<p>Mathematical modelling has become a powerful tool used to predict the spread of infectious diseases in populations. Successful analysis and modeling of historical infectious disease data can explain changes in the pattern of past epidemics and lead to a better understanding of epidemiological processes. The lessons learned can be used to predict future epidemics and help to improve public healthstrategies for control and eradication.</p> <p>This thesis is focused on the analysis and modelling of smallpox dynamics based on the weekly smallpox mortality records in London, England, 1664-1930. Statistical analysis of these records is presented. A timeline of significant historical events related to changes in variolation and vaccination uptake levels and demographics was established. These events were correlated with transitions observed in smallpox dynamics. Seasonality of the smallpox time series was investigated and the contact rate between susceptible and infectious individuals was found to be seasonally forced. Seasonal variations in smallpox transmission and changes in their seasonality over long time scale were estimated. The method of transition analysis, which is used to predict qualitative changes in epidemiological patterns, was used to explain the transitions observed in the smallpox time series. We found that the standard SIR model exhibits dynamics similar to the more realistic Gamma distributed SEIR model if the mean serial interval is chosen the same, so we used the standard SIR model for our analysis. We conclude that transitions observed in the temporal pattern of smallpox dynamics can be explained by the changes in birth, immigration and intervention uptake levels.</p> / Doctor of Philosophy (PhD)

abstract: This dissertation analyzes the fourteenth-century English and nineteenth-century Hopi experiences with the unwelcomed traveler of disease, specifically the Black Death and the smallpox outbreak of 1898-1899. By placing both peoples and events beside one another, it becomes possible to move past the death toll inflected by disease and see the role of diseases as a catalyst of historical change. Furthermore, this study places the Hopi experience with smallpox, and disease in general, in context with the human story of disease. The central methodical approach is ethnohistory, using firsthand accounts to reconstruct the cultural frameworks of the Hopi and the English. In analyzing the English and Hopi experiences this study uses the Medicine Way approach of three dimensions. Placing the first dimension approach (the English and the bubonic plague) alongside the third dimension approach (the Hopi and smallpox) demonstrates, not only the common ground of both approaches (second dimension), but the commonalities in the interactions of humans and disease. As my dissertation demonstrates, culture provides the framework, a system for living, for how individuals will interpret and react to events and experiences. This framework provides a means, a measure, to identify and strive for normalcy. There is a universal human drive to restore normalcy after one's world turns upside down, and in seeking to restore what was lost, society undergoes transformation. Disease creates opportunity for change and for balance to be restored. This study concludes disease is a catalyst of change because of how humans respond to it. / Dissertation/Thesis / Doctoral Dissertation History 2014

Le virus Ebola, responsable d'une fièvre hémorragique virale létale et le virus de la variole, agent étiologique de la variole, sont des armes biologiques potentielles. Il n'existe pas de traitement ou de prophylaxie autorisés contre le virus Ebola, quelques candidats vaccins étant en cours de développement. Concernant la variole, des vaccins dits de première génération (virus de la vaccine) ont permis l'éradication de la maladie cependant ils sont à l'origine de complications post-vaccinales parfois sévères alors que des vaccins plus récents dits de troisième génération, non-réplicatifs, ont été développés pour leur innocuité mais restent faiblement immunogènes. Nous avons récemment développé plusieurs vecteurs viraux de type virus de la vaccine (VACV) par délétion d'un certain nombre de facteurs de virulence. Nous avons évalué leur innocuité, leur immunogénicité et leur efficacité en tant que candidats vaccins antivarioliques chez la souris puis utilisé l'un de ces vecteurs pour développer un candidat vaccin bivalent antivariolique et anti-virus Ebola. Ces virus de la vaccine délétés sont réplicatifs mais fortement atténués. Ils induisent une réponse en anticorps neutralisants spécifiques anti-vaccine similaire à celle induite par le vaccin antivariolique de première génération et induisent des réponses immunitaires cellulaires CD4+ et CD8+ spécifiques suffisantes pour protéger l'animal d'un challenge létal de cowpoxvirus en intranasal, simulant une infection par le virus de la variole. Le virus délété le plus immunogène et le plus sûr, nommé MVL, a été utilisé pour construire un vecteur viral codant pour la glycoprotéine du virus Ebola (EGP). Le gène entier d'EGP ou une forme chimérique d'EGP (fusion entre l'ectodomaine d'EGP et le domaine transmembranaire de la glycoprotéine B5 du VACV) ont été clonés dans le génome du vecteur viral. Ces deux vecteurs produisent des virus ayant incorporé EGP dans leur enveloppe. Ces deux candidats vaccins recombinants induisent de fortes réponses humorales spécifiques anti-EGP et anti-vaccine chez la souris immunocompétente. En conclusion, nous avons développé plusieurs candidats vaccins antivarioliques aussi immunogènes et efficaces que le vaccin historique et avec une atténuation similaire aux vaccins de troisième génération. L'un de ces candidats (MVL) a été utilisé comme vecteur viral pour exprimer la glycoprotéine hétérologue EGP, contre laquelle il induit une réponse immunitaire humorale forte / Ebola virus, causing a lethal haemorrhagic fever and variola virus, the agent of smallpox are potential biological weapons. There is no treatment and no prophylaxis authorised against Ebola, although some vaccine viral vectors were developed these last years. Concerning smallpox, several types of vaccines exist against smallpox (based on vaccinia virus), first generation that allowed the disease eradication but responsible of some post-vaccination complications and some non-replicative 3rd generation vaccines which are safe but not very immunogenic. We have recently developed several vaccinia virus (VACV) vectors by deletion of some virulence genes, and we have evaluated their safety, immunogenicity and efficacy as smallpox vaccine in mice and used one of them as a bivalent vaccine against Ebola and smallpox. These viral vectors are higly attenuated and replicative competent. They induce a neutralizing specific-VACV antibodies response similar to that of the historical vaccine and induce VACV-specific CD8+ and CD4+ immune responses efficient to protect immunocompetent mouse model intranasally infected by cowpox virus, simulating variola virus infection.The most safety and immunogenic vaccinia virus vector, named MVL, has been used to construct a vector encoding the Ebola glycoprotein (EGP) for immunization against Ebola. The native EGP gene or a chimeric EGP gene (a fusion between the EGP ectodomain and the transmembrane domain of the VACV B5 glycoprotein) have been cloned into the viral vector genome. These two recombinant vaccine candidates induce specific humoral immune responses against Ebola and vaccinia virus in immunocompetent mice. In conclusion, we have developed several vaccine candidates against smallpox as immunogenic and protective as the historical vaccine and as safe as 3rd generation vaccines. One of these candidates, MVL, has been used as a viral vector to express the heterologous glycoprotein EGP, against which it induce a strong humoral immune response.