Vaccination has proven a cost-effective method of managing infectious diseases, but attempts to develop an effective fetal vaccine have proven difficult due to the immaturity of the immune system and the propensity of the developing immune system to induce tolerance to immunizing antigens. This thesis is concerned with the induction of specific immunity in the second trimester ovine fetus using the oral DNA immunization method. In utero oral delivery of naked DNA plasmid was selected as the method of immunization due to previous successes in the third trimester ovine fetus and the immunostimulatory properties of the bacterial DNA backbone, which may help overcome developmental tolerance. Transfection and expression studies in the third trimester ovine fetus revealed the oral mucosal epithelium as the primary site of transgene expression and functionally active antigen was also localized to lymph nodes draining the oral cavity. Efficient transfection and expression of plasmid following oral delivery was specific to the fetus and correlated with a lesser degree of epithelial differentiation. Oral DNA delivery in the second trimester resulted in detection of transgene activity in 100% of treated fetuses and the level of transgene activity was greater than in fetuses treated in the mid-third trimester. Using a plasmid encoding the gene for bovine herpesvirus-1 truncated glycoprotein D (tgD), immunization studies were then conducted in the second trimester fetus. A new lower age limit for fetal immunization was established at 55-60 days gestation (gestation period is 148 days), which coincides with the appearance of lymphocytes in peripheral tissues. Antigen-specific antibody, interferon-× responses and/or neonatal anamnestic responses were detected in 66% of fetuses immunized between 55 and 84 days gestation. The duration of fetal primary immune responses was equivalent to that achieved in young lambs following optimized DNA vaccination, but the magnitude of fetal immune responses was limited. The persistence of immune memory from the second trimester to birth was consistent with experimental data which showed that the duration of immune memory had a stronger correlation to the duration, as compared to the magnitude, of the primary antibody response. Overall, the experiments within showed that oral DNA immunization of the early second trimester fetus is feasible and not associated with the induction of tolerance. These findings suggest that it may be possible to protect against mother-to-child transmission of infectious pathogens by targeting protection at the level of the fetus.

Background: An estimated 50,000 adults in the United States (U.S.) die each year from one of 10 vaccine preventable diseases. For those who survive vaccine preventable infections, health care costs and loss of income become more significant. While children in the U.S. aged 0-2 exhibit vaccine prevalence rates of almost 90%, some adult vaccine prevalence rates in the U.S. population are reported to be nearly 30-40% less than the goals set forth by Healthy People 2010. The purpose of this study was to examine the associations between socio-demographic characteristics of U.S. adults and adult vaccination prevalence for pneumococcal, hepatitis A, hepatitis B, tetanus, and pertussis. Methods: Data from the 2008 National Health Interview Survey were assessed examining various health indicators and characteristics of non-institutionalized adults and children. The sample was restricted to adults ≥18 years of age. Odds ratios were calculated and multivariate logistic regression was also conducted. P-values of Results: There were 21781 total observations; 19.3% received the pneumococcal vaccine, 9.4% received the hepatitis A vaccine, 27.2% received the hepatitis B vaccine, 55.1% received the tetanus vaccine, and 15.2% received the pertussis vaccine. Of the socio-demographic characteristics examined, age, health insurance, marital status, and education were significant for either all five or at least four of the vaccines included in this study. As one might expect those who reported health insurance and those who had a higher level of education usually had a higher likelihood of vaccine receipt as compared to those without health insurance and those with less than a high school education. Age associations varied due to age-related recommendations for certain vaccines such as pneumococcal (recommended for adults ≥65). Compared to the married population (referent), marital status results varied, but for reasons unclear. Whites, the referent group, were the most likely to be vaccinated as compared to Blacks, Hispanics/Latinos, and Asians. Hispanics/Latinos typically had the lowest likelihood of vaccination in this examination. Conclusions: This study further explores the impact of socio-demographic disparities on vaccination status and adds new information to the literature regarding adult vaccination rates for preventable diseases. While research exists related to strengthening interventions such as patient reminder systems, those who do not see the same health care providers on a regular basis remain at risk for lower vaccination prevalence. It is important to better understand the role of social determinants of health, specifically in terms of vaccinations. Future research is needed to further characterize the association of socio-demographic factors with receipt of optional vaccines in adults.

L'utilisation de l'amidon comme agent de remplissage, agent liant ou agent désagrégeant est très répandue dans l'industrie pharmaceutique. Des modifications chimiques effectuées sur ce polymère auront une influence sur ses propriétés rhéologiques. La carboxyméthylation de l'amidon génère un excipient dont les propriétés de gastro-protection ainsi que de libération contrôlée pour plusieurs catégories de principes bioactifs ont été démontrées lors de différentes études (Calinescu et al., 2005; 2007; Massicotte et al., 2008). Le concept d'immunisation mucosale lors de la vaccination est basé sur le fait que plusieurs pathogènes ont comme porte d'entrée dans l'organisme les muqueuses (par exemple celles du tractus respiratoire ou gastro-intestinal). Dans cette optique, pour contrer ou prévenir une infection, il faut cibler l'induction de l'immunité mucosale au site d'entrée du pathogène afin d'obtenir une protection optimale. Les protéines végétales incluant des fragments immunogènes spécifiques d'agents infectieux peuvent être utilisées à des fins d'immunisation orale pour une stimulation de l'appareil lymphoïde de la muqueuse intestinale. Une limite à cette approche est la barrière stomacale par rapport au pH gastrique et à l'activité protéolytique pouvant dégrader le matériel immunogène d'intérêt. Il était important de protéger les protéines immunogènes en incorporant les extraits végétaux dans une matrice polymérique utilisée à des fins de transport jusqu'à la muqueuse intestinale. Pour ce faire, les extraits végétaux lyophilisés ont été formulées avec le carboxyméthyl amidon (CMA) offrant une protection gastrique et une libération ciblée de l'actif au niveau intestinal. Lors de la libération des extraits végétaux dans la solution simulant les conditions intestinales (SIF), une destruction des protéines à été observée. L'utilisation d'inhibiteurs de protéases a été testée d'une part dans le milieu de libération et d'autre part dans la formulation elle-même. La libération des agents bioactifs non dégradés a été observée avec l'utilisation du Pefabloc SC à une concentration de 1,6 % (w/w) dans la formulation. A cette concentration, une stabilisation des protéines dans le SIF est observée pendant 6 h. L'utilisation de la lipase comme marqueur enzymatique à permis de donner une information sur la conservation de la structure protéique des éléments bioactifs lors de leur libération. ______________________________________________________________________________ MOTS-CLÉS DE L’AUTEUR : Vaccination, Plantes transgéniques, Polymères biocompatibles, Amidon, Voie orale, Gastro protection, Libération contrôlée, Inhibiteur de protéases.

In this thesis we discuss deterministic compartmental epidemic models. We study the asymp- totic stability of the disease-free solution of models with pulse vaccination campaigns. The main contributions of this thesis are to extend the literature of pulse vaccination models with delay. We take results for ordinary differential equation models and extend them to models with delay differential equations. Model generalizations include the use of a general incidence term as an upper bound for the actual incidence, and the use of switch parameters to approximate time-varying parameters. In particular, we look at contact rate parameters which are piecewise constant or time-varying. We extend literature results for non-delay general incidence models to find uniform asymptotic stability of the disease-free solution which helps us to add delay. We find an upper bound for the susceptible population under pulse vaccination and use this bound to tighten results for eradication thresholds: that is, we use this upper bound to find sufficient conditions for the uniform asymptotic stability of the disease-free solution of delayed pulse vaccination models. We extend literature results for constant contact rate bilinear incidence delay models to models with periodic time-varying contact rate, and determine conditions under which the disease-free solution is uniformly asymptotically stable for small delay. We also find conditions for disease permanence in the corresponding non-delay, time-varying-parameter pulse vaccination model. For piecewise- constant contact rate bilinear incidence models we again find thresholds which guarantee uniform asymptotic stability under small delay. We additionally discuss the effects of time-varying total population on our results, through a change of variables to population fractions. The total population is commonly held constant in the literature, for analytical simplicity, so we survey the methods for time-varying total population and the effects of such variation on the pulse vaccination schemes. We retain thresholds for eradication by considering the compartment populations as fractions of the total, instead of population numbers. The result is also applied to constant-population delay systems. When changing from standard incidence to bilinear incidence in delay systems, we discuss a way to estimate the effect of time-varying N. We support our theory with simulation results.

Vaccination has proven a cost-effective method of managing infectious diseases, but attempts to develop an effective fetal vaccine have proven difficult due to the immaturity of the immune system and the propensity of the developing immune system to induce tolerance to immunizing antigens. This thesis is concerned with the induction of specific immunity in the second trimester ovine fetus using the oral DNA immunization method. In utero oral delivery of naked DNA plasmid was selected as the method of immunization due to previous successes in the third trimester ovine fetus and the immunostimulatory properties of the bacterial DNA backbone, which may help overcome developmental tolerance. Transfection and expression studies in the third trimester ovine fetus revealed the oral mucosal epithelium as the primary site of transgene expression and functionally active antigen was also localized to lymph nodes draining the oral cavity. Efficient transfection and expression of plasmid following oral delivery was specific to the fetus and correlated with a lesser degree of epithelial differentiation. Oral DNA delivery in the second trimester resulted in detection of transgene activity in 100% of treated fetuses and the level of transgene activity was greater than in fetuses treated in the mid-third trimester. Using a plasmid encoding the gene for bovine herpesvirus-1 truncated glycoprotein D (tgD), immunization studies were then conducted in the second trimester fetus. A new lower age limit for fetal immunization was established at 55-60 days gestation (gestation period is 148 days), which coincides with the appearance of lymphocytes in peripheral tissues. Antigen-specific antibody, interferon-× responses and/or neonatal anamnestic responses were detected in 66% of fetuses immunized between 55 and 84 days gestation. The duration of fetal primary immune responses was equivalent to that achieved in young lambs following optimized DNA vaccination, but the magnitude of fetal immune responses was limited. The persistence of immune memory from the second trimester to birth was consistent with experimental data which showed that the duration of immune memory had a stronger correlation to the duration, as compared to the magnitude, of the primary antibody response. Overall, the experiments within showed that oral DNA immunization of the early second trimester fetus is feasible and not associated with the induction of tolerance. These findings suggest that it may be possible to protect against mother-to-child transmission of infectious pathogens by targeting protection at the level of the fetus.

With regard to infectious diseases, the most economical, direct, and efficient way to prevent them is timely inoculation and a comprehensive policy of vaccination. Such steps not only reduce the overall mortality rate, but also lessen a patient¡¦s susceptibility to serious complications once infected, and therefore their length of hospital stay. It is the foundation of disease prevention in all countries, and should be the primary focus of every public health department. This survey is based on a health belief model and a self-constructed questionnaire. Its sample base are parents whose children have visited one of two local hospitals, each of which is in a different administrative region. A total of 350 questionnaires were distributed. Recoveries were 270, of which 237 were useable. The effective response rate, therefore, is 67.7%. The useable recoveries were analyzed by SPSS, 17th edition, and verified and assumed by mean, standard deviation, t-test, one-way ANOVA, Pearson correlation analysis and Logistic regression analysis. The most influential factors on parents¡¦ decision whether or not to accept streptococcus pneumoniae vaccination (SPV) were as follows: 1.The greater the understanding of SPV and its policy, the greater the number of vaccinations 2.The perceived importance of good health 3. Age variability 4. The interrelationship between the perception and the policy of vaccination, the benefits of - and barriers to ¡V action, and the virulence and severity of the disease The results of this research suggest the public perception of SPV is the most important factor governing its efficacy. It is recommended, therefore, that public health departments campaign for SPV in a variety of different ways,( e.g. in newspapers and magazines, on TV, at pediatric clinics, at health centers, etc.) in order to establish a free and open flow of information to the public at large. It is in the hope of reducing the current mortality rate, length and cost of hospital stay and the serious complications arising from infection, that we offer the following data as reference for future planning.

Reproduction de : Thèse doctorat : Médecine. Immunologie et biologie parasitaire : Reims : 2005. / Titre provenant de l'écran-titre. Bibliogr. p.121-141.

Reproduction de : Thèse d'exercice : Médecine vétérinaire : Toulouse 3 : 2007. / Titre provenant de l'écran titre. Bibliogr. p. 108-125.

Lymph nodes (LNs) are dynamic organs responsible for providing a supportive and centralized environment for the generation of immune response. Utilizing a highly organized network of non-hematopoietic stromal cells, the LN serves as the context in which the immune system collects and presents antigen, promotes innate and adaptive immune interaction, and generates protective cell-mediated and humoral immunity. In this way, proper organization and function of the LN environment is a critical component of effective immunity, and understanding its complexity has direct impact on the ability to generate and modulate primary immune response to specific antigens. To this end, the LN architecture, underlying stromal networks, and environmental and cellular responses to influenza vaccination were investigated. Using novel approaches to conduit imaging, details of the collagen network that comprises the LN scaffolding have been integrated into current understandings of LN architecture. The cellular compartment responsible for the maintenance of that scaffolding, fibroblastic reticular cells (FRCs), have been studied using an induced diptheria toxin receptor model. By specifically ablating the FRC population in mice, their role in the maintenance of T cell homeostasis has been confirmed in vivo. More surprisingly, a disruption of the FRC network resulted in a loss of B cell follicle structure within LNs, and a reduction in humoral immunity to influenza vaccination. These findings led to the identification of a new subset of FRCs which reside in B cell follicles, and serve as a critical source of the B cell survival factor BAFF. Turning towards the hematopoietic response to influenza vaccination, a highly unexpected lymph node resident dendritic cell (LNDC) response has been identified following vaccine antigen deposition within specialized sites in the LN medulla. Rapid migration of LNDCs into these sites optimizes exposure of the population to viral antigen, and de novo synthesis of a CXCL10 chemokine gradient by activated LNDCs ensures efficient antigen specific \(CD4^+\) T cell response, and protective humoral immunity - independent of migratory dendritic cell status. Altogether, these studies highlight a highly dynamic, responsive LN environment with direct influence on primary immune response - the understanding of which has broad implications in vaccine biology.

Purpose: To identify barriers to implementing practice recommendations regarding HPV (human papillomavirus) vaccination for male adolescent patients among Family Nurse Practitioners (FNPs). Rationale/Background: HPV infection is a source of numerous cancers. More than one-quarter of the HPV-associated cancers in the United States occur in males. The quadrivalent vaccine is approved in young males and is effective in the prevention of genital warts and reducing HPV related cancers yet vaccination rates are low and expected to remain low. Barriers to vaccination exist even after the 2011 recommendation for routine use. Method: Quantitative, surveys. A 22-item instrument was administered to FNPs working in primary care settings. Participants were surveyed regarding financial, logistic, provider, and parental barriers to vaccination among adolescent males. Results: Descriptive analysis at both the item and scale level demonstrated that FNPs report financial barriers as the most significant barrier. The barriers of least concern were provider attitudes. Barriers regarding FNPs' perception of parental attitudes were seen as moderately concerning. Independent samples t-tests showed that FNPs who did not administer the HPV vaccine to male adolescent patients reported having significantly more financing barriers as compared to FNPs who did. Conclusion: Results suggested that financial issues may constrain FNPs' implementation of practice recommendations for the HPV vaccine and that FNPs who did not administer the HPV vaccination to adolescent male patients may be unable to do so due to financial reasons. Perceptions of parental attitudes are also seen as playing a role in preventing male adolescent patients from receiving the HPV vaccine. Efforts to reduce barriers to implementing recommended HPV vaccine practices should focus on lessening the expense of the vaccine for both providers and parents and increasing parental knowledge and understanding of the HPV vaccine for their sons. Definitions: HPV4 is used to reference the quadrivalent and Gardasil® vaccinations; permissive refers to the 2009 Advisory Committee on Immunization Practices (ACIP) support of allowing adolescent males aged 9-26 to decide, in collaboration with their health care providers, to vaccinate; recommended is the ACIP's modification from permissive to routine recommendation.