DOI: 10.3384/diss.diva-105921ISBN: 978-91-7519-381-6 (print)OAI: oai:DiVA.org:liu-105921DiVA: diva2:712234
Public defence
2014-05-21, Berzeliussalen, Hälsouniversitetet, Campus US, Linköpings universitet, Linköping, 09:00 (English)
Opponent
Supervisors
Available from: 2014-04-14 Created: 2014-04-14 Last updated: 2014-04-14Bibliographically approved
List of papers
1. Ixodes ricinus ticks removed from humans in Northern Europe: seasonal pattern of infestation, attachment sites and duration of feeding
Open this publication in new window or tab >>Ixodes ricinus ticks removed from humans in Northern Europe: seasonal pattern of infestation, attachment sites and duration of feeding
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2013 (English)In: Parasites & Vectors, ISSN 1756-3305, E-ISSN 1756-3305, Vol. 6, no 362Article in journal (Refereed) Published
Abstract [en]

BACKGROUND:

The common tick Ixodes ricinus is the main vector in Europe of the tick-borne encephalitis virus and of several species of the Borrelia burgdorferi sensu lato complex, which are the etiological agents of Lyme borreliosis. The risk to contract bites of I. ricinus is dependent on many factors including the behaviour of both ticks and people. The tick's site of attachment on the human body and the duration of tick attachment may be of clinical importance. Data on I. ricinus ticks, which were found attached to the skin of people, were analysed regarding potentially stage-specific differences in location of attachment sites, duration of tick attachment (= feeding duration), seasonal and geographical distribution of tick infestation in relation to age and gender of the tick-infested hosts.

METHODS:

During 2008-2009, 1770 tick-bitten persons from Sweden and the Åland Islands removed 2110 I. ricinus ticks. Participants provided information about the date of tick detection and location on their body of each attached tick. Ticks were identified to species and developmental stage. The feeding duration of each nymph and adult female tick was microscopically estimated based on the scutal and the coxal index.

RESULTS:

In 2008, participants were tick-bitten from mid-May to mid-October and in 2009 from early April to early November. The infestation pattern of the nymphs was bimodal whereas that of the adult female ticks was unimodal with a peak in late summer. Tick attachment site on the human body was associated with stage of the tick and gender of the human host. Site of attachment seemed to influence the duration of tick feeding. Overall, 63% of nymphs and adult female ticks were detected and removed more than 24 hours after attachment. Older persons, compared to younger ones, and men, compared to women, removed "their" ticks after a longer period of tick attachment.

CONCLUSIONS:

The infestation behaviour of the different tick stages concerning where on the host's body the ticks generally will attach and when such ticks generally will be detected and removed in relation to host age and gender, should be of value for the development of prophylactic methods against tick infestation and to provide relevant advice to people on how to avoid or reduce the risk of tick infestation.

Place, publisher, year, edition, pages
BioMed Central, 2013
Keyword
Ixodes ricinus; Tick infestation; Tick bite; Attachment site; Feeding behaviour; Feeding duration; Host-seeking behaviour; Seasonal activity; Sweden; Åland
National Category
Medical and Health Sciences
Identifiers
urn:nbn:se:liu:diva-103499 (URN)10.1186/1756-3305-6-362 (DOI)000330064200001 ()24360096 (PubMedID)
Available from: 2014-01-20 Created: 2014-01-20 Last updated: 2017-12-06Bibliographically approved
2. Tick-borne encephalitis virus in ticks detached from humans and follow-up of serological and clinical response.
Open this publication in new window or tab >>Tick-borne encephalitis virus in ticks detached from humans and follow-up of serological and clinical response.
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2014 (English)In: Ticks and Tick Borne Diseases, ISSN 1877-959X, Vol. 5, no 1, 21-28 p.Article in journal (Refereed) Published
Abstract [en]

The risk of tick-borne encephalitis virus (TBEV) infection after a tick bite remains largely unknown. To address this, we investigated the presence of TBEV in ticks detached from humans in an attempt to relate viral copy number, TBEV subtype, and tick feeding time with the serological and clinical response of the tick-bitten participants. Ticks, blood samples, and questionnaires were collected from tick-bitten humans at 34 primary health care centers in Sweden and in the Aland Islands (Finland). A total of 2167 ticks was received from 1886 persons in 2008-2009. Using a multiplex quantitative real-time PCR, 5 TBEV-infected ticks were found (overall prevalence 0.23%, copy range <4 X 10(2)-7.7 X 10(6) per tick). One unvaccinated person bitten by a tick containing 7.7 x 10(6) TBEV copies experienced symptoms. Another unvaccinated person bitten by a tick containing 1.8 x 10(3) TBEV copies developed neither symptoms nor TBEV antibodies. The remaining 3 persons were protected by vaccination. In contrast, despite lack of TBEV in the detached ticks, 2 persons developed antibodies against TBEV, one of whom reported symptoms. Overall, a low risk of TBEV infection was observed, and too few persons got bitten by TBEV-infected ticks to draw certain conclusions regarding the clinical outcome in relation to the duration of the blood meal and virus copy number. However, this study indicates that an antibody response may develop without clinical symptoms, that a bite by an infected tick not always leads to an antibody response or clinical symptoms, and a possible correlation between virus load and tick feeding time. (C) 2013 Elsevier GmbH. All rights reserved.

Place, publisher, year, edition, pages
Jena, Germany: Elsevier, 2014
National Category
Microbiology in the medical area
Identifiers
urn:nbn:se:liu:diva-103491 (URN)10.1016/j.ttbdis.2013.07.009 (DOI)000329007300004 ()24275477 (PubMedID)
Available from: 2014-01-20 Created: 2014-01-20 Last updated: 2015-08-10Bibliographically approved
3. Determining factors for successful vaccination against tick-borne encephalitis virus in older individuals
Open this publication in new window or tab >>Determining factors for successful vaccination against tick-borne encephalitis virus in older individuals
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2014 (English)Manuscript (preprint) (Other academic)
Abstract [en]

We performed a cross-sectional study including 533 persons (median age 61) from the highly TBE endemic Åland Islands in the archipelago between Sweden and Finland. Blood samples, questionnaires and vaccination records were obtained from all study participants. The aim was to investigate if there was any association between TBEV antibody titer and 14 healthrelated factors: [age, gender, number of vaccine doses (0-5), time since last vaccine dose, previous TBE disease, vaccination against other flaviviruses, ≥2 tick-bites during the previous 3 months, pet-ownership, asthma, smoking, allergy, diabetes, medication, and previous tumor]. Measurement of TBEV IgG antibodies was performed using two commercial ELISA assays (Enzygnost and Immunozym), and a third in-house rapid fluorescent focus inhibition test was used to measure TBEV neutralizing antibodies. The age of the person and the number of vaccine doses were the two most important factors determining successful vaccination. The response to each vaccine dose declined linearly with increased age. A 35 year age difference corresponds to a vaccine dose increment from 3 to 4 to achieve the same response. Participants receiving medication and participants previously vaccinated against other flaviviruses had lower TBEV antibody titers on average, while those with self-reported asthma had higher titers. By comparing the 3 serological assays we show that the Enzygnost and Immunozym assay differ due to choice of cutoffs, but not in overall accuracy.

National Category
Medical and Health Sciences
Identifiers
urn:nbn:se:liu:diva-105919 (URN)
Available from: 2014-04-14 Created: 2014-04-14 Last updated: 2014-04-14Bibliographically approved
4. Tick-borne encephalitis virus sequenced directly from questing and blood-feeding ticks reveals quasispecies variance
Open this publication in new window or tab >>Tick-borne encephalitis virus sequenced directly from questing and blood-feeding ticks reveals quasispecies variance
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2014 (English)In: PLoS ONE, ISSN 1932-6203, E-ISSN 1932-6203, Vol. 9, no 7, e103264- p.Article in journal (Refereed) Published
Abstract [en]

The increased distribution of the tick-borne encephalitis virus (TBEV) in Scandinavia highlights the importance of characterizing novel sequences within the natural foci. In this study, two TBEV strains: the Norwegian Mandal 2009 (questing nymphs pool) and the Swedish Saringe 2009 (blood-fed nymph) were sequenced and phylogenetically characterized. Interestingly, the sequence of Mandal 2009 revealed the shorter form of the TBEV genome, similar to the highly virulent Hypr strain, within the 3´ non-coding region (3´NCR). A different genomic structure was found in the 3´NCR of Saringe 2009, as in-depth analysis demonstrated TBEV variants with different lengths within the poly(A) tract. This shows that TBEV quasispecies exists in nature and indicates a putative shift in the quasispecies pool when the virus switches between invertebrate and vertebrate environments. This prompted us to further sequence and analyze the 3´NCRs of additional Scandinavian TBEV strains and controls, Hypr and Neudoerfl. Toro 2003 and Habo 2011 contained mainly a short (A)3C(A)6 poly(A)  tract. A similar pattern was observed for the human TBEV isolates 1993/783 and 1991/4944; however, one clone of 1991/4944 contained an (A)3C(A)11 poly(A) sequence, demonstrating that quasispecies with longer poly(A) could be present in human isolates. Neudoerfl has previously been reported to contain a poly(A) region, but to our surprise the re-sequenced genome contained two major quasispecies variants, both lacking the poly(A) tract. We speculate that the observed differences are important factors for the understanding of virulence, spread, and control of the TBEV.

Place, publisher, year, edition, pages
Public Library of Science, 2014
National Category
Medical and Health Sciences
Identifiers
urn:nbn:se:liu:diva-105920 (URN)10.1371/journal.pone.0103264 (DOI)000341354800074 ()25058476 (PubMedID)
Available from: 2014-04-14 Created: 2014-04-14 Last updated: 2017-12-05Bibliographically approved

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