L'objectif de cette étude était double. Il s'agissait dans un premier temps de caractériser l'immunosuppression produite chez des porcs infectés par une souche de virus influenza H3N2. La deuxième partie de cette étude consistait à tester le potentiel adjuvant d'un dérivé de mannose (l'Acemannan) aux propriétés immunostimulantes. Lors de la première partie de cette étude, les effets d'une infection par le virus influenza furent évalués chez le porc. Il fut démontré par différents essais que la prolifération mitogène-dépendante ainsi que la sous-population de lymphocytes T auxilliaires sont affectées de façon négative lors de ce type d'infection. L'activité des cellules N. K est grandement influencée par le stress des animaux. Dans la deuxième partie de cette étude, les effets de l'Acemannan furent déterminés sur la réponse immunitaire du porc en réponse à un vaccin anti-virus influenza. Ceci a été effectué dans le but de vérifier le potentiel de l'Acemannan comme adjuvant couplé à des vaccins. Ces expériences ont permis de démontrer que l'Acemannan possède des effets activateurs ou inhibiteurs selon le type cellulaire en cause. Des effets activateurs ont été mis en évidence au niveau de la production d'anticorps et de la réponse proliférative des lymphocytes mononucles du sang périphérique du porc (PBML) tandis qu'un effet inhibiteur a été rapporté au niveau de l'activité des cellules N. K. [Résumé abrégé par UMI].

No description available.

No description available.

O vírus influenza A (IAV) é um agente zoonótico de grande relevância tanto para saúde humana como animal. A influenza suína teve seu primeiro reconhecimento clínico em 1918, em suínos do Meio Oeste dos EUA, coincidindo com a pandemia de influenza em humanos. Desde então, o IAV permanece como um importante patógeno para a indústria suinícola em todo o mundo. A grande variabilidade genética destes vírus é causada por dois principais mecanismos genéticos: mutações pontuais e recombinações genéticas. A influenza é endêmica em muitos países e a emergências de recombinantes tem desafiado o controle e o diagnóstico desta enfermidade. No Brasil, a infecção pelo IAV em suínos (swIAV) não está bem caracterizada; poucos relatos evidenciam a prevalência deste agente antes do ano de 2009, especialmente no Estado do Rio Grande do Sul, que alberga um dos maiores rebanhos de suínos do Brasil. Em vista disso, este trabalho teve como objetivo investigar ocorrência de swIAV em alguns rebanhos suínos comerciais do Estado do Rio Grande do Sul, Brasil, no período de 2013-2014, e determinar os tipos e subtipos de vírus circulantes naquelas propriedades. O primeiro capítulo deste estudo reporta os aspectos clínicos, patológicos e virológicos da ocorrência de influenza suína e co-infecções identificadas em seis propriedades suinícolas selecionadas na região do Vale do Taquari. Neste estudo foram analisados suabes nasais coletados de 66 animais e 6 amostras de tecido pulmonar de suínos com sinais de infecção respiratória. A detecção viral foi feita através de uma PCR de triagem e confirmada através do isolamento viral em células MDCK. A identificação dos subtipos virais foi feita através de uma PCR em Tempo Real (rRT-PCR) para o subtipo A(H1N1)pdm09 ou através de uma PCR multiplex (RT-PCR) para outros subtipos de swIAV. A detecção de agentes bacterianos foi realizada apenas nas amostras de tecido pulmonar, através da pesquisa de genomas bacterianos por PCR. O subtipo A(H1N1)pdm09 foi identificado em 4/6 granjas e o subtipo H1N2 em 2/6 granjas. Além disso, agentes envolvidos no complexo respiratório dos suínos foram identificados em todas as granjas; Pasteurella multocida foi identificada em 5/6 granjas e Mycoplasma hyopneumoniae em 3/6 granjas. Actinobacillus pleuropneumoniae (1/6), Haemophilus parasuis (1/6) e PCV2 (1/6) também foram detectados. O segundo capítulo deste estudo teve como objetivo o sequenciamento do genoma completo de um novo recombinante H1N2 de origem humana, detectado em suínos. O genoma completo foi gerado através de uma RT-PCR. Os produtos foram purificados e submetidos ao sequenciamento utilizando a plataforma MiSeq (illumina). A análise filogenética revelou que as sequencias dos genes HA e NA correspondem a genes de IAV de origem humana, enquanto que as sequencias dos genes que codificam as proteínas internas do vírus (PB1, PB2, PA, NP, M e NS) correspondem a genes de amostras do vírus A(H1N1)pdm09. O terceiro capítulo reporta o sequenciamento completo dos genomas de 8 amostras de vírus influenza identificados nas populações de suínos amostradas. Foram identificados dois subtipos virais de origem humana (H1N2 e H3N2), além do vírus A(H1N1)pdm09. Os subtipos de origem humana possuem os genes HA e NA similares a vírus sazonais de humanos e os genes internos são estreitamente relacionados com o vírus A(H1N1)pdm09. / Influenza A virus (IAV) is a zoonotic agent of great relevance to human and animal health. Swine influenza was first recognized clinically in pigs in the Midwestern U.S., in 1918, coinciding with the human influenza pandemic. Since that time swine influenza has remained of importance to the swine industry throughout the world. The great genetic variability of influenza viruses is caused by two main genetic mechanisms: point mutations (antigenic drift) and gene reassortment (antigenic shift). Influenza is endemic in pigs in many countries and the emergence of new viruses has been challenging its control and diagnostics. Influenza virus (swIAV) infection in Brazilian swine population is not well characterized, and little evidence existed of swIAV circulation before 2009, especially in Rio Grande do Sul State, which hosts one of the largest swine populations in Brazil. Thus, this study aimed to investigate the occurrence of IAV in commercial swine herds in the state of Rio Grande do Sul, Brazil, between 2013-2014 and to know the types and subtypes of swine influenza viruses that are circulating in these herd. The first chapter of this study reports the clinical, pathological and virological aspects of the occurrence of swine influenza and related co-infections in six pig properties of the Taquari Valley region. In this study were analyzed nasal swabs collected from 66 animals and six lung tissue samples from pigs showing clinical signs of respiratory disease. IAV detection was performed by PCR screening and confirmed by virus isolation in MDCK cells and hemagglutination (HA). Influenza A subtyping was performed by real-time reverse transcription PCR (rRT-PCR) to detect the 2009 H1N1pandemic A(H1N1)pdm09; other swIAV subtypes were identifieded by multiplex RT-PCR. Bacterial infections were identified through detection of bacterial genomes by PCR, only in lung samples. Influenza A was detected by screening PCR in 46/66 swab samples and from 5/6 lungs. Virus was recovered from pigs of the six herds. Subtype A(H1N1)pdm09 was detected in 4/6 herds and H1N2 in the other 2/6 herds. In lung tissues, further agents involved in porcine respiratory disease complex were detected in all cases; Pasteurella multocida was identified in 5/6 samples and Mycoplasma hyopneumoniae in 3/6. Actinobacillus pleuropneumoniae (1/6), Haemophilus parasuis (1/6) and PCV2 (1/6) were also detected. The aim of the second chapter was to sequence the whole-genome of a novel human-like H1N2 swine influenza virus. Wholegenome sequences were generated by RT-PCR. Amplicons were purified followed by sequencing in the MiSeq sequencing platform (Illumina). Phylogenetic analyses revealed that the HA and NA genes clustered with influenza viruses of human lineage, whereas the internal genes (PB1, PB2, PA, NP, M and NS) clustered with the A(H1N1)pdm09. The third chapter reports the genetic sequencing of the full genomes of eight swine influenza viruses circulating in the sampled pig population. Two swine human-like subtypes (H1N2 and H3N2) and the A(H1N1)pdm09 virus were identified. The human-like subtypes have the HA and NA genes similar to the human seasonal strains and the internal genes are closely related to the virus A(H1N1)pdm09.

Diss. (sammanfattning) Stockholm : Karol. inst., 2006. / Härtill 4 uppsatser.

O vírus influenza A (IAV) é um agente zoonótico de grande relevância tanto para saúde humana como animal. A influenza suína teve seu primeiro reconhecimento clínico em 1918, em suínos do Meio Oeste dos EUA, coincidindo com a pandemia de influenza em humanos. Desde então, o IAV permanece como um importante patógeno para a indústria suinícola em todo o mundo. A grande variabilidade genética destes vírus é causada por dois principais mecanismos genéticos: mutações pontuais e recombinações genéticas. A influenza é endêmica em muitos países e a emergências de recombinantes tem desafiado o controle e o diagnóstico desta enfermidade. No Brasil, a infecção pelo IAV em suínos (swIAV) não está bem caracterizada; poucos relatos evidenciam a prevalência deste agente antes do ano de 2009, especialmente no Estado do Rio Grande do Sul, que alberga um dos maiores rebanhos de suínos do Brasil. Em vista disso, este trabalho teve como objetivo investigar ocorrência de swIAV em alguns rebanhos suínos comerciais do Estado do Rio Grande do Sul, Brasil, no período de 2013-2014, e determinar os tipos e subtipos de vírus circulantes naquelas propriedades. O primeiro capítulo deste estudo reporta os aspectos clínicos, patológicos e virológicos da ocorrência de influenza suína e co-infecções identificadas em seis propriedades suinícolas selecionadas na região do Vale do Taquari. Neste estudo foram analisados suabes nasais coletados de 66 animais e 6 amostras de tecido pulmonar de suínos com sinais de infecção respiratória. A detecção viral foi feita através de uma PCR de triagem e confirmada através do isolamento viral em células MDCK. A identificação dos subtipos virais foi feita através de uma PCR em Tempo Real (rRT-PCR) para o subtipo A(H1N1)pdm09 ou através de uma PCR multiplex (RT-PCR) para outros subtipos de swIAV. A detecção de agentes bacterianos foi realizada apenas nas amostras de tecido pulmonar, através da pesquisa de genomas bacterianos por PCR. O subtipo A(H1N1)pdm09 foi identificado em 4/6 granjas e o subtipo H1N2 em 2/6 granjas. Além disso, agentes envolvidos no complexo respiratório dos suínos foram identificados em todas as granjas; Pasteurella multocida foi identificada em 5/6 granjas e Mycoplasma hyopneumoniae em 3/6 granjas. Actinobacillus pleuropneumoniae (1/6), Haemophilus parasuis (1/6) e PCV2 (1/6) também foram detectados. O segundo capítulo deste estudo teve como objetivo o sequenciamento do genoma completo de um novo recombinante H1N2 de origem humana, detectado em suínos. O genoma completo foi gerado através de uma RT-PCR. Os produtos foram purificados e submetidos ao sequenciamento utilizando a plataforma MiSeq (illumina). A análise filogenética revelou que as sequencias dos genes HA e NA correspondem a genes de IAV de origem humana, enquanto que as sequencias dos genes que codificam as proteínas internas do vírus (PB1, PB2, PA, NP, M e NS) correspondem a genes de amostras do vírus A(H1N1)pdm09. O terceiro capítulo reporta o sequenciamento completo dos genomas de 8 amostras de vírus influenza identificados nas populações de suínos amostradas. Foram identificados dois subtipos virais de origem humana (H1N2 e H3N2), além do vírus A(H1N1)pdm09. Os subtipos de origem humana possuem os genes HA e NA similares a vírus sazonais de humanos e os genes internos são estreitamente relacionados com o vírus A(H1N1)pdm09. / Influenza A virus (IAV) is a zoonotic agent of great relevance to human and animal health. Swine influenza was first recognized clinically in pigs in the Midwestern U.S., in 1918, coinciding with the human influenza pandemic. Since that time swine influenza has remained of importance to the swine industry throughout the world. The great genetic variability of influenza viruses is caused by two main genetic mechanisms: point mutations (antigenic drift) and gene reassortment (antigenic shift). Influenza is endemic in pigs in many countries and the emergence of new viruses has been challenging its control and diagnostics. Influenza virus (swIAV) infection in Brazilian swine population is not well characterized, and little evidence existed of swIAV circulation before 2009, especially in Rio Grande do Sul State, which hosts one of the largest swine populations in Brazil. Thus, this study aimed to investigate the occurrence of IAV in commercial swine herds in the state of Rio Grande do Sul, Brazil, between 2013-2014 and to know the types and subtypes of swine influenza viruses that are circulating in these herd. The first chapter of this study reports the clinical, pathological and virological aspects of the occurrence of swine influenza and related co-infections in six pig properties of the Taquari Valley region. In this study were analyzed nasal swabs collected from 66 animals and six lung tissue samples from pigs showing clinical signs of respiratory disease. IAV detection was performed by PCR screening and confirmed by virus isolation in MDCK cells and hemagglutination (HA). Influenza A subtyping was performed by real-time reverse transcription PCR (rRT-PCR) to detect the 2009 H1N1pandemic A(H1N1)pdm09; other swIAV subtypes were identifieded by multiplex RT-PCR. Bacterial infections were identified through detection of bacterial genomes by PCR, only in lung samples. Influenza A was detected by screening PCR in 46/66 swab samples and from 5/6 lungs. Virus was recovered from pigs of the six herds. Subtype A(H1N1)pdm09 was detected in 4/6 herds and H1N2 in the other 2/6 herds. In lung tissues, further agents involved in porcine respiratory disease complex were detected in all cases; Pasteurella multocida was identified in 5/6 samples and Mycoplasma hyopneumoniae in 3/6. Actinobacillus pleuropneumoniae (1/6), Haemophilus parasuis (1/6) and PCV2 (1/6) were also detected. The aim of the second chapter was to sequence the whole-genome of a novel human-like H1N2 swine influenza virus. Wholegenome sequences were generated by RT-PCR. Amplicons were purified followed by sequencing in the MiSeq sequencing platform (Illumina). Phylogenetic analyses revealed that the HA and NA genes clustered with influenza viruses of human lineage, whereas the internal genes (PB1, PB2, PA, NP, M and NS) clustered with the A(H1N1)pdm09. The third chapter reports the genetic sequencing of the full genomes of eight swine influenza viruses circulating in the sampled pig population. Two swine human-like subtypes (H1N2 and H3N2) and the A(H1N1)pdm09 virus were identified. The human-like subtypes have the HA and NA genes similar to the human seasonal strains and the internal genes are closely related to the virus A(H1N1)pdm09.

O vírus influenza A (IAV) é um agente zoonótico de grande relevância tanto para saúde humana como animal. A influenza suína teve seu primeiro reconhecimento clínico em 1918, em suínos do Meio Oeste dos EUA, coincidindo com a pandemia de influenza em humanos. Desde então, o IAV permanece como um importante patógeno para a indústria suinícola em todo o mundo. A grande variabilidade genética destes vírus é causada por dois principais mecanismos genéticos: mutações pontuais e recombinações genéticas. A influenza é endêmica em muitos países e a emergências de recombinantes tem desafiado o controle e o diagnóstico desta enfermidade. No Brasil, a infecção pelo IAV em suínos (swIAV) não está bem caracterizada; poucos relatos evidenciam a prevalência deste agente antes do ano de 2009, especialmente no Estado do Rio Grande do Sul, que alberga um dos maiores rebanhos de suínos do Brasil. Em vista disso, este trabalho teve como objetivo investigar ocorrência de swIAV em alguns rebanhos suínos comerciais do Estado do Rio Grande do Sul, Brasil, no período de 2013-2014, e determinar os tipos e subtipos de vírus circulantes naquelas propriedades. O primeiro capítulo deste estudo reporta os aspectos clínicos, patológicos e virológicos da ocorrência de influenza suína e co-infecções identificadas em seis propriedades suinícolas selecionadas na região do Vale do Taquari. Neste estudo foram analisados suabes nasais coletados de 66 animais e 6 amostras de tecido pulmonar de suínos com sinais de infecção respiratória. A detecção viral foi feita através de uma PCR de triagem e confirmada através do isolamento viral em células MDCK. A identificação dos subtipos virais foi feita através de uma PCR em Tempo Real (rRT-PCR) para o subtipo A(H1N1)pdm09 ou através de uma PCR multiplex (RT-PCR) para outros subtipos de swIAV. A detecção de agentes bacterianos foi realizada apenas nas amostras de tecido pulmonar, através da pesquisa de genomas bacterianos por PCR. O subtipo A(H1N1)pdm09 foi identificado em 4/6 granjas e o subtipo H1N2 em 2/6 granjas. Além disso, agentes envolvidos no complexo respiratório dos suínos foram identificados em todas as granjas; Pasteurella multocida foi identificada em 5/6 granjas e Mycoplasma hyopneumoniae em 3/6 granjas. Actinobacillus pleuropneumoniae (1/6), Haemophilus parasuis (1/6) e PCV2 (1/6) também foram detectados. O segundo capítulo deste estudo teve como objetivo o sequenciamento do genoma completo de um novo recombinante H1N2 de origem humana, detectado em suínos. O genoma completo foi gerado através de uma RT-PCR. Os produtos foram purificados e submetidos ao sequenciamento utilizando a plataforma MiSeq (illumina). A análise filogenética revelou que as sequencias dos genes HA e NA correspondem a genes de IAV de origem humana, enquanto que as sequencias dos genes que codificam as proteínas internas do vírus (PB1, PB2, PA, NP, M e NS) correspondem a genes de amostras do vírus A(H1N1)pdm09. O terceiro capítulo reporta o sequenciamento completo dos genomas de 8 amostras de vírus influenza identificados nas populações de suínos amostradas. Foram identificados dois subtipos virais de origem humana (H1N2 e H3N2), além do vírus A(H1N1)pdm09. Os subtipos de origem humana possuem os genes HA e NA similares a vírus sazonais de humanos e os genes internos são estreitamente relacionados com o vírus A(H1N1)pdm09. / Influenza A virus (IAV) is a zoonotic agent of great relevance to human and animal health. Swine influenza was first recognized clinically in pigs in the Midwestern U.S., in 1918, coinciding with the human influenza pandemic. Since that time swine influenza has remained of importance to the swine industry throughout the world. The great genetic variability of influenza viruses is caused by two main genetic mechanisms: point mutations (antigenic drift) and gene reassortment (antigenic shift). Influenza is endemic in pigs in many countries and the emergence of new viruses has been challenging its control and diagnostics. Influenza virus (swIAV) infection in Brazilian swine population is not well characterized, and little evidence existed of swIAV circulation before 2009, especially in Rio Grande do Sul State, which hosts one of the largest swine populations in Brazil. Thus, this study aimed to investigate the occurrence of IAV in commercial swine herds in the state of Rio Grande do Sul, Brazil, between 2013-2014 and to know the types and subtypes of swine influenza viruses that are circulating in these herd. The first chapter of this study reports the clinical, pathological and virological aspects of the occurrence of swine influenza and related co-infections in six pig properties of the Taquari Valley region. In this study were analyzed nasal swabs collected from 66 animals and six lung tissue samples from pigs showing clinical signs of respiratory disease. IAV detection was performed by PCR screening and confirmed by virus isolation in MDCK cells and hemagglutination (HA). Influenza A subtyping was performed by real-time reverse transcription PCR (rRT-PCR) to detect the 2009 H1N1pandemic A(H1N1)pdm09; other swIAV subtypes were identifieded by multiplex RT-PCR. Bacterial infections were identified through detection of bacterial genomes by PCR, only in lung samples. Influenza A was detected by screening PCR in 46/66 swab samples and from 5/6 lungs. Virus was recovered from pigs of the six herds. Subtype A(H1N1)pdm09 was detected in 4/6 herds and H1N2 in the other 2/6 herds. In lung tissues, further agents involved in porcine respiratory disease complex were detected in all cases; Pasteurella multocida was identified in 5/6 samples and Mycoplasma hyopneumoniae in 3/6. Actinobacillus pleuropneumoniae (1/6), Haemophilus parasuis (1/6) and PCV2 (1/6) were also detected. The aim of the second chapter was to sequence the whole-genome of a novel human-like H1N2 swine influenza virus. Wholegenome sequences were generated by RT-PCR. Amplicons were purified followed by sequencing in the MiSeq sequencing platform (Illumina). Phylogenetic analyses revealed that the HA and NA genes clustered with influenza viruses of human lineage, whereas the internal genes (PB1, PB2, PA, NP, M and NS) clustered with the A(H1N1)pdm09. The third chapter reports the genetic sequencing of the full genomes of eight swine influenza viruses circulating in the sampled pig population. Two swine human-like subtypes (H1N2 and H3N2) and the A(H1N1)pdm09 virus were identified. The human-like subtypes have the HA and NA genes similar to the human seasonal strains and the internal genes are closely related to the virus A(H1N1)pdm09.

Bakgrund: Influensa är ett stort folkhälsoproblem på grund av att den är det vanligaste globala smittsamma sjukdomsutbrott som leder till grava mentala och fysiska hälsobelastningar. Syfte: Vi undersökte kliniskt relevanta depressiva och belastade ångestsymptom i kvinnor i samband med förlossningen under två av 1900-talets influensapandemier, N2N2 och/eller H2N3 samt det könsmogna stadiet (mellan ålder vid menarke and ådler vid menopaus) där andra reproduktiva faktorer i den kvinnliga grekiska befolkningen beaktades. Metoder: Tvärsnitts- och historiska data uppkom från 1039 kvinnliga deltagare som deltog i studien Hellenic Longitudinal Investigation of Aging and Diet (HELIAD) där sociodemografiska variabler inkluderade ålder. Resultatet av de depressiva symtomen mättes med hjälp av den Geriatriska depressionsskalan bestående av 15-artiklar (GDS-15). En kliniskt relevant depressiv symptom börda definierades som GDS>5. Ångestsymptom mättes med de 7 ångest artiklarna från sjukhusets ångest och depressionsskala (HADS-A). En kliniskt relevant belastad ångestsymptom definierades som >8 för HADS. H2N2-pandemi perioden inträffades 1956-1958 och H2N3-pandemin, 1967-1969. Självrapporterade reproduktiva steg variabler inkluderade ålder vid menarke, ålder vid menopaus, antal graviditeter, antal barn, barnens födelseår och antal aborter. Resultat: Kliniskt relevanta depressiva och belastade ångestsymptom observerades bland 24,5% respektive 15,8% av HELIAD-deltagarna. Ingen koppling observerades mellan varken GDS >5 (Chi-square, 0,39, p = 0,56) eller HADS >8 (Chi-square, 0,06, p = 0,82) och födelse under H2N2- och / eller H2N3-pandemier. Univariat samband mellan ålder vid menarke, antal graviditeter, det könsmogna stadiet, och antal aborter var dock associerat med GDS >5 (alla p <0,10). Därför, en stegvis logistisk regressionsmodell som utvärderade reproduktiva variabler visade att det fanns högre odds för en kliniskt relevant depressiv symtombörda i samband med en äldre ålder vid menarke (OR 1.09, 95% KI 1.00, 1.18) och högre antal graviditeter (OR 1.07, 95% KI 1,01, 1,14). Inga förbindelser observerades gällande ångest. Slutsats: Vår hypotes att födelse under en influensapandemi skulle påverka förekomsten av kliniskt relevanta senare depressiva och ångestsymptom avvisades i denna analys. Vår sekundära hypotes att reproduktions variabler skulle associeras med psykisk ohälsa senare i livet avvisades dock inte för depressiva symtom. Även om sambandet mellan en kliniskt relevant belastad depressiv symtom och ålder vid menarche och antalet graviditeter inte var övertygande, framhävs den viktiga rollen kvinnors reproduktiva hälsa har under hela livet. Mer forskning behövs för att förstå det tidsmässiga och konsekventa sambandet. / Background: Influenza is a major public health concern due to increasingly frequent global infectious disease outbreaks that result in great mental and physical health burdens. Aim: We investigated clinically relevant later life depressive and anxiety symptom burdens in women in association with giving birth during two 20th century influenza pandemics, H2N2 and/or H2N3, and reproductive stage, the total reproductive years of a woman defined mathematically as the age at menopause minus the age at menarche. We also considered other reproductive factors. Methods: Cross-sectional and historical data originated from 1039 female participants age 54 and older, enrolled in the Hellenic Longitudinal Investigation of Aging and Diet (HELIAD) in Greece. Sociodemographic variables included age. The depressive symptoms outcome was measured using the 15-item Geriatric Depression Scale (GDS-15). A clinically relevant depressive symptom burden was defined as GDS >5, Anxiety symptoms were measured using the 7 anxiety items from the Hospital Anxiety and Depression Scale (HADS-A). A clinically relevant anxiety symptom burden was defined as >8 for HADS. The H2N2 pandemic period occurred from 1956-1958 and the H2N3 pandemic, from 1967-1969. Selfreported reproductive stage variables included age at menarche, age at menopause, number of pregnancies, number of offspring, offspring’ birth year, and number of abortions. Results: Clinically relevant depressive and anxiety symptom burdens were observed among 24.5% and 15.8% of HELIAD participants, respectively. No association was observed between either GDS >5 (2, 0.39, p=0.56) or HADS >8 (2, 0.06, p=0.82) and giving birth during the H2N2 and/or H2N3 pandemics. However, univariate association between age at menarche, number of pregnancies, reproductive stage, and number of abortions were associated with GDS >5 (all p <0.10). Therefore, a stepwise logistic regression model evaluating these reproductive variables showed that higher odds of a clinically relevant depressive symptom burden in association with an older age at menarche (OR 1.09, 95%CI 1.00, 1.18) and higher number of pregnancies (OR 1.07, 95% CI 1.01, 1.14). No associations were observed for anxiety. Conclusion: Our hypothesis that giving birth during an influenza pandemic would influence the occurrence of clinically relevant later life depressive and anxiety symptoms was rejected in this analysis. However, our secondary hypothesis that reproductive variables would be associated with later life mental health was not rejected for depressive symptoms. While the associations between a clinically relevant depressive symptom burden and age at menarche and number of pregnancies were not strong, they point to the important role of women’s reproductive health over the life course. More research is needed to understand the temporality and consistencies of these associations.

In this thesis I develop and implement “antibody landscapes”, a method to profile immunity against a pathogen as a function of antigenic differences between a range of strains. Theoretically applicable to any antigenically variable pathogen and measurement of immunity, the work here focusses on antibody-mediated immunity against the A/H3N2 influenza subtype. Applying the methodology to study annual serum samples from individuals monitored for influenza infection over a period of six years, patterns of influenza immunity were found to be remarkably distinct and maintained almost unchanged over time in the absence of influenza exposure. Upon infection, the initial response is strikingly antigenically broad, including responses against viruses far beyond the extent of cross-reactivity observed after a primary infection. Analysis of two vaccination cohorts, one receiving an antigenically advanced vaccine strain and one a more typical vaccine strain choice, revealed many of the same patterns of response as seen with infection. Antigenically advanced vaccination generated greater responses against later strains but surprisingly, due to equivalent boosting of prior immunity, this came at no cost to responses generated against contemporary or older strains. Exploring in more detail the development of immunity over time, analysis of a cohort of children demonstrated that - in contrast to adults with diverse exposure histories - antibody responses to a first infections were remarkably similar in pattern and magnitude. Interestingly, for second infections, although post-infection antibody titres against circulating strains were comparable to those after first infections, overall cross-reactivity of the response against future antigenic variants appeared to be diminished. The findings here underline the significant role prior-immunity plays in affecting the response to new exposures and the importance of understanding it. An important conclusion is that by failing to account for it, current approaches to influenza vaccine strain selection may be suboptimal and pre-emptive vaccine strain updates may improve overall vaccine efficacy where immunity to current strains already exists in the population. Building on the work presented here should help to optimise strain choice and vaccine efficacy even further.

Influenza is a contagious respiratory disease that has caused at least four pandemics and countless epidemics since the 20th century, impacted millions of people worldwide and the global economy. To date, the predominant influenza species circulating in humans are influenza A and B. Influenza may cause serious illness in all age groups but individuals such as the newborns and senior population whose immune systems are compromised are at higher risk for severe disease. Interestingly, during the outbreak of pandemic 2009 H1N1 (H1N1pdm), it was found that the elderly had the lowest hospitalization rate and an increased proportion of healthy adults developed severe disease. Furthermore, several clinical studies have demonstrated that most H1N1pdm infected children experienced mild to moderate illness and led to the least mortality. The difference of disease outcome in age groups between different influenza infections may be due to several factors, which include differing pathogenicity between the viruses, differential immune status and composition among the age groups, and pre-existing immunity from previous encounter(s) with a similar virus. Since the human clinical data are often complicated by secondary factors such as co-morbidities, I used the ferret model to address these questions. I first compared the clinical and pathological patterns among the pandemic and seasonal influenza strains and found H1N1pdm caused the most severe illness to healthy ferrets. Importantly, the disease severity did not correlate with viral burden but immunopathology. To study the age effect, I found that H1N1pdm infected young ferrets with mild clinical symptoms developed specialized ectopic lymphoid structures and a distinct cytokine expression profile in the lungs, which were absent in adult ferrets with severe illness. I also examined antigenic change in historical H1N1s and anti-H1 responses to explain the pre-existing immunity of H1N1pdm found in the elderly. However, low similarity was found between historical H1N1s and H1N1pdm. Lastly, I conducted a detailed influenza B comparative study. I observed the pathogenic B strain was capable to cause lower respiratory tract infection and pathology like the influenza A viruses. Overall, this thesis provides novel insights for developing therapeutic and prophylactic strategies against influenza infection.