Bartonella bacilliformis is a facultative, intracellular, aerobic, Gram-negative coccobacillus causing the so-called Carrión's disease, a human infection endemic to specific areas mainly inhabited by low-income communities of Peru but also present in other Andean communities. It is considered a truly neglected tropical disease and is transmitted through the bite of female sandflies of the genus Lutzomyia [1]. Carrión's disease has two different clinical presentations; an initial febrile and haemolytic anaemia phase, known as Oroya fever, which has a mortality rate ranging from 44% to 88% in untreated patients; and a second phase characterised by the development of dermal eruptions known as Peruvian wart [1,2]. / The study was supported by internal funds from the Universidad Peruana de Ciencias Aplicadas (Lima, Peru); by a grant from the Instituto de Salud Carlos III, Spain [PI11/00983], which included FEDER funds; by the UBS Optimus Foundation; and by Generalitat de Catalunya, Departament d’Universitats, Recerca i Societat de la Informació [2014 SGR 26]. MJP has received a postdoctoral fellowship from CONCYTEC/FONDECYT. JR has received a fellowship from the program I3 of the ISCIII [grant no. CES11/012]. / Revisión por pares

Introdução: A OMS recomendou às Américas, em 2004, implementar e aperfeiçoar sistemas específicos de vigilância epidemiológica das rickettsioses, caracterizando as áreas de transmissão dos diferentes agravos, investindo em vigilância epidemiológica e ambiental ativas. Estas são zoonoses relacionadas aos fatores fundamentais da expansão urbana, bem como ao aumento populacional de vetores e hospedeiros em contato com a população humana. Nas regiões do Vale do Paraíba paulista não há situação de endemia reconhecida, porém esta apresenta semelhanças ambientais e socioeconômicas com outras regiões ditas endêmicas, do Estado de São Paulo, não rara é a ocorrência de carrapatos das espécies descritas como vetores de doenças e ocorre importante intercâmbio de pessoas com objetivos de trabalho e lazer ao longo desta região, inclusive com freqüente fluxo internacional. Método: Avaliação do potencial de risco de transmissão de zoonoses por carrapatos em áreas selecionadas. Através de informações ambientais, prevalência de carrapatos transmissores de zoonoses e acessibilidade da população humana a áreas infestadas, criou-se uma escala para caracterização do risco. Resultados: Em 252 áreas das 6 microrregiões do Vale do Paraíba Paulista, no período de mai./2008 a mar./ 2009, foram encontrados 7.800 carrapatos adultos, além de ninfas e larvas, muitas das quais em criações familiares de coelhos e galinheiros. A classificação final apontou 42,5% das áreas inspecionadas em situação de risco iminente de transmissão de zoonoses por carrapatos. Outros 33% correspondeu ao risco limitado ou moderado. Nos restantes 24% da área estudada a classificação foi risco potencial para transmissão rickettsioses. Recomendações: Às áreas sob risco iminente, de situação de risco de transmissão de zoonoses por carrapatos, recomenda-se que os serviços de saúde locais mantenham uma vigilância acarológica programada e orientações à população. Às áreas sob risco limitado ou moderado, recomenda-se a manutenção de rotina de vigilância acarológica e inclusão da vigilância ambiental, com envolvimento da população. Às áreas sob risco potencial para transmissão de zoonoses, recomenda-se imediata elaboração de estratégias controle para as espécies encontradas, envolvendo os setores de saúde e a população. O aprimoramento da articulação com os serviços regionais e profissionais veterinários é de fundamental importância. Além disso, a estruturação dos serviços de saúde da região, adequação da área física, recursos humanos e materiais, são indispensáveis. / Introduction: OMS recommended America, in the year of 2004, implement and to improve specific systems of epidemic surveillance of the rickettsiasis, characterizing the areas of transmission of the different offences and investing in active epidemic and environmental surveillance. Those zoonosis are related to the fundamental factors of the urban expansion, as well as to the population increase of vectors and hosts in contact with the human population. In the areas called Vale do Paraíba from State of São Paulo there is no situation of recognized endemy, however this presents environmental and socioeconomic similarities with other recognized endemic areas of the State of São Paulo, no rare it is the occurrence of ticks described as vectors of diseases and it happens important exchange of people with work and leisure purposes there, besides with frequent international flow. Method: Evaluation of potential risk of zoonosis transmission by ticks in selected categorized areas. Through environmental information, the prevalence of vector ticks and accessibility of the human population to infested areas, a scale for characterization of the risk was build. Results: In 252 areas of the 6 districts of the Vale do Paraíba, in the Estado de São Paulo, on period between may/2008 and march/ 2009, they were found 7.800 adult ticks, also nymphs and larvas, many of which in family nurturing of rabbits and hen houses. The final classification pointed 42,5% of the inspected areas corresponding to the situation of imminent risk of transmission of zoonosis by ticks. Other 33% correspond to limited risk in the scale. In the remaining 24% of the studied area the classification went potential risk for transmission of tick related rickettsiasis. Recommendations: For the imminent risk areas, it is recommended that the local health services maintain proper vector surveillance and educational programmes for its populations. For the limited risk areas, it is recommended the maintenance of a proper vector surveillance routine and also the inclusion of an environmental surveillance. For the areas under potential transmission risk of those illnesses, priority elaboration of vectors control strategies is strongly recommended with proper engagement of all local health services, as well as the population. The enhancement of the articulation with the regional services and professional veterinarians is fundamental. Besides, an adequate structuring for the local health services administration, with rational and efficient managing of material and human resources, is indispensable.

It is generally assumed that when natural habitat is converted to human-dominated cover such area is “lost” to its native species. Extinctions will ensue. The literature generally assumes that species are extirpated as natural area is reduced, following the well-known species-area relationship (SAR). However, SARs have consistently over-estimated species losses resulting from conversion of natural habitat to human-dominated land covers. We hypothesize that the overestimation occurs because these area-based models assume that converted habitat is “lost”, eliminating all species. However, in the real world, conversion of natural land cover to human-dominated cover frequently produces new land covers, different from the original habitat, but not necessarily completely inhospitable to biodiversity. We evaluated the responses of total avian richness, forest bird richness and open habitat bird richness to remaining natural area within 991 quadrats, each 100 km2, across southern Ontario. Total bird species richness does not follow SAR predictions; rather, the number of bird species peaks at roughly 50% natural land cover. The richness of forest birds does follow the usual SAR power-law as a function of forested area. In contrast, richness of birds that prefer open-habitat does not increase monotonically with either natural- or human-dominated land cover. However, we can partition human-dominated land cover into an “available human-dominated” component and “lost” habitat. Richness of open-habitat species relates to the amount of available human-dominated cover. Distinguishing three habitat types (natural, available human-dominated, and lost) permits accurate predictions of species losses in response to natural habitat conversion.

A esquistossomose mansoni apresenta-se como uma doenÃa parasitÃria de importÃncia para a saÃde pÃblica, nÃo sà por sua ampla distribuiÃÃo no mundo, mas tambÃm pelos impactos causados por ela nas atividades da populaÃÃo infectada. A esquistossomose deve ser analisada como um processo dependente da interaÃÃo de vÃrios fatores, como fatores ambientais, sociais e econÃmicos, importantes para reduzir a transmissÃo da doenÃa bem como para interromper o ciclo do parasito. O objetivo do estudo foi avaliar a influÃncia de fatores ambientais e socioculturais na transmissÃo da esquistossomose em Ãrea de baixa endemicidade no Estado do CearÃ, na localidade do Planalto do Cajueiro, atravÃs da anÃlise de questionÃrios aplicados no ano de 2009 e em 2012. O estudo foi desenvolvido em duas etapas. A primeira consiste em um estudo transversal, onde foram analisados 167 questionÃrios dos pacientes que forneceram material sorolÃgico para a realizaÃÃo do mÃtodo ELISA, que serviu como triagem. A segunda etapa consiste em um estudo de caso controle, onde foram aplicados e analisados questionÃrios em 54 indivÃduos ELISA reativo e nÃo reativo que entregaram amostra fecal para anÃlise. As anÃlises dos questionÃrios das 167 pessoas mostraram que a maioria delas eram adultos jovens (19,76% na faixa etÃria de 15 a 25anos e 29,94% entre 26 a 46 anos), do sexo feminino (67,66%) e que 29% nÃo eram naturais de Maranguape. Em torno de 52,5% dos pacientes que afirmaram utilizar Ãgua do rio, tiveram resultado Elisa reativo para esquistossomose. Na segunda etapa, observou-se que a diferenÃa entre os sexos masculinos e femininos era insignificante, nos casos positivos para esquistossomose. Com relaÃÃo à escolaridade, a maioria (68,32%) possuÃa apenas o ensino fundamental incompleto. Nas associaÃÃes entre variÃveis ambientais e resultado positivo para a doenÃa, observou-se que 34,2% dos indivÃduos responderam nÃo ter contato com coleÃÃes hÃdricas e 37,5% disseram que tiveram contato. Este ponto ainda està em anÃlise mais aprofundada. A comunidade do Planalto do Cajueiro em Maranguape-CE mantÃm caracterÃsticas ambientais semelhantes à de comunidades rurais (mesmo sendo peri-urbana) e a transmissÃo da esquistossomose sofre grande influencia dos fatores comportamentais. / Schistosomiasis mansoni is presented as a parasitic disease of public health importance, not only for its wide distribution in the world, but also the impacts caused by it in the activities of the infected population. Schistosomiasis should be analyzed as a process dependent on the interaction of various factors, such as environmental, social and economic importance to reduce transmission of the disease and to stop the cycle of the parasite. The aim of the study was to evaluate the influence of environmental and sociocultural factors in the transmission of schistosomiasis in low endemic area in the state of CearÃ, in the locality of the Planalto do Cajueiro- Maranguape-Ce, through the analysis of questionnaires applied in 2009 and 2012. The study was conducted in two stages. The first consists of a cross-sectional study, which analyzed 167 questionnaires from patients who provided material for the realization of the serological ELISA, which served as a screen. The second stage consists of a case-control study where questionnaires were applied and analyzed in 54 individuals ELISA reactive and nonreactive who delivered fecal sample for analysis. The analysis of the questionnaires of 167 people showed that most of them were young adults (19.76% in the age group of 15 to 25years and 29.94% between 26-46 years), female (67.66%) and 29% were not natives of Maranguape. Around 52.5% of patients reported using water from the river, had reactive ELISA result for schistosomiasis. In the second stage, it was observed that the difference between male and female sexes was negligible in cases positive for schistosomiasis. With regard to education, the majority (68.32%) had only elementary education. Associations between environmental variables and positive for the disease, it was observed that 34.2% of subjects reported not to have contact with water collections and 37.5% said they had contact. This point is still under further investigation. The community of Planalto do Cajueiro, Maranguape-Ce maintains environmental characteristics similar to rural communities (even as peri-urban) and schistosomiasis transmission is greatly influences behavioral factors.

Introdução: A OMS recomendou às Américas, em 2004, implementar e aperfeiçoar sistemas específicos de vigilância epidemiológica das rickettsioses, caracterizando as áreas de transmissão dos diferentes agravos, investindo em vigilância epidemiológica e ambiental ativas. Estas são zoonoses relacionadas aos fatores fundamentais da expansão urbana, bem como ao aumento populacional de vetores e hospedeiros em contato com a população humana. Nas regiões do Vale do Paraíba paulista não há situação de endemia reconhecida, porém esta apresenta semelhanças ambientais e socioeconômicas com outras regiões ditas endêmicas, do Estado de São Paulo, não rara é a ocorrência de carrapatos das espécies descritas como vetores de doenças e ocorre importante intercâmbio de pessoas com objetivos de trabalho e lazer ao longo desta região, inclusive com freqüente fluxo internacional. Método: Avaliação do potencial de risco de transmissão de zoonoses por carrapatos em áreas selecionadas. Através de informações ambientais, prevalência de carrapatos transmissores de zoonoses e acessibilidade da população humana a áreas infestadas, criou-se uma escala para caracterização do risco. Resultados: Em 252 áreas das 6 microrregiões do Vale do Paraíba Paulista, no período de mai./2008 a mar./ 2009, foram encontrados 7.800 carrapatos adultos, além de ninfas e larvas, muitas das quais em criações familiares de coelhos e galinheiros. A classificação final apontou 42,5% das áreas inspecionadas em situação de risco iminente de transmissão de zoonoses por carrapatos. Outros 33% correspondeu ao risco limitado ou moderado. Nos restantes 24% da área estudada a classificação foi risco potencial para transmissão rickettsioses. Recomendações: Às áreas sob risco iminente, de situação de risco de transmissão de zoonoses por carrapatos, recomenda-se que os serviços de saúde locais mantenham uma vigilância acarológica programada e orientações à população. Às áreas sob risco limitado ou moderado, recomenda-se a manutenção de rotina de vigilância acarológica e inclusão da vigilância ambiental, com envolvimento da população. Às áreas sob risco potencial para transmissão de zoonoses, recomenda-se imediata elaboração de estratégias controle para as espécies encontradas, envolvendo os setores de saúde e a população. O aprimoramento da articulação com os serviços regionais e profissionais veterinários é de fundamental importância. Além disso, a estruturação dos serviços de saúde da região, adequação da área física, recursos humanos e materiais, são indispensáveis. / Introduction: OMS recommended America, in the year of 2004, implement and to improve specific systems of epidemic surveillance of the rickettsiasis, characterizing the areas of transmission of the different offences and investing in active epidemic and environmental surveillance. Those zoonosis are related to the fundamental factors of the urban expansion, as well as to the population increase of vectors and hosts in contact with the human population. In the areas called Vale do Paraíba from State of São Paulo there is no situation of recognized endemy, however this presents environmental and socioeconomic similarities with other recognized endemic areas of the State of São Paulo, no rare it is the occurrence of ticks described as vectors of diseases and it happens important exchange of people with work and leisure purposes there, besides with frequent international flow. Method: Evaluation of potential risk of zoonosis transmission by ticks in selected categorized areas. Through environmental information, the prevalence of vector ticks and accessibility of the human population to infested areas, a scale for characterization of the risk was build. Results: In 252 areas of the 6 districts of the Vale do Paraíba, in the Estado de São Paulo, on period between may/2008 and march/ 2009, they were found 7.800 adult ticks, also nymphs and larvas, many of which in family nurturing of rabbits and hen houses. The final classification pointed 42,5% of the inspected areas corresponding to the situation of imminent risk of transmission of zoonosis by ticks. Other 33% correspond to limited risk in the scale. In the remaining 24% of the studied area the classification went potential risk for transmission of tick related rickettsiasis. Recommendations: For the imminent risk areas, it is recommended that the local health services maintain proper vector surveillance and educational programmes for its populations. For the limited risk areas, it is recommended the maintenance of a proper vector surveillance routine and also the inclusion of an environmental surveillance. For the areas under potential transmission risk of those illnesses, priority elaboration of vectors control strategies is strongly recommended with proper engagement of all local health services, as well as the population. The enhancement of the articulation with the regional services and professional veterinarians is fundamental. Besides, an adequate structuring for the local health services administration, with rational and efficient managing of material and human resources, is indispensable.

It is generally assumed that when natural habitat is converted to human-dominated cover such area is “lost” to its native species. Extinctions will ensue. The literature generally assumes that species are extirpated as natural area is reduced, following the well-known species-area relationship (SAR). However, SARs have consistently over-estimated species losses resulting from conversion of natural habitat to human-dominated land covers. We hypothesize that the overestimation occurs because these area-based models assume that converted habitat is “lost”, eliminating all species. However, in the real world, conversion of natural land cover to human-dominated cover frequently produces new land covers, different from the original habitat, but not necessarily completely inhospitable to biodiversity. We evaluated the responses of total avian richness, forest bird richness and open habitat bird richness to remaining natural area within 991 quadrats, each 100 km2, across southern Ontario. Total bird species richness does not follow SAR predictions; rather, the number of bird species peaks at roughly 50% natural land cover. The richness of forest birds does follow the usual SAR power-law as a function of forested area. In contrast, richness of birds that prefer open-habitat does not increase monotonically with either natural- or human-dominated land cover. However, we can partition human-dominated land cover into an “available human-dominated” component and “lost” habitat. Richness of open-habitat species relates to the amount of available human-dominated cover. Distinguishing three habitat types (natural, available human-dominated, and lost) permits accurate predictions of species losses in response to natural habitat conversion.

Einleitung Die Frühsommer-Meningoenzephalitis (FSME) zählt europaweit zu den bedeutendsten Zecken-übertragenen Krankheiten und ist verantwortlich für mehrere tausend Tote jedes Jahr. Hauptüberträger in Zentraleuropa ist Ixodes ricinus, der Gemeine Holzbock. In Deutschland konzentrieren sich die humanen Fälle vorrangig auf Süddeutschland mit anteilig 83,8% der Fälle, wobei anhand einer Falldefinition, die sich auf humane Meldedaten stützt, Risikogebiete definiert werden. Dabei wird ein Landkreis dann als Risikogebiet gewertet, wenn in einem Fünf-Jahresintervall die Inzidenz von einem Fall pro 100.000 Einwohnern pro Jahr überschritten wird. In Sachsen erscheint diese Risikoabschätzung erschwert, da hier nur wenige sporadische Fälle gemeldet werden. Jedoch wurde im April 2014 der Vogtlandkreis als erstes sächsisches Risikogebiet ernannt. Ziele der Untersuchungen Eine Risikobewertung, die sich alleine auf humane gemeldete Erkrankungsfälle stützt, erscheint überholt, weshalb schon in der Vergangenheit nach einem optimalen Sentineltier für Seroprävalenzstudien gesucht wurde. Im Rahmen dieser Dissertation wurden zwei Veröffentlichungen angefertigt, in denen mithilfe von Seroprävalenzstudien bei Wildtieren und bei Hunden das Risiko für eine Infektion mit der FSME in Sachsen bewertet werden sollte. Materialien und Methoden In der ersten Veröffentlichung wurden 1.886 Wildtierseren, vorrangig von Wildschweinen, auf das Vorhandensein von Antikörpern gegen das FSMEV untersucht. Die zweite Veröffentlichung befasste sich mit 331 Seren von Hunden, die Sachsen in den letzten fünf Jahren nicht verlassen hatten. Für die Untersuchung wurde zunächst ein ELISA (Enzyme-linked-immunosorbent Assay) und zur Bestätigung der positiven Proben ein SNT (Serumneutralisationstest) durchgeführt. Ergebnisse Bei den Wildtierseren wurde eine Gesamtprävalenz von 10,5% ermittelt. Im aktuell ernannten Risikogebiet Vogtlandkreis wurden 20% seropositive Tiere gefunden, im Kreis Meißen sogar 23% flächendeckend nachgewiesen. Sieben der untersuchten Hundeseren waren positiv, wobei vier Tiere hiervon Hunde von Förstern waren. Die positiven Proben kamen aus den Landkreisen Mittelsachsen (1), Erzgebirgskreis(1), Leipziger Land (2) und Sächsische-Schweiz-Osterzgebirge (3). Schlussfolgerungen In ganz Sachsen konnten Antikörper gegen das FSMEV gefunden werden was auf ein flächendeckendes Vorkommen des Virus in Sachsen hinweist. Die Eignung von Wildtieren und Hunden als Sentinels wurde bestätigt. Die jeweiligen Vor- und Nachteile werden dargestellt. Eine stichprobenhafte Untersuchung auf FSME im Rahmen von Screeningprogrammen könnte auch zukünftig zur besseren Lokalisation von FSMEV-Naturherden in Sachsen beitragen. Weiterhin ungeklärt bleibt die Diskrepanz zwischen der hohen ermittelten Seroprävalenz bei den Wildtieren und den wenigen humanen gemeldeten Fällen. Auch die Hundestudie konnte hierzu keine weiteren Informationen liefern. Eine Impfung ist vor allem für Menschen sinnvoll, die sich im Vogtlandkreis aufhalten.

Einleitung Die Frühsommer-Meningoenzephalitis (FSME) zählt europaweit zu den bedeutendsten Zecken-übertragenen Krankheiten und ist verantwortlich für mehrere tausend Tote jedes Jahr. Hauptüberträger in Zentraleuropa ist Ixodes ricinus, der Gemeine Holzbock. In Deutschland konzentrieren sich die humanen Fälle vorrangig auf Süddeutschland mit anteilig 83,8% der Fälle, wobei anhand einer Falldefinition, die sich auf humane Meldedaten stützt, Risikogebiete definiert werden. Dabei wird ein Landkreis dann als Risikogebiet gewertet, wenn in einem Fünf-Jahresintervall die Inzidenz von einem Fall pro 100.000 Einwohnern pro Jahr überschritten wird. In Sachsen erscheint diese Risikoabschätzung erschwert, da hier nur wenige sporadische Fälle gemeldet werden. Jedoch wurde im April 2014 der Vogtlandkreis als erstes sächsisches Risikogebiet ernannt. Ziele der Untersuchungen Eine Risikobewertung, die sich alleine auf humane gemeldete Erkrankungsfälle stützt, erscheint überholt, weshalb schon in der Vergangenheit nach einem optimalen Sentineltier für Seroprävalenzstudien gesucht wurde. Im Rahmen dieser Dissertation wurden zwei Veröffentlichungen angefertigt, in denen mithilfe von Seroprävalenzstudien bei Wildtieren und bei Hunden das Risiko für eine Infektion mit der FSME in Sachsen bewertet werden sollte. Materialien und Methoden In der ersten Veröffentlichung wurden 1.886 Wildtierseren, vorrangig von Wildschweinen, auf das Vorhandensein von Antikörpern gegen das FSMEV untersucht. Die zweite Veröffentlichung befasste sich mit 331 Seren von Hunden, die Sachsen in den letzten fünf Jahren nicht verlassen hatten. Für die Untersuchung wurde zunächst ein ELISA (Enzyme-linked-immunosorbent Assay) und zur Bestätigung der positiven Proben ein SNT (Serumneutralisationstest) durchgeführt. Ergebnisse Bei den Wildtierseren wurde eine Gesamtprävalenz von 10,5% ermittelt. Im aktuell ernannten Risikogebiet Vogtlandkreis wurden 20% seropositive Tiere gefunden, im Kreis Meißen sogar 23% flächendeckend nachgewiesen. Sieben der untersuchten Hundeseren waren positiv, wobei vier Tiere hiervon Hunde von Förstern waren. Die positiven Proben kamen aus den Landkreisen Mittelsachsen (1), Erzgebirgskreis(1), Leipziger Land (2) und Sächsische-Schweiz-Osterzgebirge (3). Schlussfolgerungen In ganz Sachsen konnten Antikörper gegen das FSMEV gefunden werden was auf ein flächendeckendes Vorkommen des Virus in Sachsen hinweist. Die Eignung von Wildtieren und Hunden als Sentinels wurde bestätigt. Die jeweiligen Vor- und Nachteile werden dargestellt. Eine stichprobenhafte Untersuchung auf FSME im Rahmen von Screeningprogrammen könnte auch zukünftig zur besseren Lokalisation von FSMEV-Naturherden in Sachsen beitragen. Weiterhin ungeklärt bleibt die Diskrepanz zwischen der hohen ermittelten Seroprävalenz bei den Wildtieren und den wenigen humanen gemeldeten Fällen. Auch die Hundestudie konnte hierzu keine weiteren Informationen liefern. Eine Impfung ist vor allem für Menschen sinnvoll, die sich im Vogtlandkreis aufhalten.:1 Einleitung 1 2 Literaturübersicht 2 2.1 Klassifikation, Taxonomie und geschichtlicher Hintergrund 2 2.2 Aufbau des FSMEV 4 2.3 Epidemiologie 5 2.4 Übertragungswege 8 2.4.1 Zeckenstich 8 2.4.2 Alimentärer Infektionsweg 10 2.5 Rolle verschiedener Spezies als Wirte der FSME 11 2.6 Pathogenese 13 2.7 Klinik beim Menschen 14 2.8 Klinik bei Tieren 15 2.8.1 Wild 15 2.8.2 Hund 15 2.8.3 Weitere Tierarten 17 Pferd 17 Mufflon 17 Affe 17 Ziege 17 2.9 Diagnose 18 2.10 Prävalenzstudien 20 2.10.1 Wild 20 2.10.2 Hund 21 2.10.3 Weitere Tierarten 22 Pferd 22 Mäuse 22 Zecken 22 Füchse 23 Ziegen 24 Schafe 24 Rinder 24 Vögel 25 2.11 Vorbeugung und Kontrolle 26 2.11.1 Impfung beim Menschen 26 2.11.2 Impfung bei Tieren 27 2.12 Sachsen 29 3 Veröffentlichung 1 30 4 Veröffentlichung 2 42 5 Gemeinsame Diskussion und Schlussfolgerung 55 6 Zusammenfassung 59 7 Summary 61 8 Referenzen 63 Literaturverzeichnis 63 Abbildungsverzeichnis 71 Tabellenverzeichnis 71 9 Danksagung 72

Einleitung Die FSME ist die medizinisch bedeutsamste zeckenübertragene Krankheit in Europa und Asien. In Europa erkranken jährlich mehrere tausend Menschen an der FSME. Zur Seroprävalenz der FSME liegen wenige Daten vor, da seit dem Aufkommen der FSME-Impfung in den 80er Jahren in Deutschland eine Unterscheidung von Impf- und Infektionsantikörpern mittels konventioneller serologischer Methoden nicht mehr möglich war. Die Entwicklung eines neuen ELISAs im Jahr 2020, der auf dem Nichtstrukturprotein 1 (NS1) basiert, macht diese Unterscheidung möglich. Ziele der Arbeit Die Ziele der durchgeführten Studie waren die Bestimmung von epidemiologischen Zielgrößen wie Seroprävalenz, Infektions- und Immunitätsrate sowie das Generieren neuer Daten zum Manifestationsindex im endemischen Landkreis Ortenaukreis in Baden-Württemberg. Das Vorliegen historischer Daten zur Seroprävalenz, die vor Einführung der Impfung im Landkreis Ortenaukreis erhoben wurden, schaffte zudem die interessante Möglichkeit, die Häufigkeit der FSME-Infektionen in einem endemischen Gebiet über einige Jahrzehnte zu vergleichen. Des Weiteren wurden die Blutproben auf neutralisierende Antikörper hin untersucht und die serologische Immunitätsrate der Proben mit vom Robert Koch-Institut bereitgestellten Zahlen zum Impfschutz in der Bevölkerung verglichen. Material und Methoden Insgesamt wurden 2220 Blutspenderestproben, die größtenteils aus dem Landkreis Ortenaukreis in Baden-Württemberg stammen, beprobt. Die FSME-Meldezahlen für das untersuchte Gebiet wurden vom RKI bereitgestellt. Zuerst wurden alle Blutproben mit einem IgG-ELISA auf IgG-Antikörper gegen die FSME getestet. Alle in diesem ELISA positiven Proben wurden im weiteren Verlauf mit dem neuen NS1-ELISA auf IgG-Antikörper gegen das NS1-Protein getestet. Alle im IgG-ELISA positiven und im NS1-ELISA negativen Proben wurden mittels SNT auf das Vorhandensein neutralisierender Antikörper überprüft. Der IIFT wurde zur Überprüfung von kreuzreaktiven Antikörpern verwendet. Die auf Daten der Krankenversicherungen basierende Durchimpfungsrate für den Ortenaukreis wurde vom Robert Koch-Institut bereitgestellt. Ergebnisse Von den 2220 Proben wiesen 57 % (1257/2220) IgG-Antikörper gegen die FSME auf. 125 der 2220 Proben, also 5,6 %, wurden mithilfe des NS1-ELISAs positiv auf eine vorangegangene FSME-Infektion getestet. Bei wenigen Proben wurden kreuzreagierende Antikörper gefunden, die durch andere Flaviviren induziert wurden (7/2220). Es konnte ein Manifestationsindex von ca. 2 % ermittelt werden, sowie eine hohe Anzahl an stillen Infektionen von über 250 pro 100.000 Einwohnern pro Jahr. Für ca. 55 % (1150/2104) der Proben wurde ein neutralisierender Antikörpertiter gegen das FSME-Virus ermittelt. Schlussfolgerung In den dieser Arbeit zugrunde liegenden Studien wurden neue Daten zu FSME-Inzidenz und Manifestationsindex in einem endemischen Gebiet generiert. Nach Vergleich mit Daten aus dem Jahr 1986 ist festzustellen, dass die Ergebnisse für einen etwa siebenfachen Anstieg der FSME-Infektionsraten im untersuchten Gebiet trotz der Verfügbarkeit eines hochwirksamen Impfstoffs sprechen. Die serologische Immunitätsrate ist signifikant höher als die vom Robert Koch-Institut für den Ortenaukreis erhobenen Zahlen zum Impfschutz (ca. 20 %), was für eine längere Haltbarkeit der von der Impfung induzierten Antikörper sprechen könnte, als ursprünglich angenommen. Diese Arbeit verdeutlicht außerdem den Nutzen von Seroprävalenzstudien zur Ergänzung Inzidenz-basierter Risikobewertung von Gebieten, in denen das FSME-Virus endemisch ist.:1 Einleitung......................................................................................1 2 Literaturübersicht.........................................................................2 2.1 Frühsommer-Meningoenzephalitis-Virus (FSME-Virus)................2 2.1.1 Virologie................................................................................2 2.1.2 Virusreplikation.....................................................................3 2.1.3 Epidemiologie in Deutschland..............................................4 2.1.4 Übertragungszyklus des FSME-Virus...................................6 2.1.5 Infektion und Krankheitsverlauf............................................8 2.1.6 Impfung.................................................................................9 2.1.7 Diagnostik............................................................................10 2.1.8 Serologische Methoden.......................................................11 3 Publikationen...............................................................................14 3.1 Eigenanteil Publikation 1..............................................................14 3.1.1 Publikation 1........................................................................16 3.2 Eigenanteil Publikation 2..............................................................25 3.2.1 Publikation 2........................................................................26 4 Diskussion....................................................................................36 5 Zusammenfassung.......................................................................44 6 Summary......................................................................................46 7 Referenzen...................................................................................48 7.1 Literatur........................................................................................48 7.2 Abbildungsverzeichnis.................................................................59 8 Danksagung.................................................................................60 / Introduction TBE is the medically most significant tick-borne disease in Europe and Asia. In Europe, several thousand people fall ill with TBE every year. There is little data available on the seroprevalence of TBE, because the availability of TBE vaccination since the 1980s in Germany has made it no longer possible to distinguish between vaccine- and infection-induced antibodies using conventional serological methods. The development of a new ELISA in 2020 based on the non-structural protein 1 (NS1) makes this distinction possible. Objectives The study’s objectives were to determine epidemiological target points such as seroprevalence, infection and serological immunity rates and to generate new data on the manifestation index in the endemic district of Ortenaukreis in Baden-Württemberg. The availability of historical seroprevalence data collected before the introduction of TBE vaccination in the Ortenaukreis district also provided the interesting opportunity to compare the prevalence of TBE infections in an endemic area over several decades. Additionally, the blood samples were analysed for neutralising antibodies, and the serological immunity rate of the sample size was compared with numbers on the vaccination rate in the population provided by the Robert Koch Institute (RKI). Material and Methods A total of 2220 blood donor samples, most of which came from the Ortenaukreis district in Baden-Württemberg, were sampled. The RKI provided TBE reporting numbers for the region of interest. All blood samples were initially tested for IgG antibodies against TBE using an IgG ELISA. All samples positive in this ELISA were subsequently tested for IgG antibodies against the NS1 protein in the new NS1 ELISA. All samples positive in the IgG ELISA and negative in the NS1 ELISA were tested for the presence of neutralising antibodies with the SNA. The IIFA was used to check for cross-reactive antibodies. The vaccination rate for the Ortenaukreis district, based on health insurance data, was provided by the RKI. Results Of the 2220 samples, 57 % (1257/2220) showed IgG antibodies against TBE. 125 of the 2220 samples, i.e. 5.6 %, tested positive for a previous TBE infection in the NS1 ELISA. In a few samples, cross-reacting antibodies induced by other flaviviruses were found (7/2220). A manifestation index of ca. 2 % could be determined, as well as a high number of silent infections of more than 250 per 100.000 inhabitants per year. A neutralising antibody titer against the TBE virus could be determined for ca. 55 % (1150/2104) of the sample size. Conclusion In the studies on which this work is based, new TBE incidence and manifestation index data were generated for an endemic area. After comparing the data from 1986, the results indicate an approximately sevenfold increase in TBE infection rates in the studied area despite the availability of a highly effective vaccine. The serological protection rate is significantly higher than the immune protection rate numbers collected by the RKI for the Ortenaukreis (approx. 20 %), which could speak for longer durability of the antibodies induced by the vaccination than originally assumed. Furthermore, this study illustrates the use of seroprevalence studies in addition to incidence-based risk assessment of TBE endemic areas.:1 Einleitung......................................................................................1 2 Literaturübersicht.........................................................................2 2.1 Frühsommer-Meningoenzephalitis-Virus (FSME-Virus)................2 2.1.1 Virologie................................................................................2 2.1.2 Virusreplikation.....................................................................3 2.1.3 Epidemiologie in Deutschland..............................................4 2.1.4 Übertragungszyklus des FSME-Virus...................................6 2.1.5 Infektion und Krankheitsverlauf............................................8 2.1.6 Impfung.................................................................................9 2.1.7 Diagnostik............................................................................10 2.1.8 Serologische Methoden.......................................................11 3 Publikationen...............................................................................14 3.1 Eigenanteil Publikation 1..............................................................14 3.1.1 Publikation 1........................................................................16 3.2 Eigenanteil Publikation 2..............................................................25 3.2.1 Publikation 2........................................................................26 4 Diskussion....................................................................................36 5 Zusammenfassung.......................................................................44 6 Summary......................................................................................46 7 Referenzen...................................................................................48 7.1 Literatur........................................................................................48 7.2 Abbildungsverzeichnis.................................................................59 8 Danksagung.................................................................................60