Salmonella infections remain one of the most common food borne diseases worldwide. Gastroenteritis, which can be caused by many non-typhoidal Salmonella (NTS) serovars, is relatively common in North America. One of the main risk factors of NTS gastroenteritis is travel to endemic areas in the developing world. The current treatment of NTS infections with antibiotics is reserved for severe cases. A growing concern with antibiotic use is that clinical isolates are becoming drug resistant. Although most NTS infections are self-limiting in nature, the burden on the body and recovery can take several months. Thus, it is vital to prevent NTS infections rather than solely rely on treatment. We have previously discovered two novel surface associated polysaccharides in Salmonella: O-Antigen capsule and X-factor. Not only O-Antigen Capsule is considered a common surface antigen, but its’ genes were found to be expressed during in vivo infections in mice. Such an antigen would be a suitable candidate in developing a vaccine against Salmonella induced gastroenteritis. The goal of this research was to evaluate the use of O-Antigen capsule to develop a traveler’s vaccine for NTS associated gastroenteritis. Results and Conclusions: We have developed a purification protocol and purified the capsule and X-factor from Salmonella Typhimurium, Enteritidis, and Heidelberg. Lipopolysaccharide (LPS) was co-isolated with O-Antigen capsule, but removed using Triton extraction. Salmonella LPS is strain-specific and an adaptive immune response against LPS will not provide cross-protection. We generated specific immune sera in rabbits to recognize O-Antigen capsule and X-factor produced by Salmonella Typhimurium and Enteritidis. We used a mouse model to determine the immunization dose of O-Antigen capsule and showed that conjugation is necessary to enhance the immune response in mice. To boost capsule production, we analyzed PyihUTSRQPO activity using a luciferase-based reporter system. Deletion of a putative transcriptional repressor (YihW) resulted in over 100-fold increase in PyihUTSRQPO confirming YihW as a repressor. We have also looked at the effect of growth media, temperature, and sugar precursors on PyihUTSRQPO activity, and were able to show that PyihUTSRQPO has highest activity in Tryptone broth at 30oC in the absence of any additional sugars.

This study evaluates the ecology of Streptococcus pneumoniae (SP) nasopharynx (NP) colonization in response to the pneumococcal conjugate vaccines, specifically 7-Valent Pneumococcal Conjugate Vaccine (2000-2009), 13-Valent Pneumococcal Conjugate Vaccine (2010-2023) and 20-Valent Pneumococcal Conjugate Vaccine (2023-future date). It is anticipated that the replacement of PCV13 with PCV20, a pneumococcal conjugate vaccine with 7 additional polysaccharide conjugates to CRM197 will enhance the protection against non-vaccine serotypes which are in circulation in communities. The project will evaluate the dynamic changes in pneumococcal colonization over the 5-year time line from 2021-2026. Pneumococcal nasopharynx colonization is detected through nasopharyngeal culture and molecular techniques. The primary source of pneumococcal transmission occurs among the pediatric population and between children and adults. The impact of PCV7 and 13 on pneumococcal colonization over the prior 20 years created a herd effect that resulted in a reduction in pneumococcal disease in unimmunized children and adults. Studies of NP colonization has led to a deeper understanding of pneumococcal conjugate vaccine (PCV) effectiveness and the role of herd immunity in protecting the population, the emergence of replacement serotypes, the variation in invasive capability of each serotype and evolution of antimicrobial resistance resulting from the evolving ecology. In this 5-year-study, researchers at the Pelton Lab in Boston Medical Center set out to understand the prevalence of NP carriage of 13vPnC serotypes, the 7 unique 20vPnC serotypes and NVST (non-vaccine serotypes) within the pediatric population prior to and subsequent to the introduction of PCV 20 (Fall 2023).

No description available.

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.

INTRODUÇÃO: Infecções causadas por Streptococcus pneumoniae são uma das maiores causas de morbidade e mortalidade no mundo, particularmente em países em desenvolvimento, gerando um impacto clínico e econômico significante. Crianças com menos de dois anos de idade, adultos com mais de 60 anos e pessoas com condições crônicas são as populações mais afetadas. Devido ao aumento da resistência a antibióticos e do impacto crescente das consequências da doença, vem sendo discutida a prevenção primária por meio das vacinas antipneumocócicas como uma das estratégias de saúde pública mais eficaz na redução da carga da doença. OBJETIVO: Revisar sistematicamente e avaliar a qualidade do relato dos estudos de avaliação econômica da vacina pneumocócica polissacarídea 23-valente em idosos, com o intuito de comparar as diferentes estratégias metodológicas adotadas pelos estudos publicados e discutir os parâmetros e premissas que possam ter influenciado os resultados dos modelos econômicos. MÉTODOS: Pesquisou-se nas bases de dados eletrônicas Medical Literature Analysis and Retrieval System Online (via PubMed), Excerpta Medica database, Cochrane reviews, Centre for Reviews and Dissemination Database, Web of Science, Scopus Citation Index e Literatura LatinoAmericana e do Caribe em Ciências da Saúde por avaliações econômicas completas da vacina pneumocócica polissacarídea 23-valente, publicadas até março de 2016. Dois revisores independentes selecionaram artigos relevantes de acordo com critérios de inclusão e exclusão e extraíram seus dados. As principais características dos estudos e métodos (dados clínicos e econômicos, custo e relação de custo-efetividade incremental) foram extraídas e comparadas. Custos foram atualizados para dólar internacional de 2016. RESULTADOS: Vinte e sete avaliações econômicas publicadas entre 1980 e 2016 foram incluídas na revisão sistemática, grande parte publicada nos Estados Unidos e na Europa. Apenas três estudos foram conduzidos na América Latina (dois no Brasil, um na Colômbia). Soma-se a esse cenário de comparação entre a vacinação e a não vacinação com a vacina pneumocócica polissacarídea 23-valente, três estudos que também cotejaram a vacina pneumocócica polissacarídea 23valente com a conjugada 13-valente. Todos os estudos utilizaram modelos estáticos. A maioria considerou horizonte temporal para toda a vida (44,4%) ou de cinco a seis anos de horizonte (33,3%). Apenas três estudos consideraram a proteção indireta causada pela imunização da vacina pneumocócica conjugada 13-valente em crianças no modelo. Apesar da diversidade de síndromes clínicas incluídas, das diferentes definições de cada síndrome clínica, da variação nas estimativas de eficácia e de coberturas vacinais e dos custos hospitalares e ambulatoriais das doenças pneumocócicas, a maioria dos estudos incluídos apresentou relações de custo-efetividade incremental favoráveis (menos de US$ 50.000,00 por ano de vida ganho ou por ano de vida ajustado pela qualidade, Quality Adjusted Life Year) e algumas vezes econômicas. Nos estudos, a relação de custo-efetividade incremental variou de costsaving a US$ 84.636,00 por ano de vida ajustado pela qualidade (Quality Adjusted Life Year). As estimativas de impacto da doença, a eficácia/efetividade da vacina pneumocócica polissacarídea 23valente e os efeitos da proteção indireta pela imunização em crianças foram os parâmetros que mais influenciaram os resultados do modelo. Em relação à qualidade do relato dos estudos, as principais limitações foram: descrição clara e completa do resumo, declaração do financiamento do estudo e declaração dos conflitos de interesse. CONCLUSÃO: Esta revisão sistemática revelou que os resultados de custo-efetividade foram variados, de cost-saving a não custo-efetivo. Estudos de custo-efetividade bem estruturados da vacina pneumocócica polissacarídea 23-valente que representam a epidemiologia atual e reduzem a incerteza de parâmetros chave, como a eficácia/efetividade da vacina, são extremamente importantes para auxiliar no processo de decisão / INTRODUCTION: Infections caused by Streptococcus pneumoniae are one of the main causes of morbidity and mortality in the world, particularly in developing countries, generating a significant clinical and economic impact. Children under 2 years old, adults ³60 years old and populations with cronic conditions are the most affected populations. Due to the increase in antibiotic resistance and the increase of the disease\'s consequences, primary prevention of the disease is being discussed with antipneumococcal vaccination as one of the most effective public health strategies in reducing the burden of the disease. OBJECTIVE: To systematically review and evaluate the quality of the reported economic evaluation studies of the 23-valent pneumococcal polysaccharide vaccine in the elderly immunization with the aim to compare the different methodological strategies adopted by the published studies and discuss the parameters and premises that may have influenced the results of economic models. METHODS: It was searched in the electronic databases Medical Literature Analysis and Retrieval System Online (PubMed), Excerpta Medica database, Cochrane reviews, Centre for Reviews and Dissemination Database, Web of Science, Scopus Citation Index and Latin-American and Caribbean Health Sciences Literature for full economic evaluations of 23-valent pneumococcal polysaccharide vaccine published up to March 2016. Two independent reviewers screened articles according to inclusion and exclusion criterias and extracted the data. Main studies characteristics and methods (clinical and economic data, cost and incremental cost-effectiveness ratio) were extracted and compared. Costs were updated to 2016 International Dollar. RESULTS: Twenty seven evaluations published between 1980 and 2016 were included in the systematic review, most of them being published in the United States and Europe. Only three studies were conducted in Latin America (two in Brazil, one in Colombia). In addition to the scenario comparing 23-valent pneumococcal polysaccharide vaccine vaccination to non-vaccination, three studies also compared 23-valent pneumococcal polysaccharide vaccine to 13-valent pneumococcal conjugate vaccine. All studies used static models. The majority considered a lifetime time horizon (44.4%) or from 5 to 6 years of time horizon (33.3%). Only three studies considered the indirect protection from 13-valent pneumococcal conjugate vaccine immunization in children in the model. Despite the diversity of clinical syndromes included, from the different definitions of each clinical syndrome, the variation in vaccine efficacy and inpatient and outpatient costs for the pneumococcal disease, most of the included studies showed and favorable incremental cost-effectiveness ratio (less than US$ 50,000.00 per year of life or Quality Adjusted Life Year) and sometimes cost-saving. In the evaluations, incremental cost-effectiveness ratio ranged from cost-saving to US$ 84,636.00/Quality Adjusted Life Year. The estimates of disease burden, the efficacy/effectiveness of 23-valent pneumococcal polysaccharide vaccine, and the effects of herd protection from childhood immunization had most influence on the results. Regarding the study quality, the main limitations were: clear and complete summary description, statement of the study founding source and declaration of conflicts of interest. CONCLUSIONS: This systematic review revealed that the cost-effectiveness results have conflicting results, from cost-saving to not cost-effective at all. Welldesigned cost-effectiveness studies of 23-valent pneumococcal polysaccharide vaccine that represent the current epidemiological scenario and reduce uncertainty related to efficacy/effectiveness are extremely relevant to informing the decision-making process