Dissertations / Theses on the topic 'Invasive Pneumococcal Vaccines'

Pneumococcal disease is a leading cause of morbidity and mortality in children globally. Pneumococcal conjugate vaccines (PCVs), available since early 2000, had proven efficacy to prevent invasive pneumococcal disease (IPD)-the sever form of pneumococcal infections. For Australian children PCV had been publicly funded through the national immunisation program, initially in 2001 for those with increased disease risk which included Aboriginal and Torres Strait Islander children and from 2005 for all children. The schedule of PCV used in Australia comprising three doses at age 2, 4 and 6 months (called 3+0 schedule) was unique for a developed country. The first PCV used was one covering 7 serotypes of pneumococcus (7vPCV) and in 2011 a PCV that covered 6 more serotypes (13vPCV) replaced 7vPCV. Research contained in this thesis is the first to assess how well PCV prevented IPD among Australian children. After 9 years of combined PCV use IPD in young children declined by over 80%. Together with the added benefit of herd immunity that led to large reductions in IPD in older age groups there was a halving of the all-age total IPD burden. Vaccine effectiveness (VE) of 3 doses against vaccine-type IPD in infancy was ~90% for both PCVs. A major finding in this research was the 5 times higher odds of vaccine-type IPD if the last PCV dose was 24–36 months ago compared to within the last 12 months. This finding of waning VE was a vital piece of evidence that supported the recommendation to move the 3rd dose of 13vPCV in the 3+0 schedule to become a booster dose (i.e. 2+1 schedule) for Australian children from July 2018. Using a data linkage method the impact of PCVs on IPD in children with underlying medical conditions predisposing to pneumococcal infection was explored separately. This highlighted the persistent IPD burden in children with immunosuppression, splenic dysfunction and breach in the CSF barrier, possibly due to opportunistic infection from non-vaccine serotypes.

Deux vaccins sont actuellement disponibles pour la prévention des infections invasives à pneumocoques (IIP) : un vaccin polysaccharidique Pneumovax® (PPV23) et un vaccin conjugué Prevenar13® (PCV13), induisant respectivement une protection contre 23 et 13 sérotypes. Le PPV23 est considéré comme faiblement immunogène, en particulier chez les personnes âgées et les patients immunodéprimés. Le PCV13, en revanche, en raison de la conjugaison à une protéine porteuse, présente l'avantage d'induire une réponse immunitaire T-dépendante, non observée avec le vaccin PPV23. Dans notre travail nous avons donc évalué l'impact des stratégies vaccinales utilisant le PCV13 et le PPV23 sur différentes populations de patients à risque. Dans une première étude, nos résultats sur la vaccination anti-pneumococcique chez des patients atteints de myélome indolent (SMM) ont montré qu'une dose de PCV13 seul, induisait une réponse immune transitoire et de faible persistance. Ces résultats suggéraient l'utilisation d'un schéma vaccinal incluant plusieurs doses de PCV13 ou une association avec le PPV23. Depuis 2013, ce schéma combiné du PCV13 et du PPV23 est le schéma recommandé par la Haute Autorité de Santé en France chez les patients à risque, avec les délais suivants : une dose de PCV13 suivie d'une dose de PPV23, 8 semaines après. Nous avons par la suite étudié cette stratégie vaccinale combinée chez des patients à risque d'IIP : patients atteints de lupus érythémateux systémique (SLE) et patients atteints de polyarthrite rhumatoïde (PR). Nos résultats montrent une immunogénicité à court terme de la stratégie combinée, mais une protection qui ne persiste pas au-delà de deux ans. De façon surprenante, les taux d'anticorps 2 ans après la vaccination, sont inférieurs aux taux pré-vaccinaux pour les patients PR. Cet effet délétère du PPV23 sur la réponse vaccinale induite par le PCV13 est appelé hyporéponse. Ce phénomène, observé chez les patients PR, ne se retrouve pas chez les patients SLE dont la vaccination PPV23 a été effectuée plus à distance du PCV13. Ces résultats suggèrent que le schéma vaccinal plus tardif (c'est-à-dire une vaccination par le PPV23 six mois après le PCV13 au lieu de deux mois) inhiberait le phénomène d'hyporéponse. Dans une troisième partie, nous avons comparé différents schéma vaccinaux modulant les doses des vaccins et les délais d'injection chez des volontaires sains mais également dans un modèle murin d'hyporéponse développé au sein du laboratoire. Notre hypothèse était que la modulation du schéma vaccinal utilisant les 2 vaccins pouvait à la fois induire une protection à long terme et prévenir l'hyporéponse. Nos résultats ont montré que l'utilisation d'une dose diminuée de PPV23 ou l'injection concomitante des deux vaccins n'empêchaient pas l'hyporéponse. En revanche, en allongeant le délai entre le PCV13 et le PPV23, le phénomène d'hyporéponse est limité. Des études cliniques chez les patients à risque d'IIP sont nécessaires afin d'évaluer une stratégie combinée tardive, où le PPV23 serait reçu au moins 6 à 12 mois après le PCV13<br>Two vaccines are currently available for the prevention of invasive pneumococcal diseases (IPD): a polysaccharide vaccine, Pneumovax® (PPV23) and a conjugate vaccine, Prevenar13® (PCV13), inducing protection against 23 and 13 serotypes, respectively. PPV23 is considered to be weakly immunogenic, particularly in the elderly and immunocompromised patients. PCV13, however, due to the conjugation to a carrier protein, has the advantage of inducing a T-dependent immune response, not observed with PPV23 vaccine. In our work, we therefore evaluated the impact of vaccine strategies using PCV13 and PPV23 on different populations of patients at risk of IPD. In a first study, our results on anti-pneumococcal vaccination in patients with smoldering myeloma (SMM) showed that a single dose of PCV13 induces a transient immune response and long term persistence. These results suggested the use of a vaccination schedule including several doses of PCV13 or association with the PPV23. Since 2013, this combined strategy of PCV13 and PPV23 is recommended by la Haute Autorité de Santé (HAS) for patients at risk, with the following delays: a dose of PCV13 followed by a dose of PPV23, 8 weeks later. We then studied this combined vaccine strategy in patients at risk of IPD: patients with systemic lupus erythematosus (SLE) and patients with rheumatoid arthritis (RA). Our results show a short-term immunogenicity of the combined strategy, but a protection that does not persist beyond two years. Surprisingly, antibody levels 2 years after vaccination are lower than pre-vaccine levels for RA patients. This negative effect of PPV23 on PCV13-induced immune response is called hyporesponsiveness. This phenomenon, observed in RA patients, is not found in SLE patients who received PPV23 vaccination at distance from PCV13. These results suggest that the delayed vaccination schedule (ie, PPV23 vaccination six months after PCV13 instead of two months) could inhibit the hyporesponsiveness phenomenon. In a third study, we compared different vaccine strategies modulating vaccine doses and injection times in healthy volunteers but also in a mouse model of hyporesponsiveness developed in our laboratory. Our hypothesis was that modulation of the vaccine schedule using both vaccines could both induce long-term protection and prevent hyporesponsiveness. Our results showed that decreased doses of PPV23 or concomitant injection of both vaccines did not prevent hyporesponsiveness. However, by increasing the delay between PCV13 and PPV23, the phenomenon of hyporesponsiveness is limited. Clinical studies in patients at risk of IPD are needed to evaluate a delayed combined strategy, where PPV23 would be received at least 6 to 12 months after PCV13

Many children under the age of 5 die each year of invasive pneumococcal disease. Childhood vaccination against this disease reduces morbidity and mortality. Despite the introduction of a pneumococcal conjugate vaccine (PCV13) in a central African country in 2011, all provinces have not yet been vaccinated. The purpose of this quantitative quasi-experimental study was to determine whether there was an association between the introduction of PCV13 and new cases of pneumococcal disease in 2 provinces in central Africa. The sample size for the study was 380. The theoretical framework for this study was the epidemic model supported by the concept of herd immunity. Key research questions examined the incidence of pneumococcal disease in children by age, gender, and province. The independent variables were age, gender, province, and introduction of PCV13. The dependent variable was incidence of invasive pneumococcal disease. The research questions were evaluated using chi-square test of independence and logistic regression. The results of the study indicated that vaccination with PCV13 significantly reduced incident cases of invasive pneumococcal diseases (aOR 0.333, 95% CI 0.628-0.177, p = 0.001). However, this association was not significant for age (aOR 0.574, 95% CI 1.186-0.278, p = .134), and there were no significant gender differences (aOR 1.047, 95% CI 1.929-0.569, p = 0.882). Positive social change may result by enabling the protection of more children in the central Africa country provinces that have not yet adopted using PCV13 and by introducing the vaccine in other African countries.

Objectives: By summarizing and comparing the pattern of invasive pneumococcal disease (IPD) in the 4 areas (namely Hong Kong, other parts of China, United States and Thailand) at different stages of implementation of universal pneumococcal vaccination, a snapshot picture could be obtained to visualize how pneumococcal vaccination has impacted upon various important measures, including the burden of IPD, prevalent serotypes, antimicrobial resistance, risk factors of IPD, to guide us on the next step to optimize our ability to combat against IPD. Methods: To achieve the objective, a systematic search through PubMed, Medline, Cochrane Library, EmBase, CINAHL, and the China Journal Net (for Chinese journal articles to obtain a more comprehensive data for “other parts of mainland) has been performed. Articles were selected according to the inclusion and exclusion criteria, and in straight accordance to the literature search and article retrieval steps as described in the methodology. The quality of the articles was assessed by the STROBE (Strengthening the Reporting of Observational studies in Epidemiology) checklists. Results: In general, there was decline in IPD incidence after PCV vaccination, but the problem of serotype replacement and antimicrobial resistance was still an ongoing problem, which differs geographically. Conclusion: From the above data, we could see the significant impact on PCV on reduction of incidence in IPD as shown in United States, however, it was also very clear that unless development of non-serotype specific vaccine become available to us, we are still facing the problem of serotype replacement and that we need to have regular surveillance, as in the case of United States, to supply the data for timely replacement of new PCV combating the emerging serotypes, such that we would still be in the safe ground. In Hong Kong, the statutory reporting of IPD to Centre for Health and Protection (CHP) has been effective since 2/1/201443, after the start of universal immunization since October 2008, followed by PCV10 in 2009 and PCV13 in December 2011, we seems lacking behind on the surveillance. With the surveillance started by CHP, we hope to understand the Hong Kong situation better and with more published data for our local burden and serotype pattern of IPD. It is interesting to note that the antimicrobial pattern does vary geographically, even in US with universal immunization. This suggests that while PCV was helping us to reduce the penicillin resistant strain, another more important factor – the practice of use of antibiotics- is still operating to effect on the overall antibiotic resistance. The pattern that rural Thailand was having much much less penicillin resistance as compared to urban Bangkok, where antibiotic is more readily available, also supports this explanation.<br>published_or_final_version<br>Public Health<br>Master<br>Master of Public Health

Submitted by Ana Maria Fiscina Sampaio (fiscina@bahia.fiocruz.br) on 2013-10-18T18:53:21Z No. of bitstreams: 1 Vivian Galvão. Caracterizaçao de cepas...2012.pdf: 1132531 bytes, checksum: c5a7374a74f6f74d8bd7cc7573c224f5 (MD5)<br>Made available in DSpace on 2013-10-18T18:53:21Z (GMT). No. of bitstreams: 1 Vivian Galvão. Caracterizaçao de cepas...2012.pdf: 1132531 bytes, checksum: c5a7374a74f6f74d8bd7cc7573c224f5 (MD5) Previous issue date: 2012<br>Fundação Oswaldo Cruz. Centro de Pesquisas Gonçalo Moniz. Salvador, BA, Brasil<br>A doença pneumocócica invasiva (DPI) continua sendo uma das principais causas de morbidade e mortalidade no mundo, mesmo com a disponibilidade atual de terapias antimicrobianas e vacinas conjugadas. O objetivo desse estudo foi caracterizar o perfil fenotípico e genotípico das cepas invasivas de Streptococcus pneumoniae isoladas de diferentes sítos de infecção que circulam em hospitais públicos e privados da cidade de Salvador-Brasil no período de janeiro de 2008 a julho de 2011. Os isolados de S. pneumoniae de doença invasiva foram identificados por métodos microbiológicos clássicos e submetidos à determinação capsular através da técnica de Multiplex-PCR. A sensibilidade aos antimicrobianos foi determinada pela técnica de microdiluição em caldo. A caracterização genotípica foi realizada por PFGE e MLST. No período do estudo foram identificados 75 casos de DPI com cultura positiva, sendo 82,7% provenientes de hemocultura, 9,3% de líquido pleural e 8,0% de líquor. As crianças representaram 37,9% e os idosos 24,0% da população em estudo. Os sorotipos mais prevalentes foram o 14 (14,7%), 19F (13,3%), 6B (10,7%), 23F (9,3%), 3 (9,3%) e 19A (6,7%). Um total de 57,3% dos sorotipos identificados estão representados na vacina PCV10. Não-susceptibilidade à penicilina (CIM ≥ 4μg/mL) foi observada em 5,3% dos isolados. Para o SMX-TMP, tetraciclina e eritromicina, os índices de não-susceptibilidade foram de 55%, 15% e 11%, respectivamente. A tipagem por PFGE classificou 61,3% dos isolados de DPI como não-clonais e 29 (38,7%) em 10 perfis clonais. Quando comparados aos isolados de meningite isolados no Hospital Couto Maia, 22,7% apresentaram perfis semelhantes, que foram distribuídos em seis grupos clonais (quatro grupos clonais com isolados não-susceptíveis à penicilina e dois sensíveis). Foram encontrados 22 STs diferentes entre as 26 amostras caracterizadas por MLST. Quando comparado aos clones já caracterizados pelo PMEN, verificou-se que na cidade de Salvador circulam clones já identificados em outros países, a exemplo dos clones: Colombia23F-26 (SLV 338), Portugal19F-21 (ST 177), Spain9V-3 (SLV 156) e Netherlands3-31 (ST 180). Os isolados de pneumococos deste estudo apresentam maior taxa de resistência, incluindo resistência a múltiplas drogas quando comparados aos dos casos de meningite identificados em casos de meningite, com exceção da penicilina. Embora os clones mais frequentemente associados aos casos de meningite pneumocócia em Salvador tenham sido identificados nesta casuistica, os isolados de pneumococos provenientes de outras formas de doença invasiva apresentaram uma maior diversidade fenotípica e genotípica, ressaltando a importância do monitoramento contínuo das cepas invasivas nas diferentes manifestações da doença pneumocócica no tempo das vacinas conjugadas.<br>Invasive pneumococcal disease (IPD) remains one of the major causes of morbidity and mortality worldwide, even with the current availability of antimicrobial therapies and conjugate vaccines. The objective of the present study was to characterize the phenotypic and genotypic profiles of invasive pneumococcal isolates obtained from patients admitted to public and private hospitals in Salvador, from the period of Jan/2008 to Jul/2011. The pneumococcal isolates from invasive disease were identified by classical microbiological methods and submitted to capsular deduction by multiplex-PCR. The antimicrobial susceptibility was performed by broth microdilution method. The genotypic profile was accessing by PFGE and MLST. During the study period, 75 consecutive culture-positive cases of IPD were characterized, being 82.7% from blood, 9.3% from pleural fluid and 8.0% from CSF. The study population comprised of 37.9% of children (under 5 years old) and 24.0% of elderly (upper 64 years old). The most prevalent serotypes were: 14 (14.7%), 19F (13.3%), 6B (10.7%), 23F (9.3%), 3 (9.3%) and 19A (6.7%). A total of 57.3% of the serotypes identified are represented in the vaccine PCV10. Non-susceptibility to penicillin (MIC ≥ 4μg/mL) was observed in 5.3% of the isolates. The non-susceptibility rate for SMX-TMP, tetracycline and erythromycin was found in 55%, 15% and 11% of the isolates, respectively. The PFGE pattern analysis classified 61.3% of IPD isolates as non-clonal and 29 (38.7%) isolates were clustered in ten PFGE profiles. When the clonal strains were compared with pneumococcal meningitis isolates from Hospital Couto Maia, 22.7% showed similar profiles by PFGE, being distributed into six clonal groups (four clonal groups of penicillin non-susceptible and two of penicillin susceptible). Twenty-two STs were observed among the 26 samples characterized by MLST. When compared to already characterized PMEN clones, it was found that some circulating clones in the city of Salvador have been identified in other countries, such as: Colombia23F-26 (SLV 338), Portugal19F-21 (ST 177), Spain9V-3 (SLV 156) and Netherlands3-31 (ST 180). The pneumococcal strains in the study have a higher rate of resistance, including multidrug resistance when compared to cases of meningitis identified in the HCM, except for penicillin. Although the clones most frequently associated with cases of meningitis in Salvador have been identified in this study, isolates of pneumococci from other forms of IPD had a higher phenotypic and genotypic diversity, highlighting the importance of continuous monitoring of invasive strains in different manifestations of pneumococcal infection in the time of conjugate vaccines.

La enfermedad neumocócica invasiva (ENI) constituye un problema grave de Salud Pública en la edad infantil, con una morbimortalidad considerable. En los últimos años se han introducido vacunas adecuadas para la edad infantil (año 2001:vacuna heptavalente conjugada, PCV7, año 2010:vacunas decavalente y trecevalente conjugadas). Desde la comercialización de la PCV7 se ha observado una emergencia de la ENI por serotipos no incluidos en la PCV7 (SNV) en nuestro medio. Esta tesis pretende a partir del análisis de la ENI que ha tenido lugar en los últimos años en nuestro medio (cuando la PCV7 era la única vigente) en una área sin vacunación sistemática, identificar los factores clínicos y microbiológicos asociados a la emergencia de ENI por SNV. Los objetivos de la tesis son: determinar la incidencia de ENI en menores de 5 años en nuestro medio, sus principales características clínicas y microbiológicas y las características clínicas y moleculares de la ENI producida por el serotipo 19A. Los 2 artículos publicados que componen la tesis y que permiten contestar estos objetivos son: 1/Clinical presentation of invasive pneumococcal disease in Spain in the era of heptavalent conjugate vaccine (Pediatr Infect Dis J. 2012; 31(2):124-8) y 2/ Emergence of invasive pneumococcal disease caused by multidrug-resistant serotype 19A among children in Barcelona (J Infect.2009; 59(2):75-82). El primer artículo expone un estudio prospectivo en el que se incluyen los niños < 5 años con ENI diagnosticados en los hospitales Sant Joan de Déu y Vall d’Hebron. La recogida se hizo durante 3 años consecutivos (2007-2009). Se incluyen pacientes diagnosticados por cultivo y/o PCR. Los principales resultados fueron:se incluyeron 319 pacientes, con una media de edad de 29.6 meses. Comparando las incidencias del 2007 y 2009 (76.2 y 109.9 casos/100000 habitantes,respectivamente) se observa un incremento del 44%. La principal manifestación clínica fueron las neumonías (79.6%), seguido de las meningitis (9.1%) y bacteriemias (7.8%). El diagnóstico se hizo por cultivo en 38.6% pacientes y en 61.4% por PCR en tiempo real. Pudo hacerse el serotipado en 300 casos, 91% eran SNV. El serotipo más frecuente fue el 1 (20.7%), seguido del 19A (15.7%) y el 3(12.3%). Una concentración mínima inhibitoria a la penicilina ≥ 0.12 g/ml se detectó en 34.4%. El secuenciotipo 306 expresando el serotipo 1 fue el más frecuente (20.3%). El segundo artículo se centra en la caracterización del 19A. Este serotipo se asocia a multirresistencia a antibióticos por lo que su estudio es relevante. Se trata de un estudio prospectivo realizado entre 1997 y 2007 en el que se incluyen los niños < 18 años con ENI por 19A del Hospital Sant Joan de Déu. Los principales resultados fueron:comparando la época prevacunal (1997-2001) con la vacunal inicial (2002-2004) y la vacunal tardía (2005-2007) se observa un incremento de ENI causada por 19A: 1.7% vs 14.8% vs 21.9% respectivamente (p:0.002). Todos los 19A aislados en la época prevacunal fueron sensibles a la penicilina, mientras que en la vacunal tardía, 44% eran resistentes (p:0.01). Se detectaron 15 secuenciotipos diferentes expresando el 19A, 10 de los cuales eran secuenciotipos preexistentes asociados al 19A, incluyendo los multirresistentes ST320 y ST276. Las principales conclusiones de la tesis son: -La ENI continúa aumentando en Barcelona, la incidencia es mayor que la descrita previamente debido a la baja sensibilidad del cultivo. -Los SNV fueron los responsables del 91% de los casos de ENI y la neumonía fue el principal diagnóstico. -El 19A se está extendiendo rápidamente y se está convirtiendo en una causa importante de ENI en la era vacunal. -El aumento del 19A se relaciona con la emergencia de clones sensibles y resistentes, varios de ellos relacionados con clones multirresistentes conocidos.<br>Clinical and microbiological characteristics of pediatric invasive pneumococcal disease in Barcelona in the era of heptavalent conjugate vaccine The aim of this doctoral thesis is to analyze the rate of incidence, clinical presentation, serotype, and clonal distribution of invasive pneumococcal disease (IPD) in the era of heptavalent pneumococcal conjugate vaccine (PCV7) in Barcelona and to describe the epidemiology of IPD caused by Streptococcus pneumoniae serotype 19A. The 2 published articles that compose the thesis are: 1/Clinical presentation of invasive pneumococcal disease in Spain in the era of heptavalent conjugate vaccine (Pediatr Infect Dis J. 2012; 31(2):124-8) and 2/ Emergence of invasive pneumococcal disease caused by multidrug-resistant serotype 19A among children in Barcelona (J Infect.2009; 59(2):75-82). The first paper describes a prospective study comprising all children <5 years with IPD who were managed in 2 tertiary-care pediatric hospitals during 3 years (2007-2009). The diagnosis was made by positive culture and/or by real-time PCR. In this study, 319 patients were included. Comparing rates in 2007 and 2009 an increase of 44% was observed. The main clinical presentation was pneumonia (79.6%). Serotype study was performed in 300 episodes and 91% were non-PCV7 serotypes. The most frequent serotypes were 1 (20.7%), 19A (15.7%) and 3 (12.3%). Sequence type 306 expressing serotype 1 was the most frequent clonal type detected (20.3%). The second paper describes the clinical and molecular epidemiology of serotype 19A. This is a prospective study that includes all children <18 years with IPD caused by 19A who were admitted to a Children’s Hospital in Barcelona (1997-2007).Serotyping, antibiotic susceptibility and clonal analysis were performed. Comparing the pre-vaccine period (1997-2001) with the early vaccine period (2002-2004) and the late vaccine period (2005-2007) there was an increase of IPD caused by 19A. All 19A isolated in the pre-vaccine and early vaccine periods were penicillin susceptible, while in the late vaccine period, 44% were penicillin nonsusceptible (p:0.01).A clonal analysis revealed 15 different sequence types expressing serotype 19A.10 of them were pre-existing STs associated with 19A including the multidrug-resistant ST 320 and ST276. The main conclusions of the thesis are: -IPD continues to increase in Barcelona. -Non-PCV7 serotypes were responsible for 91% of episodes and pneumonia was the main clinical presentation. -There was an increase of IPD caused by 19A which was mainly related with the emergence of pre-existing clones several of them closely related with.

The overall aim of this thesis is to improve knowledge about the prevention of infectious and bleeding complications in patients with hematological malignancies, primarily in those with chronic lymphocytic leukemia (CLL) and myelodysplatic syndrome (MDS). Hypogammaglobulinemia, impaired production of immunoglobulins (Ig), is an established risk factor for infection, but the impact of IgG pure subclass deficiency (IgG subclass deficiency with adequate production of IgG, IgA, and IgM) has been debated. In a retrospective single institution study, we concluded that pure IgG subclass deficiency in CLL patients is rare and is not associated with an increased risk of infection. Hence, routine analysis of IgG subclasses in patients with CLL is not warranted. There is no consensus on recommending vaccination against Streptococcus pneumoniae to CLL patients mainly because comparative studies are lacking. In our randomized trial, the efficacy of a conjugated pneumococcal vaccine on immune response was superior or equal to a polysaccharide vaccine for all pneumococcal serotypes common for the two vaccines. A conjugate pneumococcal vaccine should therefore be included in vaccination programs for patients with CLL. Bronchoalveolar lavage (BAL) is a well-established invasive method to identify the cause of pulmonary infiltrates in immunocompromised patients. In a retrospective trial, we have studied the diagnostic yield of BAL in patients with hematological malignancies. We concluded that BAL is highly useful in either verifying or excluding some of the important respiratory tract infections affecting these patients, particularly invasive pulmonary aspergillosis (IPA) and Pneumocystis jirovecii pneumonia (PJP). However, standardized procedures for BAL sampling should be continually revised to avoid unnecessary microbiological tests. Thrombocytopenia, an adverse prognostic factor in patients with MDS, can be aggravated by azacitidine, first-line treatment for high-risk MDS. Eltrombopag, a thrombopoietin-receptor agonist (TPO-R), alleviates thrombocytopenia in patients with immune thrombocytopenic purpura (ITP). In a phase I clinical trial, we concluded that the combination of eltrombopag and azacitidine in high-risk MDS patients with thrombocytopenia is feasible and well tolerated in doses up to 200 mg eltrombopag daily.

As infecções por Streptococcus pneumoniae (pneumococo) ainda desafiam os sistemas de saúde em todo mundo. Este é um estudo observacional, de seguimento retrospectivo, que avaliou aspectos microbiológicos e clínicos das cepas de pneumococo isoladas de pacientes com doença invasiva pneumocócica (DIP) isolados nos Departamentos Regionais de Saúde (DRS) de Araraquara, Barretos, Franca e Ribeirão Preto, em um período de 16 anos (1998-2013). As informações foram obtidas junto ao Instituto Adolfo Lutz e, no banco de dados do Hospital das Clínicas de Ribeirão Preto (HCRP). Analisou-se 796 linhagens, com predominio do gênero masculino (58,9%), da faixa etária de 20 a menores de 60 anos de idade (32,2%) e do período de 2003 a 2010 (60,2%). As DIPs mais comuns foram a meningite (45,7%) e a pneumonia (45,0%). Quanto aos sorotipos mais frequentes, observou-se em 83,3%: 14, 3, 19F, 1, 6A, 6B, 23F, 9V, 18C, 19A, 12F, 4, 7F, 5, 22F, 11A, 8, 9N, 10A e 15C, sendo o 14 o mais comum nos quatro DRS estudados. Os sorotipos 14, 3 e 19F foram mais frequentes na meningite, enquanto os sorotipos 14, 3 e 1 na pneumonia. Após 2010, verificou-se diminuição dos sorotipos 14, 1, 23F e 5 e aumento de 12F, 11A e 8, não contidos na vacina. A resistência à penicilina foi de 14,8%, sendo 3,0% resistência intermediária e 11,8% de resistência plena. Para ceftriaxona, 5,3% foram não sensíveis. A sensibilidade ao cloranfenicol, eritromicina e ceftriaxona manteve-se acima dos 90%, no período estudado. O maior nível de resistência foi observado para Sulfametoxazol/trimetoprim (49,4%). Destaca-se o aumento dos sorotipos 12F, 11A e 8 após a vacinação, considerando que nenhum deles compõe as vacinas conjugadas disponíveis. Observou-se variabilidade de resistência entre os diferentes sorotipos de pneumococo. A DIP mais frequente nos pacientes cadastrados no HCRP foi a pneumonia (67,8%), seguida da meningite (22,9%) tendo como sorotipos mais frequentes 14, 6A, 23F, 1, 3, 18C, 19F, 12F, 4,9V, 6B e 19A. Destes pacientes 67,5% apresentaram cura sem sequelas, 6,9% tiveram algum tipo de sequela e 25,6% evoluíram para óbito. A pneumonia causou 18,2% dos óbitos, principalmente na faixa etária de 20 a menores de 60 anos de idade. Os sorotipos 12F, 14, 18C, 9V, 18A, 19A e 23F foram responsáveis por 64,9% dos óbitos por meningite, enquanto os sorotipos 3, 14, 9V, 6B, 23F e 19F estiveram envolvidos em 63,4% das mortes por pneumonia. Entre os pacientes que morreram 68,2% tinham algum tipo de comorbidade, sendo HIV/AIDS, alcoolismo e câncer as mais comuns. A faixa etária com 60 anos ou mais foi a mais significativa (OR=4,2) para o insucesso, independente da presença de comorbidade. A presença do sorotipo 18C foi fator de risco significativo tanto na análise bruta (OR=3,8), quanto ao ajustar por comorbidade (OR=5,0) ou ajustada por idade (OR=5,4). O mesmo ocorreu para o sorotipo 12F (respectivamente, OR=5,1, OR=5,0 e OR=4,7). Observou-se alterações na circulação de alguns sorotipos de pneumococo no período pós VPC10. Ressalta-se a importância da continuidade da vigilância das DIPs, afim de determinar oscilações clínicas e microbiológicas da doença. Além disto, na era das vacinas conjugadas, o contínuo monitoramento sobre a distribuição de sorotipos na população é necessário para a avaliação do impacto e adequação da imunização<br>Infections by Streptococcus pneumoniae (pneumococcus) are still a challenge to health systems worldwide. An observational retrospective study was developed to assess microbiological and clinical aspects of pneumococcus strains isolated from patients with invasive pneumococcal diseases (IPD) which were isolated in the Regional Health Departments (DRS) of Araraquara, Barretos, Franca and Ribeirão Preto, in a period of 16 years (1998-2013). Data were obtained at the Adolfo Lutz Institute and in databases of the Clinics Hospital of Ribeirão Preto (HCRP). A total of 796 strains were analyzed, with prevalence of male individuals (58.9%), aged between 20 and 60 years (32.2%), and in the period between 2003 and 2010 (60.2%). The most common IPD were meningitis (45.7%) and pneumonia (45.0%). Regarding the most frequent serotypes, in 83.3% they were: 14, 3, 19F, 1, 6A, 6B, 23F, 9V, 18C, 19A, 12F, 4, 7F, 5, 22F, 11A, 8, 9N, 10A and 15C, with 14 being the most common in the four DRS studied. Serotypes 14, 3 and 19F were more frequent in meningitis, whereas serotypes 14, 3 and 1 were more frequent in pneumonia. After 2010, there was a decrease in serotypes 14, 1, 23F and 5, and an increase in 12F, 11A and 8, which are not included in the vaccine. Resistance to penicillin was 14.8%, with 3.0% being intermediate, and 11.8% full resistance. For ceftriaxone, 5.3% were not sensitive. Sensitivity to chloramphenicol, erythromycin and ceftriaxone remained over 90% in the studied period. The highest level of resistance was observed for Sulfamethoxazole/trimethoprim (49.4%). It is noteworthy that there was an increase in the s serotypes 12F, 11A and 8 after vaccination, considering that none of them make up the combined vaccines available. Resistance varied among the different serotypes of pneumococcus. The most frequent IPD in the patients registered in the HCRP was pneumonia (67.8%), followed by meningitis (22.9%), with the most frequent serotypes being 14, 6A, 23F, 1, 3, 18C, 19F, 12F, 4, 9V, 6B and 19A. Of these patients, 67.5% were cured without sequela, 6.9% had some sort of sequela and 25.6% evolved to death. Pneumonia caused 18.2% of the deaths, mainly in the age range between 20 and 60 years. Serotypes 12F, 14, 18C, 9V, 18A, 19A and 23F were responsible for 64.9% of the deaths by meningitis, whereas serotypes 3, 14, 9V, 6B, 23F and 19F were involved in 63.4% of the deaths by pneumonia. Among the patients who died, 68.2% had some sort of comorbidity, with HIV/AIDS, alcoholism and cancer being the most common. The age range over 60 years was the most significant (OR=4.2) for failure, regardless of the presence of a comorbidity. The presence of serotype 18C was a significant risk factor both in the gross analysis (OR=3.8), and in the adjustment as for comorbidity (OR=5.0) or age (OR=5.4). This was also true for the serotype 12F (respectively, OR=5.1, OR=5.0 and OR=4.7). There were alterations in the circulation of some pneumococcus serotypes in the period after VPC10. it is emphasized the importance of continued monitoring of DIPs, in order to determine clinical and microbiological fluctuations of the disease. In addition, in the era of combined vaccines, it is necessary to keep monitoring the distribution of serotypes in the population to assess the impact and adequacy of immunization

博士<br>國立臺灣大學<br>流行病學與預防醫學研究所<br>106<br>Background and Aims: There are limited evidence describing the post-licensure vaccine effectiveness (VE) of a combination of pneumococcal conjugate vaccines (PCVs) of different valences (7-valent PCV, PCV7/10-valent PCV, PCV10/13-valnt PCV, PCV13) and/or the duration of protection they offer against IPD in children. Additionally, most evidence identified 23-valent pneumococcal polysaccharide vaccine (PPV23) VE against IPD in adults comes from western counties. This study was to evaluate the PCV VE before PCV introduction into routine immunization in children and PPV23 VE in the elderly for whom the public-funded PPV23 program targeted at in Taiwan. Methods: A matched case-control study using the national IPD surveillance database and the national vaccination registry was applied to select four age-matched, gender-matched and neighborhood-matched controls for each incident IPD case ≦5 years with disease onsets between October 2007 and December 2013. Conditional logistic regression was used to assess VE against all-serotype and serotype 19A IPD (the dominant serotype) in children. Additionally, we investigated PPV23 VE in adults ≧75 years against IPD from July 2008 to June 2016 using the screening method and the indirect cohort (Broome) method. Results: In children, a similar VE against all-serotype IPD was found between PCV13 (76%; 61–85%) and combined PCV7/PCV10 plus PCV13 (78%; 56–89%). Regarding serotype 19A, a significantly reduced risk was observed for both PCV13 (82%; 63–91%) and combined PCV7/PCV10 plus PCV13 (87%; 61–96%). VE was 81% (69–88%) within 6 months of the last dose of PCV and 19% (95% CI: -21–45%) after 2 years. PPV23 VE estimated with the screening method was 32.5% (95% CI: 17.5–44.7), 33.9% (95% CI: 25.2–41.5) and 43.4% (95% CI: 34.4–51.2) against death within 30 days of IPD onset, all-serotype IPD and PPV23-serotype IPD in adults aged ≧75 years, respectively. VE against PPV23 serotypes by the indirect cohort method was 39.0% ((95% CI: 15.5–50.9) overall, 44.9% (95% CI: 20.8–61.7) within 5 years of vaccination, and 15.5% (95%: -47.1–51.4) after 5 years, respectively. Conclusions: PCVs are effective against IPD during immunization with either the same or with a mixed series, but protection might be differential over time. Furthermore, PPV23 was estimated to have moderate protection against PPV23-serotype IPD in adults aged 75 years and older and the protection may last for about 5 years.

Masters of Science<br>Invasive pneumococcal disease (IPD), which includes potentially fatal conditions such as meningitis, septicaemia and pneumonia poses a threat in children aged <5 years, pneumonia being the leading cause of child mortality worldwide. Even though capsular polysaccharides are the main antigens involved in the immunity to encapsulated bacteria, it was found that in children in that age group, the immune system was unresponsive. Conjugate vaccines however induce immunologic memory and provide long-term protective immunity. Therefore the aim of this project was to develop novel conjugation strategies towards a pneumococcal conjugate vaccines and focuses mainly on the serotypes that are a burden to the African continent. The chemistry involved in developing a conjugate vaccine is of importance beacuse while some polysaccharides contain chemical grouping which can be conveniently utilized for conjugation, many medically important ones require derivatization before they can be coupled to protein. Derivatization of which can be achieved through various strategies, important to note is through hypervalent iodine oxidants. Two hypervalent iodine reagents, O-Methyl substituted-1-hydroxy-1,2-benziodoxol-3(1H)-one 1-oxide (Me-IBX)and modified 1-hydroxy-1,2-benziodoxol-3(1H)-one 1-oxide (mIBX)were successfully synthesized in preparation for the use in polysaccharide, polyribitol phosphate, (PRP) oxidation. The polysaccharide to be oxidised was first size reduced by microfluidisation to allow maximum oxidation. However, the extent to which oxidisation was achieved was not enough to conjugate the polysaccharide to the protein of preference, Bovine Serum Albumin, (BSA).

碩士<br>國立成功大學<br>公共衛生研究所<br>98<br>Pneumonia is the most common infectious disease among children under 5 years old and elderly over 65 years old. According to the report from WHO, pneumonia is the most common cause of death in children less than 5 years of age. However, 30 to 50% of pneumonia cases resulted from Streptococcus pneumonia infection. Except pneumonia, Streptococcus pneumonia was responsible for meningitis, septicemia, and empyema, which collected into invasive pneumococcal disease (IPD). Antibiotics is not the only way to treat or to eradicate pneumococcal disease. 7-valent pneumococcal conjugate vaccine ( PCV7) has been incorporated into USA vaccination program since 2000. Direct and indirect vaccine effects were published enormously during the past 10 years. PCV7 started to enter Taiwan market since 2005. The aim of this study was to survey the efficacy of PCV7 based on the prevalence of invasive pneumococcal disease before and after the introduction of PCV-7. The author involved in a big nasopharyngeal carriage survey conducted by 3 major medical centers located at north, central and south Taiwan. Nasopharyngeal carriage rate of children in Taiwan reduced year by year after 2006. The peak carriage rate appeared at the age of 18 to 24 months old, followed by age group between 2 and 5 years. The main serotypes of Streptococcus pneumoniae isolated from cases were 6B, 14, 19F and 23F which were included in PCV7. It showed that the phenomenon of serotype replacement had not presented in observing period from 2006 to 2009. Data from Taiwan Bureau of Health Insurance from 1997 to 2008 revealed hospitalization and mortality rate owing to IPD were high in children less than 12 months of age. The case fatality rate is more than 5% at 1997 and decreased to 1.36% at 2008. The hospitalization rate per 100000 due to IPD analyzing from 1997 to 2008 showed the trend of moving down. According to the highest carriage rate in children of18-24 months old, the maximum age of PCV7 vaccination in order to get immune before colonization is 1 year old. Increasing coverage rate of PCV7 vaccine should be considered seriously in Taiwan to continue lower down the prevalence of IPD.

The National Centre for Immunisation Research and Surveillance (NCIRS) is located within the Kids Research Institute (KRI) at Westmead Children’s Hospital. It is somewhat hidden away from the children’s hospital, and no easier to navigate internally once you find the building on your first day. During my two years there, I was part of the Coverage, Evaluation and Surveillance (CES) Program Stream, which met monthly to discuss achievements and deliverables of the group. As an active member, I was encouraged to keep the group up to date on my progress throughout my MAE journey. The Western Sydney Public Health Unit (WSPHU) is located at Cumberland Hospital adjacent to Westmead Children’s Hospital. I spent two weeks at the PHU, observing and assisting wherever possible. I helped with a measles outbreak, including contract tracing, interviewing people, maintaining clinical line lists, informing high-risk people of a measles-clinic and assisting medical staff during the running of the measles-clinic. During this emergency response, all high-risk people (including pregnant mothers and newborn babies) were contacted and provided with appropriate prophylaxis to prevent illness. During my time there, I was also very fortunate to lead a Salmonella outbreak investigation (Chapter 3). The Communicable Diseases Branch (CDB) is located in the Ministry of Health building in North Sydney. I spent almost four months there conducting the epidemiological investigation (Chapter 4). During my time at the CDB, I attended staff meetings, afternoon debriefs, surveillance meetings and an in-house emergency response workshop. I was also very fortunate to be funded to attend the OzFoodNet whole genome workshop in Melbourne. I also assisted with two Legionella outbreaks, where I helped to maintain line-lists and the Sit-Rep, and attended the afternoon meetings, where I was asked to take, transcribe and distribute minutes of meeting from time to time. I truly enjoyed my experience at the CDB, NSW Health. 1.2 Summary of my public health experience 1.2.1 Analysis of a public health dataset (Chapter 2) In November 2005, hepatitis A vaccine was funded under the Australian National Immunisation Program for Indigenous children aged 12-24 months in the targeted jurisdictions of Queensland, South Australia, Western Australia and the Northern Territory. I reviewed the epidemiology of hepatitis A from 2000-2014 using data from the Australian National Notifiable Diseases Surveillance System, the National Hospital Morbidity Database, and Australian Bureau of Statistics causes-of-death data. Overall, the national hepatitis A immunisation program has had a significant impact in the targeted population with relatively modest vaccine coverage, with evidence of substantial herd protection effects. 1.2.2 Outbreak Investigation (Chapter 3) During May 2015, an increase in Salmonella Agona cases was reported from western Sydney, Australia. I present the public health actions used to investigate and control this increase. A descriptive case-series investigation was conducted. Six outbreak cases were identified; all had consumed cooked tuna sushi rolls purchased within a western Sydney shopping complex. Onset of illness for outbreak cases occurred between 7 April and 24 May 2015. Salmonella was isolated from food samples collected from the implicated premise and a prohibition order issued. No further cases were identified following this action. In addition, this outbreak investigation also demonstrated genomics-enhanced public health action, where whole genome sequencing significantly enhanced the resolution of the epidemiological investigation. 1.2.3 Epidemiological investigation (Chapter 4) Among adults, pneumococcal pneumonia causes significant mortality and morbidity. While the funding of polysaccharide pneumococcal vaccines have reduced the incidence of invasive pneumococcal disease (IPD) in older people, uncertainty remains regarding their effectiveness against reducing the hospitalisation rate due to community acquired pneumonia. In this study I use linked-data to document that approximately one in seven hospital admissions coded for pneumococcal pneumonia in older people of NSW were due to invasive pneumococcal disease. The remaining six hospital admissions were presumptive non-invasive pneumococcal pneumonia cases. I also documented significant declines in the rate and severity of hospitalisations over time due to presumptive non-invasive pneumococcal pneumonia. The pneumococcal polysaccharide vaccine that was used for adults has not been consistently shown to be effective against non-invasive pneumococcal pneumonia hospitalisations, while the conjugate vaccine used in the children program has provided substantial indirect protection against IPD to adults. The results presented here could impact on cost-effectiveness of pneumococcal vaccine programs in Australia. 1.2.4 Evaluation of a surveillance system (Chapter 5) The AusVaxSafety enhanced active surveillance system was established in 2014 and has two main functions. Firstly, to gather near real-time data of AEFI following seasonal influenza vaccination of children aged between six months and five; secondly, to collate, interpret and disseminate these results in near real-time to stakeholders and the public. AusVaxSafety was evaluated to assess the usefulness of the information collected; identify strengths and limitations; and provide feedback to stakeholders regarding recommendations to the system. During the 2015 influenza season, the AusVaxSafety successfully demonstrated, in real-time, that influenza vaccines registered for used in children aged six months to five years were safe, well tolerated, and that the AEFIs experienced were within expected ranges.

The Communicable Diseases Branch (CDB) of Queensland Health has the role of protecting the health of Queenslanders through the monitoring, surveillance, and control of communicable diseases. From February 2016 to December 2017, I undertook a field placement within the CDB. This thesis details projects undertaken during this 22-month field placement. The projects comprise an investigation of a Q fever outbreak at an animal refuge clinic and veterinary clinic, the establishment of a surveillance system to identify newly acquired hepatitis C infections in Queensland, an analysis of vaccine breakthrough invasive pneumococcal disease in Queensland in children younger than 5 years of age, and an analysis of the risk of recurrent invasive pneumococcal disease in Queensland. Also described in this thesis are other public health experiences gained during my placement, including my role in teaching, an assessment of the need to include rheumatic heart disease as a notifiable condition in Queensland, a WHO Western Pacific Regional Office consultancy, and a lookback investigation of a dental clinic. Together, these projects and experiences fulfil the core requirements of the Master of Philosophy (Applied Epidemiology) program at Australian National University.