Cervical cancer is the second most common malignancy worldwide. Infection with HPV is a necessary cause of cervical. Hispanic women in the U.S. experience significantly higher rates of invasive disease than non-Hispanic Whites. In this population, HPV vaccines hold significant potential to eliminate further disparities in cervical cancer morbidity and mortality. The purpose of this study was to examine factors associated with Human Papillomavirus (HPV) vaccine acceptability among a national sample of Spanish speaking callers to the National Cancer Institute's (NCI) Cancer Information Service (CIS). Specifically this research aimed to identify the sociodemographic, sociocultural and attitudinal determinants of HPV vaccine acceptability. This research involved a cross-sectional study with phone-based interviews conducted in Spanish (n = 836). All female Spanish callers to the CIS were asked to respond to a three-part questionnaire that included items relating to ethnic identity and acculturation, knowledge of cervical cancer and related risk factors, and HPV vaccine acceptability. Descriptive, univariate and multivariate logistic regression were used to characterize the study population and to determine the effect of each of the demographic/sociocultural variables on vaccine acceptance. Independent predictors of HPV vaccine acceptability were determined using multivariate linear regression models. Results showed that HPV vaccine acceptance was high among this group of Hispanic women (78%) and that attitudes about vaccines in general and the HPV vaccine specifically were positive. Factors associated with vaccine acceptance included physician recommendation, awareness and accurate knowledge about HPV, and speaking only or mostly Spanish. Other important predictors included influence of peers, positive attitudes about vaccines in general, higher education and being a mother of a female adolescent. The primary reason cited by those who did not favor vaccination was concern over vaccine safety. This research was the first study looking at vaccine acceptability in a large, national sample of Hispanic women. HPV vaccination can lead to important public health benefits for Hispanic women. Targeted educational interventions must take into account the important sociocultural and attitudinal influences on the decision to vaccinate, such as those identified in the present study. Future educational efforts must involve the physician and take into the account the cultural context of attitudes and beliefs regarding vaccine safety and disease susceptibility. Further studies elucidating the interplay between culture specific beliefs and practices regarding vaccination and the decision to participate in HPV vaccination are needed.

Ruminant alphaherpesviruses related to bovine herpesvirus 1 (BoHV-1) are a cluster of viruses antigenically and genetically closely related. The prototype of this cluster, BoHV-1, is a major pathogen of cattle associated with various clinical manifestations including infectious bovine rhinotracheitis (IBR) and infectious pustular vulvovaginitis (IPV). IBR is a disease of major economic concern in many parts of the world and especially in Europe, both in countries where this infection has been eradicated and in those where the control of IBR is currently or will be undertaken. The massive use of vaccination allowed a significant reduction of the number of IBR clinical cases. However, the existence of closely related viruses to BoHV-1 is a threat for IBR eradication programmes. Consequently, the main objective of the present work is dedicated to afford a better knowledge of the interaction between alphaherpesviruses and their ruminant hosts in order to contribute to improve the control of IBR. To meet the objective, two approaches have been developed: the study of the viral diversity aiming to extend both epidemiological and virological data about ruminant alphaherpesviruses related to BoHV-1 and the study of the heterologous protection aiming to protect minor ruminant species by the concept of the cascade vaccination. Illustrating the problematic of the cluster of ruminant alphaherpesviruses related to BoHV-1, an original situation has been described recently in Belgium. During 2001 and 2002 hunting seasons, 28.9% of red deer were detected seropositive to BoHV-1. Due to an apparent lack of contact between cattle and red deer, it was suggested that a BoHV-1 related virus was spreading in the Belgian red deer population. Thus, the first isolation of cervid herpesvirus 1 (CvHV-1) in wild fauna is reported, which brings the opportunity to deeper analyse the antigenic, genomic and genetic relationship between BoHV-1 and its related ruminant alphaherpesviruses. This isolation demonstrates that a ruminant can be strongly identified as BoHV-1 positive while in actual fact it is infected with a related but distinct alphaherpesvirus and this ruminant will be declared as false positive. The problem is even greater when these viruses become latent allowing their possible reactivation and persistence for a very long time in their ecological niches. It is necessary to have tests which can differentiate related alphaherpesviruses that infect different ruminant species. The control of IBR relies on the use of BoHV-1 gB and gE blocking enzyme linked immunosorbent assays (ELISA) in order to differentiate infected and gE-negative vaccinated animals. Knowing that CpHV-1 is the most distant virus from BoHV-1, it can be hypothesised that a BoHV-1 gB blocking ELISA detects CpHV-1 but that CpHV-1 infection could be discriminated by a BoHV-1 gE blocking ELISA. CpHV-1 being mainly distributed in the Mediterranean part of Europe as Greece, Spain and Italy, the analysis was performed with field serums collected in France with the aim to update the epidemiological situation of the infection in Europe. Besides BoHV-1, CpHV-1 is the most relevant infection in Europe but is sadly neglected. The first reason is that economic losses are restricted to a herd level in contrast with IBR that brings an economical impact at a country level. The second reason is that goat is considered as a minor species. In this context, the problem is still not big enough for commercial interest towards vaccine development. The European Union has recently pointed out the problem of minor uses and minor species and allowed off label use of veterinary medicinal products or the use of a product licensed for a major species when an authorised veterinary medicinal product is not available (cascade principle). Goat being a minor species and CpHV-1 sharing close antigenic and genetic properties with BoHV-1, a live attenuated gE-negative BoHV-1 vaccine has been assessed in goats to protect against either a nasal or a genital CpHV-1 infection.

Treatment of permissive tumours with the oncolytic virus (OV) VSV-Δ51 leads to a robust anti-tumour T cell response, which contributes to efficacy; however, many tumours are not permissive to in vivo treatment with VSV-Δ51. In an attempt to channel the immune stimulatory properties of VSV-Δ51 and broaden the scope of tumours that can be treated by an OV, a potent oncolytic vaccine platform was developed, consisting of tumour cells infected with VSV-Δ51. I demonstrate that prophylactic immunization with this infected cell vaccine (ICV) protected mice from subsequent tumour challenge, and expression of GM-CSF by the virus (VSVgm-ICV) increased efficacy. Immunization with VSVgm-ICV in the VSV-resistant B16-F10 model induced maturation of dendritic cells, natural killer (NK) cells, and T cells. I demonstrate that this approach is robust enough to control the growth of established and spontaneous tumours. This strategy is broadly applicable because of VSV’s extremely broad tropism, allowing nearly all cell types to be infected at high MOIs in vitro, where the virus replication kinetics outpace the cellular IFN response. It is also personalized to the unique tumour antigen(s) displayed by the cancer cell. Histone deacetylase inhibitors (HDIs) can augment viral replication, making them particularly interesting complements to OV therapy. However, the impact of HDIs on the generation and re-stimulation of immune responses remains to be clearly elucidated. Along with my collaborators at McMaster University, I demonstrate that MS-275, but not SAHA, selectively depletes naïve and regulatory lymphocytes. Memory lymphocytes that are being boosted remain unscathed and even have enhanced cytokine production, potentially as a consequence of the depleted lymphocyte compartment. This leads to a delay in anti-VSV neutralizing antibodies and T cell responses. Interestingly, HDI treatment of B16-F10 cells appears to inhibit VSV replication but allows for a longer persistence within the tumour. When used in an oncolytic prime/boost vaccination model, MS-275 potently enhanced survival. Though the anti-tumour immune response is enhanced, a near complete reduction in autoimmune vitiligo is observed with MS-275 administration. Therefore, this HDI uniquely modulates the immune response to enhance anti-tumour immunity and decrease the anti-viral response, while also decreasing autoimmune sequelae.

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The present work confirmed that B. pertussis infection or pertussis toxin produce hypoglycaemia in mice. The hypoglycaemia was associated with hyperinsulinaemia, and both were abolished by destruction of the pancreatic β cells with alloxan. Impaired glucose counterregulatory mechanisms may also contribute to pertussis-induced hypoglycaemia, as the hypoglycaemic action of insulin was prolonged in pertussis infected mice. On the other hand, impaired responsiveness to lower doses of insulin was found. Pertussis-induced hyperinsulinaemia had two components. First, the increase in serum insulin in response to food intake was both greater and more prolonged in pertussis-infected mice. Second, infected or pertussis toxin-treated animals, unlike controls, showed a marked increase in serum insulin in response to certain stresses, such as ether, histamine, anoxia and 2-deoxyglucose. However, other stresses (LPS, cold and hypoxia) did not cause hyperinsulinaemia in pertussis infected mice. Stress-induced hyperinsulinaemia was also seen in normal mice receiving the a2- adrenoceptor blocking drug idazoxan. Stress-induced hyperinsulinaemia in a2 adrenoceptor blocked mice, but not in pertussis-treated mice, was prevented by β adrenoceptor blockade using propranolol. Adrenal demedullation or ganglionic blockade (using hexamethonium) in normal mice also allowed stress induced hyperinsulinaemia. Thus, adrenal medullary catecholamines may normally serve to prevent stress induced hyperinsulinaemia, which becomes unmasked when they are absent or when their action is prevented. Stress-induced hyperinsulinaemia in pertussis treated mice was unlikely to involve autonomic, cholinergic oropioid mechanisms as it was not blocked by hexamethonium, atropine or naloxone. Human infants with pertussis showed no hypoglycaemia compared with non-pertussis controls, although their plasma insulin concentrations were slightly but significantly raised. It remains possible that hyperinsulinaemia with resultant profound hypoglycaemia might occur in susceptible patients following exposure to pertussis-toxin (either during the disease or following vaccination).

Immunotherapy as a means for cancer treatment has been investigated for over a century. While studies have been completed using different immunological strategies, development of a clinical therapeutic cancer vaccine has proven elusive. Recently, success has been seen with prophylactic vaccines for cancers with known viral origins (Gardasil® and Cervarix for Human Papiloma Virus). However, such strategies do not address the challenge in generating effective immune response against other tumor antigens, most of which are weakly immunogenic self-antigens. Tolerance to these self-antigens could ultimately limit the patient’s ability to mount an effective anti-tumor immune response. The US Food and Drug Administration recently approved the first DC cell-based cancer vaccine, Provenge®, for use in prostate cancer. This vaccine requires cell isolations from the patient as well as in vitro DC modifications, which ultimately leads to high cost as well as multiple procedures. However, results indicate that, on average, patients live only four months longer than those receiving a placebo. While this work remains important, and offers proof that priming DCs can improve the lifespan of a patient, it ultimately does not offer a long-term cure. Direct and highly efficient in vivo delivery of antigens to DCs could overcome the challenges associated with ex vivo DC manipulation and may offer a more scalable method for generating anti-tumor immunity. This research focuses on the development of novel formulations that allow simultaneous delivery of protein/peptide-based tumor antigens and immune-modulatory nucleic acids (siRNA and immune stimulatory CpG) to the same dendritic cells (DCs) in-vivo. Such formulations allow a synthetic immune-priming center to be created at the site of immunization and simultaneously deliver the tumor antigen to DCs and modulate their immune response through IL-10 silencing. Our hypothesis is that using such a DC-targeted dual delivery system we will be able to illicit strong T helper 1 (TH1) and Cytotxic T Lymphocyte (CTL) response in vivo against a wide array of tumor antigens. This can become a platform technology where the biomolecules (antigen and immunomodulatory agents) can be easily varied based on particular cancers. / text

Campylobacter jejuni (C. jejuni) is a food-borne bacterial pathogen that is the leading cause of Traveller’s Diaharea and Guillian-Barré Syndrome. Previous research determined that bacterial surface carbohydrates are virulence factors. Specifically, the study of the capsular polysaccharide (CPS) structures has widespread applications to understanding serotype cross-reactivity and biosynthetic pathways, the function of bacterial surface carbohydrates, and glycoconjugate vaccine development. This thesis characterized the CPS of C. jejuni HS:10 and subsequently used the CPS for developing a glycoconjugate vaccine. This was accomplished through extraction and purification of sugar from the bacteria, followed by characterization using chemical degradation, GC-MS, NMR and conjugation techniques. These analyses determined that the CPS was composed of a 3-linked GalNAc backbone and 6d-Galhepf attached at the 4th position with non-stoichiometrically attached O-methyl phosphoramidate attached to the 3 position of the heptose. Using this structure, a successful glycoconjugate vaccine was prepared using periodate oxidation and reductive amination.

Background: Vaccines have been hypothesized in the etiology of autoimmune diseases including type 1 diabetes. There are cases of diabetes reported in the Vaccine Adverse Event Reporting System (VAERS) following the administration of the human papillomavirus (HPV) vaccine, however this potential association has yet to be investigated. The objective of this thesis was to determine whether there is an association between immunization against HPV and the development of type 1 diabetes mellitus in grade 8 girls eligible for Ontario’s vaccination program. Methods: A retrospective, population-based, cohort study of girls residing within an Ontario health unit and eligible for the province’s publicly funded school-based HPV vaccination program between 2007 and 2010 was executed using provincial administrative health databases and the Immunization Recording Information System (IRIS) database. To control for known, unknown and unmeasured time-independent confounders, a self-controlled case series analysis was conducted. The relative incidence and 95% confidence interval were estimated using conditional Poisson regression. Results: The study cohort was comprised of 3465 girls with a mean age of 13.2 years at cohort entry (range 12.7 to 13.6 years). The mean duration of follow up was 2.7 years and ranged from 1.6 to 3.6 years. The proportion of girls who received at least one dose of the qHPV vaccine during the observation period was 58.3% (n=2020). During the study follow-up 15 cases of new onset type 1 diabetes were observed, six of which were classified as etiologically exposed to the qHPV vaccine. Using an indefinite risk window, immunization with the qHPV vaccine was not associated with an increased risk of developing type 1 diabetes (age and season-adjusted RI 0.15; 95% CI 0.02-1.32). Conclusions: The results of this thesis regarding the risk of type 1 diabetes following immunization with the qHPV vaccine are inconclusive as a consequence of the small number of cases identified. However, the random distribution of cases across time and across exposure status suggests that there is no association. Before a definitive conclusion is reached the analysis must be re-conducted on a larger cohort. / Thesis (Master, Community Health & Epidemiology) -- Queen's University, 2012-05-28 10:39:00.73

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Background Human papillomavirus (HPV) is the most common sexually transmitted infection in the United States, and adolescents have the highest incidence. To decrease the burden of HPV and HPV-associated cancers, two vaccines were developed and require a 3 dose series. This study assesses factors that may predict whether a teen will either initiate or complete the vaccine series. Methods National Immunization Survey -Teen 2011 data was used to assess demographic (age, sex, and race/ethnicity) and socioeconomic (poverty and insurance status) factors as they related to vaccine initiation and completion. Bivariate and multivariate analyses were used to determine strength of association. Results Females were more likely than males to initiate and complete the series. Compared to whites, Hispanic teens were 1.5 times more likely to initiate but less likely to complete. Blacks were least likely to complete. Teens below the poverty line were more likely to initiate compared to teens above poverty but less likely to complete. Teens with at least one form of health insurance were 1.2 times more likely to complete than those with no insurance. Conclusion HPV vaccination rates are increasing and need to continue to do so. Emphasis needs to be placed on completing the series to confer complete resistance. This is especially true for blacks and Hispanics who are at a higher risk of HPV-related morbidities.