Bakgrund: Vaccinationer räknas till sjukvårdens mest effektiva hälsoåtgärd och räddar cirka 1.5 miljoner liv årligen. Trots möjligheten att utnyttja vaccin väljer somliga att inte vaccineras. Detta fenomen kallas för vaccintveksamhet är ett av de tio största hoten mot den globala folkhälsan. Syfte: Syftet var att beskriva vilka motiv som leder till att föräldrar är tveksamma till att vaccinera sina barn. Metod: En allmän litteraturstudie med en deskriptiv design genomfördes. En litteratursökning utfördes i databaserna Cinal och Pubmed, vilket resulterade i elva kvalitativa studier som var relevanta för denna studies syfte. Travelbees omvårdnadsteori användes som teoretisk referensram. Resultat: Resultaten från artiklarna presenterades i 6 olika teman: oro gällande vaccinets säkerhet, misstro till myndigheter, påverkan av social miljö och normer, naturlig immunisering och sjukdomars allvarlighetsgrad och hälsosam livsstil. Föräldrar ifrågasatte vaccinets säkerhet och upplevde otillräcklig information från myndigheter. En del påverkades av samhällets normer. Somliga ansåg att en naturlig immunisering var att föredra och en del trodde att sjukdomarna var ofarliga. Vissa ansåg att en hälsosam livsstil gav ett tillräckligt skydd mot sjukdomarna. Slutsats: Föräldrarnas tveksamhet till att vaccinera sina barn grundas huvudsakligen i en ofullständig förståelse för vaccinets säkerhet och effektivitet. Många kände misstro till sjukvården och föredrog naturlig immunisering framför vaccinering. Den ofullständiga förståelsen bottnade i många fall i informationsbrist och resulterade i att föräldrar kände oro inför vaccin. Sjuksköterskan har en viktig roll i att inta god handlingsberedskap och att i vårdmötet säkerställa att föräldrarna ges förutsättningar att förstå nyttan och nödvändigheten med vaccin. / Background: Vaccine is one of the most effective tools to prevent diseases and saves around 1,5 million lives yearly. Despite access to vaccines, some individuals choose to not vaccinate. This phenomenon known as vaccine hesitancy, is one of the ten biggest threats to global public health. Purpose: The purpose of this study was to describe the motives behind parents’ hesitancy to vaccinate their children. Method: A litterature study with a descriptive design was performed. A literature search was conducted using Cinahl and PubMed databases, leading to eleven qualitative studies relevant to the purpose of this study. Travelbee's nursing theory was used as a theoretical model. Results: The results from all articles are presented in six themes: Concerns regarding the vaccine’s safety, Distrust of authorities, Impact of social environment and norms, Natural immunization and disease severity and Healthy lifestyle. Parents questioned the safety of the vaccine and experienced lack of information from authorities. Some were influenced by norms of the society. Multiple parents considered that a natural immunization was preferable to the actual diseases. Several believed that a healthy lifestyle would provide enough protection against the diseases. Conclusion: Parents hesitancy to vaccinate their children are mainly based on an incomplete understanding of the vaccine's safety and effectiveness. The incomplete understanding was due to a lack of information which led parents to worry about the vaccine. The nurse has an important role in taking good action readiness and to ensure that parents are given the conditions to understand the benefit and necessity of the vaccine.

This project examines the role of immunization registries and their effect on a health care delivery system. Recent efforts to attain coverage of child populations by recommended vaccines have included initiatives by federal and state agencies, as well as private foundations, to develop and implement statewide community-based childhood immunization registries.

O S. mutans é o agente etiológico da cárie dental humana, uma doença com ampla distribuição mundial. A adesão à superfície dental depende da interação entre a proteína de superfície P1 e a aglutinina salivar (SAG) adsorvida ao dente. A região N-terminal da P1 é um alvo vacinal importante que está diretamente associada às funções de adesão e agregação. Este trabalho teve o objetivo de avaliar estratégias vacinais contra o S. mutans baseadas na proteína P1 usando linhagens recombinantes de B. subtilis. O B. subtilis é uma bactéria gram positiva, formadora de esporos, não patogênica, empregada como sistema de expressão de proteínas heterólogas e como veículo vacinal administrado por vias de mucosas. Empregamos o B. subtilis para expressar e purificar a proteína P139-512 derivada da proteína P1 de S. mutans UA159. O antígeno P139-512 apresentou epítopos lineares e conformacionais semelhantes aos presentes na proteína P1 nativa. O sítio de ligação à SAG está preservado nessa proteína assim como suas propriedades imunogênicas. A coadministração parenteral do antígeno com adjuvantes vacinais promoveu resposta sistêmica específica com anticorpos eficazes no bloqueio da adesão de S. mutans. Por fim, usamos esporos de B. subtilis como veículo de entrega de mucosa para o antígeno alvo de S. mutans. Esporos de B. subtilis foram modificados para expressar na superfície adesinas bacterianas (SlpA, InvA ou Inv600) com capacidade de ligação ao epitélio intestinal e, quando no estágio de célula vegetativa, expressar intracelularmente o antígeno P139-512. A imunização oral com os esporos adesivos induziu altas concentrações de anticorpos sistêmicos e de mucosa. A imunização nasal ou sublingual com os esporos recombinantes induziu níveis de anticorpos sistêmicos maiores do que aqueles obtidos após a imunização oral. Além disso, esses anticorpos foram mais eficientes em bloquear a adesão de S. mutans à SAG imobilizada, sem interferir com a agregação. Em conclusão, os resultados obtidos abrem perspectivas interessantes para o desenvolvimento de vacinas anti-cárie baseadas em linhagens de B. subtilis. / S. mutans is the major etiologic agent of human dental caries, a disease with worldwide distribution. The adhesion to the tooth surface is dependent on the interaction of the P1 surface protein and salivary agglutinin (SAG) adsorbed to the tooth. The N-terminal region of P1 is an important vaccine target that is directly associated with adhesion and aggregation functions. This study aimed to evaluate vaccination strategies against S. mutans based on the P1 protein using recombinant B. subtilis strains. B. subtilis is a gram positive, spore-forming, non-pathogenic bacterium used as expression system for heterologous proteins and as a vaccine vehicle administered by mucosal routes. Inicially, we employed a recombinant B. subtilis strain to express and purify the P139-512 protein derived from the S. mutans UA159 P1 protein. The P139-512 antigen showed important conformational and linear epitopes similar to those present in the native P1 protein. The SAG-binding site is preserved in P139-512 as well as immunological properties. The parenteral co-administration of antigen with vaccine adjuvants stimulated systemic antibodies effective in blocking adhesion of S. mutans to SAG. Lastly, we used B. subtilis spores as a mucosal delivery vehicle for antigen targeting. B. subtilis endospores were modified to display bacterial adhesins (SlpA, InvA or Inv600), capable to bind to the intestinal epithelium, on the spore surface and to express intracellularly the P139-512 antigen during the vegetative cell stage. Oral immunization with adhesives spores induced high systemic and mucosal specific antibodies levels. The nasal or sublingual immunization with B. subtilis recombinant spores induced higher amounts of systemic antibodies than the oral immunization. Furthermore, the specific antibodies were highly effective in blocking the adherence of S. mutans to immobilized SAG, without interfering with aggregation. In conclusion, the results open interesting perspectives for the development of anti-caries vaccines based on B. subtilis strains.

Adult immunizations effectively reduce morbidity, mortality, and transmission rates of multiple diseases; however, outpatient providers often a struggle to convince patients to accept vaccinations. This project’s aim is to address vaccination rates in our adult population, focusing first on the influenza vaccine in year one (2016), and then on pneumococcal vaccine in year two (2017), by 1) using a strong quality improvement strategy (known as a Champion Team) and 2) implementing a clinic program consisting of provider training, improved documentation, and informative posters targeted at patients. A quality improvement strategy known as a “Champion Team” provided a strong mechanism through which we developed and implemented the interventions across both years. Specifically, the Champion Team consisted of key stakeholders (nurses, residents, physician faculty, and informatics expert) who identified, developed, and evaluated the program. Programming included an annual health care professional training session for each vaccine (early fall of 2016 and 2017 for flu, spring 2017 for pneumococcal), improved documentation strategies and nursing uptake, and informative posters in the clinic. We assayed data from our patient electronic health record to evaluate: the percentage of our patient population for whom an immunization was documented relative to the number of unique patients seen in our clinic during that time frame. This approach in year one showed a marked increase in influenza vaccination rates in our clinic. During the 2014/2015 and 2015/2016 flu seasons our clinic vaccination rates were 39.98% and 42.05% respectively. After implementation of our champion team and clinic wide program to increase rates in 2016 our vaccination rates for the 2016/2017 flu seasons was 50.88%. Pneumonia data for a full year are under analyses and will be included in this presentation. We anticipate a similar increase in rates for our pneumococcal vaccinations. Our Champion Team and clinic wide program were perceived as relatively low-effort interventions yet appeared to increase vaccinations over the course of this study. The replication of these findings across pneumonia data (pending) and, in future work, with the herpes zoster vaccine (planned for Year 3), will increase our confidence that increases in rates were attributable to these very accessible interventions.

MPH / Department of Public Health

The encompassing aim of this project was to gain a better understanding of the role of the cellular immune response to dengue virus (DV) infection. Dengue virus occurs as four distinct serotypes, called D1-D4. Symptomatic DV infection occurs as two forms of illness. The more severe form of DV infection, dengue hemorrhagic fever (DHF), is characterized by increased capillary permeability resulting in decreased plasma volume, which may be accompanied by hemorrhagic manifestations. At its most severe, DHF can result in circulatory shock and death. Epidemiological studies indicate that DHF is more likely to occur following a secondary infection with a serotype of DV other than that which caused the primary infection, and there is evidence of increased T cell activation in more severe disease. These data and others indicate that DHF may be of an immunopathological nature. The memory CD4+ T cell response of a D4-immune donor was analyzed. Bulk culture proliferative responses of peripheral blood mononuclear cells (PBMC) to noninfectious DV antigens showed the highest proliferation to D4V antigen, with lesser, crossreactive proliferation to D2V antigen. CD4+ cytotoxic T lymphocyte (CTL) clones were established by stimulation with D4 antigen using a limiting dilution method. Seven out of 15 clones recognized the D4V capsid protein. The clones showed heterogeneity in their usage of T cell receptor Vα and Vβ genes. Six of these CTL clones were crossreactive between 02 and 04, and one clone was specific for D4. Using synthetic peptides, the D4V-specific clone was found to recognize an epitope between amino acids (aa) 47-55 of the capsid protein, while the crossreactive CTL clones each recognized epitopes in a separate location, between aa 83 and 92, which is conserved between D2 and D4. These results showed that the DV capsid protein can be a target of the cellular immune response following DV infection. The bulk culture response of the donor's PBMC to the epitope peptide spanning aa 84-92 was also examined. Peptides containing this epitope induced proliferation of the donor's PBMC in bulk culture, but peptides not containing the entire epitope did not induce proliferation. Also, PBMC stimulated in bulk culture with noninfectious D4V antigen lysed autologous target cells pulsed with peptides containing aa 84-92. These results indicate that this donor exhibits memory CD4+ T cell responses directed against the DV capsid protein and suggest that the response to the capsid protein is dominant not only in vitro at the clonal level, but in bulk culture responses as well. Experiments were performed demonstrating that the CD4+ CTL clones were capable of mediating bystander lysis of non-antigen presenting target cells. Following activation on plate-bound anti-CD3 antibody or in the presence of unlabeled antigen-presenting target cells, these clones could lyse both Jurkat cells and HepG2 cells as bystander targets. Bystander lysis of neighboring, non-infected cells by activated CD4+ CTL clones might contribute to the pathology of DHF. The mechanisms of lysis employed by the T cell clones against both cognate and bystander target cells were assessed using chemical inhibitors of either the perforin- or Fas/FasL-mediated pathways. Three CD4+ CTL clones were demonstrated to lyse cognate, antigen-presenting target cells by a mechanism that primarily involves perforin, while bystander lysis occurred through Fas/FasL interactions. In contrast, one clone used a Fas/FasL mechanism to lyse both cognate and bystander targets. These experiments indicated that the perforin- and FasL-mediated mechanisms of target cell lysis are not mutually exclusive, in that a single clone can kill target cells using either mechanism. Additionally, the ability of CD4+ CTL clones to lyse target cells by the perforin pathway indicates that, like CD8+ CTL, these clones might play a role in viral clearance and recovery from infection through lysis of virus-infected cells. Cytokine production by the capsid-specific CTL clones was also examined. Six of six clones studied produced high quantities of IFN-γ in response to either D2V antigen or the epitope peptide. IFN-γ was also produced by PBMC in a bulk culture from this donor stimulated with D4V antigen. All of the clones produced both TNF-α and TNF-β following stimulation. Four of six clones produced low amounts of IL-2, and only three of six clones produced detectable amounts of IL-4. Production of cytokines by activated CD4+ T cell clones in vivo could contribute to both viral clearance and immunopathology. To better understand the role that cytokine production might play in vivo in response to DV infection, cytokine mRNA levels were examined by PCR in DV-infected Thai children. mRNA for the cytokines IFN-γ, TNF-β, TNF-α, IL-1β, and IL-6 were detectable in the PBMC of DV-infected children. Semi-quantitative PCR analysis indicated that TNF-α mRNA levels were elevated in Thai children with DHF compared to children with classical dengue fever, the less severe form of illness (p=.013). All other cytokines showed no statistically significant difference between children with DHF and those with DF, although IFN-γ showed a trend toward elevation in more severe disease (p=.l). Increased production of TNF-α and/or IFN-γ in vivo could potentially contribute to the immunopathology of severe dengue illness. Taken as a whole, the data presented in this thesis provide a better understanding of the role of the cellular immune response to dengue virus infection and its potential contribution to the immunopathology of dengue hemorrhagic fever.

BACKGROUND: The widespread use of vaccines led to significant decline in multiple potentially fatal infectious diseases. Recently, there has been an increase in vaccine hesitancy. Measles and pertussis outbreaks throughout the United States have put a spotlight on this urgent healthcare issue. Motivational interviewing is a counseling tactic that is gaining popularity and is being studied for its efficacy in preventative medicine and psychological disorders. It aims to inspire people to make behavioral changes through collaborative relationships with their provider by understanding how current actions do not translate into their health goals. LITERATURE REVIEW FINDINGS: Vaccine hesitancy is growing. Communities with decreased immunization rates are associated with a higher risk of disease outbreak. Increasing rates of undervaccinated children are likely due to increases in non-medical exemptions. Many parents, regardless of their vaccine hesitancy status, are concerned about vaccine safety. Vaccine hesitant parents refuse vaccines due to philosophical and religious beliefs, conspiracy theories, and safety concerns. Parents feel that providers do not adequately address their concern. Providers report not having the training to discredit parental concerns. The majority of parents describe their child’s pediatrician as their most trusted source of vaccine information. Parents who receive vaccine information from a provider are more likely to comply with the recommended childhood vaccine schedule. The most efficient way to discuss vaccines with parents has yet to be determined. PROPOSED PROJECT: This is a proposed QI research project for the Pediatric Clinic at Boston Medical Center. Providers would be trained in motivational interviewing during several sessions that included lectures and small group practice sessions with systematic feedback. During the intervention, parents who refuse vaccines for their child, aged 0-6 years old, will receive motivational interviewing from the provider. The proportion of the vaccine hesitant parents who accept the offered vaccine after will be analyzed. The pre and post intervention vaccination rates for the entire clinic will also be assessed. Data collection will be preformed through retrospective chart review. The project aims to increase provider confidence on vaccine counseling, educate providers on reasons for hesitancy, and improve compliance with the CDC recommended vaccine schedule. CONCLUSION: While most Americans continue to vaccinate their children according to the CDC’s recommended schedule, constant vigilance is required to maintain high immunization rates to protect our communities. Motivational interviewing is goal-oriented to alter a specific behavior and would allow providers to engage in an open, persuasive dialogue about parental vaccine concerns.

The immune checkpoint blockade is a novel approach of cancer therapy, which markedly enhanced treatment efficacy of several cancer types. However, the frequency of cancer patients non-responding to this treatment is high. Establishment of predictive markers to distinguish patients suitable for the immune checkpoint blockade would enhance the number of patients receiving benefit from the therapy. This dissertation thesis focuses on the enhancement of efficacy of immune checkpoint inhibitors (ICIs) and predictive markers in experimental models of mouse tumours induced by TC-1 and TC-1/A9 cell lines and its clones with deactivation of interferon (IFN)-γ signalling (TC-1/dIfngr1 and TC-1/A9/dIfngr1), or CD80 molecule (TC-1/dCD80-1). IFN-γ is presumed to be the main inducer of programmed death ligand 1 (PD-L1) and a major histocompatibility complex I (MHC-I). Moreover, PD-L1 expression may predict sensitivity to PD-1/PD-L1 blockade. Non-functional IFN-γ signalling or downregulated MHC-I expression has been associated with resistance to ICIs in some patients. We found that IFNs type I (IFN-α and IFN-β) induced the expression of PD-L1 and MHC-I on TC-1/A9/dIfngr1 tumour cells with reversible downregulation of both molecules. We also showed that deactivation of IFN-γ signalling in TC-1/A9 cells was not a...

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The world's population is expected to grow from 6 billion to about 10 billion by 2050. The greatest population increase is expected to occur in Africa, Latin America, and Asia. To feed a world with huge increases in population and to sustain the well-being of humans, a large increase in food production must be achieved. The projected increase in food production must be accomplished on the existing cultivated areas because the expansion of new land is limited by environmental concerns, urbanization and increasing water scarcity. Different compounds have been developed for the "immunization" of plants against several pathogens. These compounds induce systemic acquired resistance (SAR) in plants, leading to broad-based, long-lasting resistance to a wide range of pathogens. The salicylic acid binding protein 2 (SABP 2) has been identified as a key enzyme in the salicylic acid mediated pathogen resistance pathway, converting methyl salicylate (MeSA) to salicylic acid (SA), a key compound responsible for SAR . S-methyl benzo [1, 2, 3,] thiadiazole-7-carbothiate (BTH) was the first commercial compound used for plant immunization. We have synthesized and characterized some new salicylic acid derivatives [methyl-2-(2-hydroxy benzoyl thio) acetate and derivatives], and we have studied the in-vitro activity with SABP2 of BTH by HPLC analysis.