Estudos sobre imunização do desamparo aprendido apresentam resultados contraditórios quando utilizam estímulos apetitivos na fase de imunização. Uma análise dos procedimentos utilizados nesses estudos sugere que eles diferem no grau de controle e previsibilidade da liberação do estímulo apetitivo. Além disso, foi demonstrado que quando a previsibilidade do estímulo é manipulada ela produz efeitos dependentes do sexo do sujeito. O presente estudo teve por objetivos avaliar se: 1) a previsibilidade e a controlabilidade de estímulos apetitivos na fase de imunização são variáveis críticas para imunizar ratos contra o desamparo; 2) esses efeitos são dependentes do sexo. Em paralelo, buscou-se explorar alguns efeitos das variáveis hormonais nesses comportamentos. Um Estudo Piloto demonstrou não haver diferença quanto ao desamparo em fêmeas nas fases de estro e diestro do ciclo estral. Quanto à imunização (Experimento 1), foi utilizado reforçamento positivo combinando-se as variáveis de controle (VI e VT) e previsão (com ou sem sinal antecedendo a disponibilização do reforço), utilizando-se grupos (n=16) com ratos machos e fêmeas em igual proporção. Em seguida esses animais foram submetidos a choques incontroláveis e por fim a um teste de fuga. Outro grupo de machos e fêmeas passou apenas pelas duas últimas fases e um grupo apenas pela fase final. Os resultados mostraram que o sexo dos animais não é uma variável importante para o desamparo, mas que essa é uma variável que interfere na imunização do desamparo aprendido. Fêmeas expostas a estímulos previsíveis e controláveis na fase de imunização apresentam um comportamento muito semelhante as fêmeas e machos do Grupo não choque. Por outro lado, apenas metade dos machos expostos a estímulos apetitivos previsíveis e controláveis na fase de imunização aprenderam a resposta de fuga no teste. Esses resultados sugerem que o sexo é uma variável que precisa ser mais investigada em experimentos que estudam o comportamento. No Experimento 2 as fêmeas foram distribuídas em dois grupos (castradas e sham), foram retirados os ovários dos animais do primeiro grupo, responsáveis pela produção do estrógeno, hormônio que as diferencia dos machos. Após a recuperação da cirurgia os animais de ambos os grupos foram expostos ao mesmo procedimento de imunização do Grupo imprevisível e controlável do Experimento 1, o único em que foram obsevadas diferenças estatísticas entre machos e fêmeas. Os resultados mostraram aproximadamente metade das fêmeas, de ambos os grupos, aprenderam fuga apresentando latências semelhantes entre si, sugerindo que a presença ou ausência do hormônio sexual em fêmeas não foi, aparentemente, o fator determinante da diferença de gênero na imunização. Discute-se a relevância dos estudos comportamentais entre gêneros mostrando a interação de fatores ambientais com orgânicos / Studies on immunization against learned helplessness have different results when using appetitive stimuli during immunization. An analysis of these studies procedures suggests that they differ in the degree of control and predictability of the release of appetitive stimulus. Furthermore, it was shown that when the predictability of the stimulus is manipulated it produces effects that depend of the subjects sex. The objective of the present study was to evaluate : 1) if the appetitive stimuli predictability and controllability during immunization are critical variables to immunize rats against learned helplessness; and if 2) these effects are sex dependent. In parallel, we explored t some effects of hormonal variables on these behaviors. A pilot study showed no difference regarding learned helplessness in estrus and diestrus phases of the estrous cycle. Concerning immunization (Experiment 1), positive reinforcement was used combining the variables of control (VI and VT) and predictability (with or without signal preceding the availability of reinforcement), using groups (n = 16) with equal proportion of male and female rats. Then these animals were subjected to uncontrollable shock and finally to an escape test. Another group with males and females was submitted only to the last two phases and a last group only to the final phase. The results showed that sex is not an important variable concerning learned helplessness, but it interferes with the immunization against learned helplessness. Females exposed to predictable and controllable stimuli during immunization showed similar behavior with females and males of Non Shock Group. On the other hand, only half of the males exposed to predictable and controllable appetitive stimuli during immunization phase learned the escape response during the test. These results suggest that sex is a variable that needs to be better investigated in behavior experiments. In Experiment 2, females were distributed into two groups (castrated and sham), the ovaries of the animals of the first group were removed, they are responsible for the estrogen production, a hormone that differentiates males from females. After recovery from surgery, both groups were exposed to the same immunization procedure of the unpredictable and controllable group from Experiment 1, the only group that statistical differences between males and females were observed. Females in both groups showed similar escape latencies suggesting that the presence or absence of sex hormone in females was apparently not the determining factor of gender difference in immunization. It is discussed the relevance of behavioral sex differences studies showing the interaction of environmental with organic factors

O objetivo deste trabalho foi estudar a ocorrência de meningites não meningo cócicas no município de Ribeirão Preto, Estado de São Paulo, no período compreendido entre 1998 e 2005. Foi realizado um estudo epidemiológico descritivo centralizado na Divisão de Vigilância Epidemiológica da Secretaria Municipal de Saúde de Ribeirão Preto, a partir dos registros do Sistema Nacional de Informação das Doenças de Notificação Compulsória (SINAN W). No período avaliado foram notificados e confirmados 1411 casos de meningites não meningocócicas. Observou-se ocorrência predominante no sexo masculino (62.9%), em todas as faixas de idade. O grupo etário mais atingido foi o das crianças de 5 a 9 anos (24.7%), seguido pelos indivíduos de 1 a 4 anos (23.5%). O grupo de 30 anos ou mais correspondeu a 20.5% dos casos, enquanto os menores de um ano de idade representaram 8.9% das ocorrências. No que diz respeito à etiologia, verificou-se predomínio das meningites virais (58.7%), seguidas das bacterianas (26.3%), de etiologia pneumocócica (5.7%) e das causadas por outros agentes (4.2%). Em 3.1% dos casos a etiologia não foi determi nada. Quanto à evolução clínica, observou-se cura em 89.2% e ocorrência de óbito em 9.4%, sendo que em 1.4% dos casos essa informação não foi registrada. Seqüelas foram referidas em 1.7% dos pacientes, com ausência dessa informação em 65.5% do total de casos. / The purpose of this investigation was to study the incidence and some charac teristics of non-meningococcal meningitis in Ribeirao Preto (Brazil) in the years 1998 to 2005. A descriptive epidemiological study was carried out using data from the National System of Compulsory Diseases Notification (SINAN W) of Ribeirao Preto Health Department. A total of 1411 cases of non-meningococcal meningitis were reported and confirmed. The general occurrence was higher for males (62.9%). The most affected groups were children from 5 to 9 years of age (24.7%), followed by the group from 1 to 4 years (23.5%). The age group of 30 years or above represented 20.5% of the cases and children under one year registered 8.9% of the total. Regarding etiology, the most frequent was viral (58.7%), followed by bacterial (26.3%), pneumococcal (5.7%), and other parasites (4.2%). For 3.1% of the cases the etiology of meningitis was not ascertained. Recovery occurred in 89.2% of the patients, 9.4% died from the disease and the information was unknown for 1.4% of them. Sequelae were reported in 1.7% of cases, but this information was lacking for 65.5% of the patients.

Submitted by Rosivalda Pereira (mrs.pereira@ufma.br) on 2017-06-22T20:05:32Z No. of bitstreams: 1 FrancelenaSousaSilva.pdf: 2963299 bytes, checksum: 6714fa8793eab0608c30a2ebded08b14 (MD5) / Made available in DSpace on 2017-06-22T20:05:32Z (GMT). No. of bitstreams: 1 FrancelenaSousaSilva.pdf: 2963299 bytes, checksum: 6714fa8793eab0608c30a2ebded08b14 (MD5) Previous issue date: 2016-01-21 / Conselho Nacional de Desenvolvimento Científico e Tecnológico (CNPQ) / Fundação de Amparo à Pesquisa e ao Desenvolvimento Científico e Tecnológico do Maranhão (FAPEMA) / Fundação de Amparo à Pesquisa do Estado de São Paulo (FAPESP) / The actions of child immunization are important to reducing child mortality, one of the Millennium development goals. For this, it is necessary that the vaccine coverage comply with the Ministry of Health recommendations. The data produced in the vaccination services are less reliable and still occur differences related to socio-economic factors associated to child vaccination. The study aimed to evaluate the factors associated to the incompleteness of basic vaccination schedule (BVS) and vaccination schedule for new vaccines (VSNV) (meningococcal C and pneumococcal 10) in children from 13 to 35 months old, from a birth cohort, in São Luis, Maranhão, Brasil. The sampling was probabilistic at birth, compound 3.076 children born in the year of 2010. The information regarding to vaccination was obtained from the vaccine card. The vaccines considered to BS were BCG, hepatitis B, polio, tetravalent, rotavirus, yellow fever and MMR, and for VSNV, were meningococcal and pneumococcal. An hierarchical analysis was held using Poisson regression with robust variance adjustment. Prevalence ratios (PR) were estimated and respective confidence intervals 95% (CI95%). The BS was incomplete in 33.2 % of children and VSNV at 51.1%. Largest incompleteness ratios of BS as VSNV were found in children whose mothers were teens (BS: PR=1.26 and CI 95% 1.10-1.45; NV: PR=1.15 and CI 95% 1.05-1.27), resided with other children (BS: PR=1,32 and CI95% 1,17-1,49; NV: PR=1,29 and CI95% 1,19-1,40 with one: BS: RP=1,55 and CI95% 1,34-1,80; NV: PR=1,3 and CI95%1,24-1,52 with two or three; BS: PR=1.81 and CI95% 1.41-2.33; NV: PR=1.36 and CI95% 1.11-1.67 with more than three), had smoking habit (BS: PR=1.52 and CI95% 1.28-1.82: NV: PR=1.22 and CI95% 1.07-1.40), don’t planned pregnancy (BS: PR=1.18 and CI95% 1.05-1.31; NV: PR=1.09 and CI95% 1.00-1.10), got pregnant just after the birth of the child under study (BS: PR=1.22 and CI95% 1.04-1.43; NV: PR=1.16 and CI95% 1.03-1.29), made a few prenatal appointment (BS: PR=1.25 and CI95% 1.11-1.40; NV: PR=1.15 and CI95% 1.06-1.25) and started it late (BS: PR=1.40 and CI95% 1.06-1.86; NV: PR=1.27 and CI95% 1.07-1.52). Sociodemographic and behavioral vulnerability indicators and low prenatal service using, were associated to incompleteness of childhood vaccination. It is suggested to consider these vulnerabilities at vaccination strategies, in order to contribute to the achievement of high vaccine coverage both from basic schedule as new vaccines introduced in childhood vaccination, and with that, to enable the child population greater protection against imunopreventable diseases. In addition to provide that pregnant women perform more prenatal appointment and do it so early. / Ações de imunização são importantes para a redução da mortalidade infantil, um dos objetivos de desenvolvimento do milênio. Para isso, é essencial que as coberturas vacinais estejam de acordo com a recomendação do Ministério da Saúde. Dados produzidos nos serviços de vacinação são inconsistentes e há divergências quantos aos fatores associados à vacinação infantil. O estudo objetivou avaliar os fatores associados à incompletude do calendário básico de vacinação (CBV) e esquema vacinal para novas vacinas (EVNV) (meningocócica C e pneumocócica 10) em crianças de 13 a 35 meses de idade, de uma coorte de nascimento, em São Luís, Maranhão, Brasil. Amostra foi probabilística no momento do nascimento, composta de 3.076 crianças do seguimento, nascidas no ano de 2010. Informações sobre a vacinação foram obtidas a partir da caderneta de saúde da criança. As vacinas consideradas para o CBV consistiram em BCG, hepatite B, pólio, tetravalente, rotavírus, febre amarela e tríplice viral e para EVNV, meningocócica e pneumocócica. Realizou-se análise hierarquizada, com regressão de Poisson com ajuste robusto da variância. Foram estimadas razões de prevalência (RP) e respectivos intervalos de confiança a 95% (IC95%). O CBV foi incompleto em 33,2% das crianças e EVNV em 51,1%. Maiores proporções de incompletudes tanto para CBV, quanto para EVNV ocorreram em crianças cujas mães eram adolescentes (CB: RP=1,26 e IC95% 1,10-1,45; NV: RP=1,15 e IC95% 1,05-1,27), residiam com outros filhos (CB: RP=1,32 e IC95% 1,17-1,49; NV: RP=1,29 e IC95% 1,19-1,40 com um; CB: RP=1,55 e IC95% 1,34-1,80; NV: RP=1,33 e IC95% 1,24- 1,52 com dois a três; CB: RP=1,81 e IC95% 1,41-2,33; NV: RP=1,36 e IC95% 1,11-1,67 com mais de três), fumavam (CB: RP=1,52 e IC95% 1,28-1,82; NV: RP=1,22 e IC95% 1,07-1,40), não planejaram a gravidez (CB: RP=1,18 e IC95% 1,05-1,31; NV: RP=1,09 e IC95% 1,00- 1,10), engravidaram logo após o nascimento da criança em estudo (CB: RP=1,22 e IC95% 1,04-1,43; NV: RP=1,16 e IC95% 1,03-1,29), realizaram poucas consultas de pré-natal (CB: RP=1,25 e IC95% 1,11-1,40; NV: RP=1,15 e IC95% 1,06-1,25) e o iniciaram tardiamente (CB: RP=1,40 e IC95% 1,06-1,86; NV: RP=1,27 e IC95% 1,07-1,52). Indicadores de vulnerabilidade sociodemográficas e comportamentais, e baixa utilização dos serviços de pré-natal foram associados à incompletude vacinal infantil. Sugere-se considerar essas vulnerabilidades nas estratégias de vacinação, a fim de contribuir para o alcance de altas coberturas vacinais tanto do calendário básico, quanto de novas vacinas introduzidas na vacinação infantil, e com isso, possibilitar à população infantil maior proteção contra as doenças imunopreveníveis. Além de oportunizar que as gestantes realizem mais consultas de pré-natal e o iniciem precocemente.

Fong, Hildy Felicia. / Thesis (Ph.D.)--Chinese University of Hong Kong, 2011. / Includes bibliographical references (leaves 221-234). / Electronic reproduction. Hong Kong : Chinese University of Hong Kong, [2012] System requirements: Adobe Acrobat Reader. Available via World Wide Web. / Abstract and appendix also in Chinese.

Streptococcus pneumoniae é um importante patógeno respiratório que causa pneumonia, meningite e otite média. A vacina atualmente utilizada, composta de polissacarídeos capsulares (PS) derivados de 23 sorotipos diferentes, tem pouca eficácia em crianças, idosos e em pacientes imunocomprometidos. Vacinas com PS conjugados à proteína são mais eficientes, mas sua produção tem alto custo para ser amplamente utilizada. Além disso, o aumento de isolados clínicos de S. pneumoniae resistentes à antibióticos suporta o desenvolvimento de uma nova e mais eficiente vacina. O uso de bactérias ácido-lácticas (LAB) recombinantes vivas, como um sistema de apresentação do antígeno, representa uma estratégia promissora de vacinação de mucosa, já que são bactérias geralmente consideradas seguras (GRAS-status) e capazes de induzir resposta imune sistêmica e de mucosa. Neste trabalho, Lactococcus lactis, Lactobacillus casei e Lactobacillus helveticus foram engenheirados para expressão constitutiva de PspA (proteína A de superfície de pneumococo), um importante fator de virulência de S. pneumoniae. As bactérias recombinantes foram capazes de expressar PspA em duas localizações celulares: intracelular ou ancorada à parede celular, como analisado por Western-blot, utilizando anticorpos policlonais produzidos contra PspA recombinante purificada de E. coli. A estimulação humoral do sistema imune foi avaliada em termos de produção de anticorpos anti-PspA do tipo IgG no soro ou do tipo IgA na saliva, após administração intranasal de LABs recombinantes em camundongos. / Streptococcus pneumoniae is an important respiratory pathogen that causes pneumonia, meningitis and otitis media. The current vaccine in use is composed of capsular polysaccharides (PS) derived from 23 different serotypes, and has little efficacy in young children, elderly and in patients with immunodeficiencies. PS-protein conjugate vaccines are more effective, but their production is expensive for widespread use. Moreover, the increase in antibiotic-resistant S. pneumoniae clinical isolates supports the development of new and more effective vaccines. The use of live recombinant lactic acid bacteria (LAB) as antigen delivery and presentation systems represents a promising strategy for mucosal vaccination, since they are generally regarded as safe bacteria (GRAS-status) and are able to elicit both systemic and mucosal immune responses. In this work, Lactococcus lactis, Lactobacillus casei and Lactobacillus helveticus were engineered for constitutive expression of PspA (Pneumococcal Surface Protein A), an important S. pneumoniae virulence factor. Recombinant bacteria were able to express PspA in two cellular locations: intracellular or cell-surface exposed, as analyzed by Western-blot, using polyclonal antibodies produced against recombinant PspA purified from E. coli. Stimulation of humoral immune system was evaluated in terms of production of anti-PspA IgG in the sera or IgA in saliva, after intranasal administration of recombinant LAB in mice.

Introdução: Ao longo do século XX, temos registros de diversos povos indígenas dizimados por epidemias de varíola, sarampo e outras doenças que se deram através do contato com a sociedade envolvente. A estratégia de vacinação foi imprescindível para a manutenção de muitas etnias, evitando que fossem acometidas por doenças imunopreveníveis ao longo dos anos. Até a década de 90 não havia ações sistemáticas de imunização para os povos indígenas. Até então, a vacinação limitava-se a ações pontuais no controle de epidemias e a algumas experiências isoladas. No Parque Indígena do Xingu (PIX), desde 1965, as atividades de imunização foram estabelecidas na rotina da assistência por meio de parceria com a Escola Paulista de Medicina, da UNIFESP. E, antes disso, pelo Serviço de Unidades Sanitárias Aéreas, criada pelo sanitarista Noel Nutels, com o objetivo de levar ações básicas de saúde a populações vivendo em áreas rurais de difícil acesso. Entre essas ações destacavam-se o diagnóstico e tratamento da tuberculose, em articulação com o Serviço Nacional de Tuberculose (SNT), a imunização e as extrações dentárias. A prática de vacinação das populações indígenas está vinculada à estratégia de campanha, especialmente nas regiões Norte e Centro-Oeste do país. Em aldeias adjacentes a centros urbanos, situação comum nas regiões Nordeste, Sudeste e Sul do país, com disponibilidade de energia elétrica em tempo contínuo e com uma maior facilidade de acesso dos profissionais de saúde, é comum encontrar-se as ações de imunização integradas à rotina dos serviços de saúde. Objetivo Geral: Analisar as atividades de imunização realizadas no PIX, uma área de difícil acesso, no que se refere aos aspectos do planejamento, execução, monitoramento e avaliação do Programa de Imunização no período de 2007 a 2015, para elaboração de um Guia de boas práticas de imunização em áreas remotas. Metodologia: Trata-se de uma sistematização de experiência, conforme propõe Oscar Jara Holliday, descritiva e qualitativa. As informações foram obtidas a partir de relatórios de trabalho, banco de dados, diário de campo e entrevistas semi-estruturadas. Considerações Finais: O transporte e manuseio de vacinas com qualidade em áreas de difícil acesso é desafiador e complexo, necessitando de estratégias singulares e de um planejamento cuidadoso devido às condições locais, que vão desde um ambiente com temperaturas médias elevadas, longas viagens em barcos sem proteção para o sol, à indisponibilidade de energia elétrica de forma contínua, o que cria uma série de particularidades, obrigando à utilização de diferentes estratégias para manutenção da cadeia de frio. O presente trabalho deu origem à elaboração de um Guia de boas práticas de imunização em áreas remotas. O impacto do Programa de Imunização desenvolvido no PIX é evidenciado pela redução da mortalidade entre as crianças- em especial por doenças preveníveis por vacinas- que não ocorre no PIX há pelo menos 4 décadas. Essas evidências permitem afirmar que o programa de imunização no Xingu tem atingido plenamente os objetivos de proteger a população contra as doenças para as quais existem vacinas disponíveis. / Introduction: Throughout the twentieth century, we have records of several indigenous peoples decimated by smallpox, measles and other epidemics diseases that occurred by the contact with the surrounding society. The vaccination strategy was essential for maintenance of many ethnic groups, preventing lots of them there were affected by vaccine preventable diseases over the years. Until the 90s, there was no systematic actions de immunization for these people. Until this period, vaccination was limited at specific actions to control of epidemics and some isolated experiences. In the Xingu Indigenous Park (PIX), since 1965, immunization activities already were established in routine care, through partnerships with universities (UNIFESP) in times of immunization campaigns. The Sanitarian Noel Nutels, in order to bring basic health care to these populations, especially in difficult access rural areas. These actions included the diagnosis and treatment of tuberculosis, in conjunction with the National Service of Tuberculosis (SNT), immunization and dental extractions. The practice of vaccination to indigenous peoples is linked to the campaign strategy, especially in the North and Midwest regions of the country. In adjacent villages to urban centers, a common situation in the Northeast, Southeast and South of the country, with continuous time electricity and with greater easy access of health professionals, it is common to find immunization actions integrated to routine of health services. Objective: This study aimed to systematize the immunization activities in the Xingu Indigenous Park - PIX, an area of difficult access, searching to describe aspects of planning, implementation, monitoring and evaluation of the Immunization Program from 2007 and 2015, building on the experience and documentary records accumulated over the years and interviews. Methodology: It is a systematization of experience, descriptive and qualitative, according to Oscar Jara Holliday. The information was obtained from the work reports, database, field diaries and semi-structured interview. Final Thoughts: The transport and handling of vaccines with quality, in difficult access areas is challenging and complex, requiring singular strategies and careful planning, due to local conditions that range since an environment with high average temperatures, long trips in boats with no sun protection to a continuous electricity unavailability, which creates a number of special features, requiring the use of different strategies for cold chain maintenance. The present work gave rise to the elaboration of a \"Guide to good immunization practices in remote areas\". The impact of the immunization program developed in PIX is evidenced by its mortality reduction among children, especially for vaccine-preventable diseases, which do not occur in PIX for at least four decades. This evidence allows us to affirm that the immunization program in the Xingu has fully achieved the objectives of protecting the population against diseases for which there are available vaccines.

Alzheimer's disease (AD) is the most prevalent form of progressive dementia and is characterized by the accumulation of amyloid beta (Aß) peptide in the brain and in the cerebral vessels forming cerebral amyloid angiopathy (CAA). As previously reported, an active immunization strategy of mice with Aß1-42 peptide results in decreased Th1 and increased Th2 cytokine responses as well as an effectively clearance of CNS Aß. This approach has also yielded favorable results for many patients, unfortunately, a small percentage of these study participants developed severe aseptic meningoencephalitis likely secondary to CNS invasion of activated T-cells. We have previously demonstrated that disruption of CD40-40L pathway reduces Aß plaque load, promotes Th2 response, and rescues from cognitive impairments. However, direct blockage of the CD40 pathway by passive vaccination with anti-CD40L antibody leads to immunosupression. Therefore, in its current form this therapeutic strategy poses an unacceptable risk to the recipient of treatment, aged individual. For those reasons, the identification and characterization of alternative modulators/inhibitors of CD40 signaling may be necessary for the development of safe and effective AD immunotherapy. This proposal introduces novel immunomodulatory therapies that are based on previous vaccination strategies or cell based therapies across medial field. We showed that transcutaneous vaccination can both be efficacious and safe, thus clearly demonstrating that the right combination of the antigens, adjuvants, and the routes of administration are crucial for the right vaccine. Furthermore, we demonstrated that the effects of current Aß vaccine strategies could be enhanced by a simultaneous blockade of CD40-40L signaling. As an alternative approach, we explored the possibility of cell-based therapies and showed that human umbilical cord blood cells, which are currently used as a treatment for systemic lupus erythematosus and leukemia, and currently investigated against stroke, amyotropic lateral sclerosis, age-related macular degeneration, multiple sclerosis, and Parkinson's disease, and showed that not just they improved the AD like pathology in transgenic animals but altered both the brain and peripheral inflammation levels. Lastly, we discussed the involvement of microglia, one of the key players in both AD pathogenesis and Aß clearance and suggesed that microglia in actuality has a continuum of physiological activation states that contribute to proinflammation, antiinflammation, and phagocytosis.

Immunization has been recognized globally as a cost-effective public health intervention. However, despite its benefits, children in northern Nigeria are still adversely affected by the negative consequences of inadequate uptake of immunization. The purpose of this study was to assess antenatal care and maternal sociocultural determinants that influence childhood immunization within 2 months of birth in northern Nigeria. Constructs of social cognitive theory were applied to this retrospective correlational cross-sectional inquiry involving women 15-49 years old in northern Nigeria. Secondary data (the 2013 Nigeria Demographic and Health Survey) were analyzed using univariate, bivariate and multivariate logistic regression. Statistically significant (p < 0.05) predictors of uptake of childhood immunization within 2 months of birth were the person who delivered antenatal care, the number of antenatal care visits, the number of tetanus injections, maternal educational level, religion, wealth index, husband/partner educational level, and the person who decides on health care. Educated Christian women from middle-class or rich homes, whose husbands/partners were also educated and who jointly decided on health care, made numerous contacts with health care professionals, and received at least one tetanus injection during antenatal care, had a higher likelihood of immunizing their children within 2 months of birth. The positive social change implications for this study include providing evidence of deterrents to childhood immunization that could lead to relevant policies and interventions leading to healthier children, communities, and society.

Cancer immunotherapy has proven to be challenging as it depends on overcoming multiple mechanisms that mediate immune tolerance to self-antigens. In situ immunization is based on the concept that it is possible to break immune tolerance by inducing tumor cell death in situ in a manner that provides antigen presenting cells such as dendritic cells (DCs) with a wide selection of tumor antigens that can then be presented to the immune system and result in a therapeutic anticancer immune response. Based on recent advances in the understanding of antitumor immunity, we designed a three-step approach to in situ immunization to lymphoma: (1) Inducing immunogenic tumor cell death with the chemotherapeutic drug Doxorubicin (Dox). Dox enhances the expression of "eat-me" signals by dying tumor cells, facilitating their phagocytosis by dendritic cells (DCs). Due to the vesicant activity of Dox, microparticles (MPs) made of PLGA (a biodegradable polymer) can safely deliver Dox intratumorally and are effective vaccine adjuvants; (2) Enhancing antigen presentation and T cell activation using anti-OX40; (3) Sustaining T cell responses by checkpoint blockade using anti-CTLA-4. In vitro, Dox MPs were less cytotoxic to DCs than to B lymphoma cells, did not require internalization by the lymphoma cells, and significantly enhanced phagocytosis of tumor cells by DCs as compared to soluble Dox. In mice, this three-step therapy induced CD4- and CD8-dependent systemic immune responses that enhanced T cell infiltration into distant lymphoma tumors leading to their eradication and significantly improving survival. Our findings demonstrate that systemic antitumor immune responses can be generated locally by three-step therapy and merit further investigation of three-step therapy for immunotherapy of lymphoma patients. Furthermore, we designed another in situ immunization approach using PLGA MPs loaded with both Dox and CpG oligodeoxynucleotides (CpG). The addition of CpG was to further enhance the Dox MP design by including an agent that addresses Step Two in situ, by enhancing tumor antigen presentation by DCs. In vitro, we show that Dox/CpG MPs can kill B and T lymphoma cells and are less toxic to DCs than soluble Dox. In vivo, Dox/CpG MPs combined with anti-CTLA-4 and anti-OX40 generated systemic immune responses that suppressed injected and distant tumors in a murine B lymphoma model, leading to tumor-free mice. The combination regimen was also effective at reducing T cell lymphoma and melanoma tumor burdens. In conclusion, Dox/CpG MPs represent a versatile, efficient and safe tool for in situ immunization that could provide a promising component of immunotherapy for patients with a variety of types of cancer.

Vaccination is one of the most efficacious public health interventions1 and has been increasingly used to combat non-infectious diseases. Mechanisms underlying vaccine responses overlap with those regulating immune responses in health and disease. Therefore, an understanding of mechanisms underpinning these responses will have broad implications. Variation in immune response genes contributes to impaired vaccine responses2-4. Understanding the contribution of genetic variants to vaccine responses is likely to be particularly important in early life given the generalized functional immaturity of the immune system in infants and the highly variable kinetics of its maturation over the first few years of life5-7. However, studies of genetic influences on early childhood vaccine responses are scarce. Since a number of genes from several pathways are likely to be important, a targeted approach is necessary. This thesis explored the effects and interactions of genes associated with atopy, as atopy, or the genetic risk for it, has been associated with modulation of early childhood vaccine responses. This thesis aimed to: 1) investigate genetic variants associated with atopy on early childhood vaccine responses; 2) examine interactions between these genetic variants and non-genetic factors; 3) approach developmental genetic influences on genetic effects and their interactions; and 4) extend findings on vaccine responses to other immunological phenotypes and disease outcomes.