Dynamics of High-Risk Nonvaccine Human Papillomavirus Types after Actual Vaccination Scheme

Human papillomavirus (HPV) has been identified as the main etiological factor in the developing of cervical cancer (CC). This finding has propitiated the development of vaccines that help to prevent the HPVs 16 and 18 infection. Both genotypes are associated with 70% of CC worldwide. In the present study, we aimed to determine the emergence of high-risk nonvaccine HPV after actual vaccination scheme to estimate the impact of the current HPV vaccines. A SIR-type model was used to study the HPV dynamics after vaccination. According to the results, our model indicates that the application of the vaccine reduces infection by target or vaccine genotypes as expected. However, numerical simulations of the model suggest the presence of the phenomenon called vaccine—induced pathogen strain replacement. Here, we report the following replacement mechanism: if the effectiveness of cross-protective immunity is not larger than the effectiveness of the vaccine, then the high-risk nonvaccine genotypes emerge. In this scenario, further studies of infection dispersion by HPV are necessary to ascertain the real impact of the current vaccines, primarily because of the different high-risk HPV types that are found in CC

Modeling the transmission dynamics and vaccination strategies for human papillomavirus infection: An optimal control approach

Human papillomavirus (HPV) vaccines have been introduced in several countries and have shown positive results in reducing HPV infection and related diseases. Nevertheless, immunization programs remain sub-optimal and more effort is needed to design efficient vaccination deployment. We formulate a two-sex deterministic mathematical model that incorporates the most important epidemiological features of HPV infection and associated cancers. To assess the population-level impact of HPV immunization programs, the model incorporates school-based vaccine delivery for juveniles and catch-up vaccination for adults. The dynamics of the model are rigorously analyzed using the next-generation operator, the center manifold theorem, and normal forms theory. We formulate an optimal control problem to determine the best deployment strategy for HPV vaccination for several plausible scenarios. We establish the existence of solutions of the optimal control problem, and use Pontryagin’s Maximum Principle to characterize the necessary conditions for optimal control solutions. The findings suggest that if girls-only programs are complemented with catch-up vaccination for adult females, such program has the potential to achieve HPV-associated cancers eradication even if boys and males do not receive the vaccine. We also find that the optimal vaccine deployment, in terms of minimizing HPV associated diseases and the cost of vaccination, is to allocate as much vaccines as possible at the initial phase of the epidemic and once a high vaccination coverage is reached then gradually decrease vaccination rates

Anti-tumor Mechanisms of HPV16 E6*

High-risk types of the human papillomavirus (HR-HPV) are the causative agents of nearly all cases of cervical cancer, as well as a significant number of head, neck, penile, vulvar and anal cancers. Like many other viruses with small genomes, HPV (~8 kb) utilizes numerous mechanisms to increase the capacity of its genome to encode the proteins necessary for successful completion of its infectious life cycle, including alternative splicing. Studies over the past few decades have focused intensively on the activities and roles of E6 proteins from HR-HPVs during the process of cellular transformation, clearly implicating E6 as a major transforming agent. In contrast, the role of the smaller splice isoform, E6*, in the carcinogenic process has not yet been established. Based on previous studies, we proposed that E6* had the potential to reduce tumor formation in vivo. To test this prediction, we injected HPV16+ SiHa and HPV16- C33A cervical cancer cells overexpressing E6* into nude mice and monitored tumor growth over several weeks while comparing them with control tumors lacking E6* overexpression. E6* was found to reduce growth in both SiHa- and C33A-derived tumors. These findings were followed up by in vitro experiments showing that E6* binds to full-length E6 and decreases the growth rate in SiHa cells. Subsequently, we sought to find the cellular pathways most influenced by E6* in attenuating SiHa and C33A tumor growth. Thus, proteomic analysis was performed on both cell lines, revealing that the β -Integrin pathway in SiHa cells and the mitochondrial dysfunction and oxidative phosphorylation pathway in C33A cells were the most significantly altered. Proteomic data was confirmed using immunoblot, microscopy, and flow cytometry techniques. These findings will assist in our quest for understanding the fundamental driving forces behind HPV-mediated and non-HPV-mediated cervical cancers and introduce novel ideas for small molecule inhibitors. Our studies provide several promising leads for future analyses, specifically in the context of human cancers, and carry with them the exciting possibility of replicating the anti-oncogenic activity of E6* in such a way as to provide therapeutic benefit

Effect measures, their estimation and interpretation : Applications to pneumococcal conjugate vaccination

The direct and indirect effects of pneumococcal vaccination on an individual and the population are of great interest. This study focuses on the definition, estimation and interpretation of different effect measures of vaccines and vaccination against pneumococcal colonisation and disease. Vaccine efficacy, effectiveness and impact are considered as epidemiological parameters of interest which are estimated using observations gathered according to some study design. In this thesis, vaccine efficacy against colonisation is defined through pneumococcal acquisition, which describes the natural process of incident occurrences of colonisation better than prevalence. Moreover, a general definition of vaccine efficacy against a multi-type pathogen is presented, with an epidemiologically meaningful interpretation as a weighted average of strain-specific efficacies. A feasible estimation method is then proposed, based on cross-sectional measurement on the current status of colonisation. When the differences in times at-risk between vaccinated and unvaccinated individuals are taken into account, the estimation of vaccine efficacy against colonisation is shown to be less biased by within-host competition between different serotypes (strains). The estimation method is exemplified with empirical data of pneumococcal colonisation in Israeli children. At the population level, vaccine effectiveness is the measure of vaccine-induced protection during an ongoing vaccination programme when both vaccinated and unvaccinated individuals experience the indirect effects of the vaccination programme. Vaccine impact is the population prevented fraction of the incidence of infection when exposure is the vaccination programme rather than each individual’s own vaccination. Both vaccine effectiveness and impact are parameters that depend on the population dynamics of pneumococcal colonisation and disease after vaccine introduction. In this thesis, the time trends of vaccine effectiveness and impact are described with a pseudo-dynamic model that incorporates the incidences of pneumococcal carriage and disease. The model shows that the effectiveness and impact against vaccine-serotype invasive pneumococcal disease (IPD) are expected to be high and largely of the same magnitude through the post-introduction period. By contrast, the vaccine effectiveness and impact against non-vaccine-serotype IPD follow very divergent paths while the vaccine-type colonisation and disease become eliminated. The practical estimation of vaccine effectiveness is exemplified with register data of Finnish children eligible for pneumococcal conjugate (PCV10) vaccination. Three parallel study designs, the cohort, nested case-control and indirect cohort designs, are shown to provide estimates that are broadly concordant with each other. The parameters of vaccine efficacy as proposed in this thesis can be interpreted as measures of the biological effect of the vaccine on new vaccine-type acquisitions and should therefore allow more robust comparisons across different epidemiological settings with differing levels of exposure by non-vaccine strains. Moreover, the thesis helps to interpret the time-varying parameters of vaccine impact and effectiveness during large-scale vaccinations, and their manifestation in Finnish children.Pneumokokkirokotusten yksilöön ja koko väestöön kohdistuvat suorat ja epäsuorat vaikutukset on tärkeää tuntea. Tämä tutkimus keskittyy pneumokokkirokotteiden tehomittojen määritelmiin, estimointiin ja tulkintaan. Rokotteen teho ennen rokotusohjelman aloittamista sekä teho ja vaikuttavuus ohjelman aikana ovat kiinnostavia parametreja, jotka estimoidaan keräämällä havaintoja jonkin koeasetelman mukaisesti. Työssä tarkastellaan pneumokokkirokotteen tehoa nenänielukantajuutta vastaan kantajuuden ilmaantuvuuden kautta. Ilmaantuvuus kuvaa kantajuuden biologista luonnetta paremmin kuin sen esiintyvyys, mutta vaatii tyypillisesti pitkittäismittauksia. Työssä osoitetaan, että rokotusteho kantajuuden ilmaantuvuutta vastaan voidaan estimoida poikkileikkausaineistosta odds-suhteena. Lisäksi näytetään, että kun rokotusteho määritellään patogeenille, jolla on monta alatyyppiä kuten pneumokokille, on huomioitava eri alatyyppien keskinäinen kilpailu nenänielussa. Tällöin rokotustehon estimaatti vastaa tarkemmin todellista rokotustehoa. Tätä havainnollistetaan israelilaisten päiväkotilasten kantajuusmittausten avulla. Laajamittaisen rokotusohjelman aikana rokotusteho mittaa rokotteen yksilölle tarjoamaa suoraa suojaa tilanteessa, jossa sekä rokotetut että rokottamattomat lapset kokevat myös epäsuoria vaikutuksia (laumasuojaa ja ei-rokotetyyppien korvautumista). Rokotusohjelman vaikuttavuus mittaa kantajuuden tai taudin ilmaantuvuuden muutosta verrattuna tilanteeseen ennen rokotusohjelmaa. Sekä rokotusteho että vaikuttavuus ovat parametreja, jotka riippuvat pneumokkikantajuuden ja -taudin väestödynamiikasta. Rokotustehon ja vaikuttavuuden aikatrendejä kuvataan pseudodynaamisella mallilla, joka ottaa huomioon kantajuuden ja taudin ilmaantuvuuden muutokset ajassa. Mallin mukaan sekä rokotusteho että vaikuttavuus rokotetyypin vakavaa pneumokokkitautia vastaan pysyvät korkeina ja liki samansuuruisina koko rokotusohjelman ajan. Sitä vastoin rokotusteho ja vaikuttavuus ei-rokotetyypin vakavaa pneumokokkitautia vastaan ovat hyvin erisuuruiset silloin, kun rokotetyypin kantajuus on vähentynyt ja poistumassa väestöstä. Rokotustehon estimointia havainnollistetaan käyttäen suomalaista terveysrekisteriaineistoa vakavan pneumokokkitaudin tapauksista lapsilla, jotka ovat oikeutettuja pneumokokkirokotusohjelmaan. Kolmen tutkimusasetelman eli kohortti-, pesäytetyn tapaus-verrokki- ja epäsuoran kohorttiasetelman näytetään tarjoavan likimain samansuuruisia estimaatteja. Esitetyt rokotustehon parametrit nenänielukantajuutta vastaan tarjoavat mahdollisuuden verrata rokotetutkimuksia erilaisissa asetelmissa, vaikka ei-rokotetyypin kantajuuden ilmaantuvuus voi vaihdella paljonkin. Lisäksi tutkimus tarjoaa keinoja tulkita ajassa muuttuvia rokotustehon ja vaikuttavuuden mittoja laajojen rokotusohjelmien aikana, erityisesti suomalaisten lasten näkökulmasta

Cost-effectiveness of prevention strategies against cervical cancer in women, Vientiane, Lao PDR

Introduction: En RDP Lao, le cancer du col de l’utérus est une des causes principales de morbidité et mortalité dues aux cancers. Le cancer du col peut être prévenu par des interventions de prévention primaire (vaccination) et secondaire (dépistage). Afin de réduire le fardeau de cette maladie, nous devrions considérer le coût et efficacité des diverses options de prévention pertinentes compte tenu des spécificités du contexte Lao. Objectives : l’objectif principal de ce travail est de simuler le coût-efficacité de stratégies préventives contre le cancer du col de l’utérus en RDP Lao. La thèse est basée sur trois études. La première étude a pour but de déterminer la sensibilité et la spécificité de la combinaison test à l’acide acétique (IVA) et frottis du col comme outil de dépistage. Ces paramètres ont été utilisés dans la troisième étude. La deuxième étude a pour but de déterminer le coût-efficacité de modalités de vaccination. La troisième étude a pour but de déterminer le coût-efficacité d'options de dépistage. Méthodologie : Une revue systématique et une méta-analyse ont été réalisées pour la première étude. Pour la deuxième et troisième étude, un modèle dynamique de la population a été établi pour refléter l’histoire naturelle du cancer du col de l’utérus. Le modèle a été calibré pour tenir compte de la structure d’âge de la population de la Capitale de Vientiane, ainsi que l'incidence du cancer du col de l’utérus et sa mortalité en RDP Lao. La principale issue d’intérêt était le coût incrémental des Années de vie ajustées pour l'incapacité (DALY), dans la perspective du système de santé publique. Le seuil utilisé pour définir si l'investissement requis devrait être considéré comme coût-efficace était celui proposé par l'OMS, soit un ratio coût-efficacité incrémental (ICER) de moins de un PNB per capita par DALY évité. Résultats : L’estimation moyenne de la sensibilité et de la spécificité de la combinaison des tests pour les cas de positivité (un de deux tests est positive) étaient de 0.87 (95% CI: 0.83-0.90) et 0.79 (95% CI: 0.63-0.89) respectivement. La deuxième étude a montré que la vaccination des jeunes filles âgées de 10 ans est très coût-efficace. Ajouter au programme de vaccination des jeunes filles un rattrapage vaccinal pour les femmes de 11 à 25 ans est plus coût-efficace qu'ajouter les garçons. Cependant, il faut augmenter l’âge maximal du rattrapage vaccinal à 75 si la couverture vaccinale est moins de 50% ou bien si la durée de protection du vaccin ou l’immunité naturelle ne dure pas plus que 10 ans ou si l’incidence de cancer du col de l’utérus est supérieure à 40% de l’estimation de Globocan, soit 17.5 cas pour 100 000 femmes. De plus, ajouter le dépistage à la vaccination des jeunes filles est une option plus coût-efficace que la vaccination seule. Parmi les stratégies de dépistage, l’IVA pour les femmes âgées de 30-65 ans tous les trois ans est l'option la plus coût-efficace. Elle est suivie par le test rapide de détection d’ADN-VPH tous les trois ans et la combinaison IVA-frottis conventionnel tous les cinq ans. La probabilité d'être coût-efficace pour ces stratégies est de 73%. Conclusion : Les décideurs devraient considérer d’étendre le programme de vaccination des jeunes filles actuellement mis en place à la capitale de Vientiane à l'ensemble du pays et de considérer l'ajout d’un composant de rattrapage vaccinal et un dépistage par IVA ou un test rapide de détection d’ADN-VPH.Introduction: In Lao PDR, cervical cancer is a leading cause of cancer morbidity and mortality. Cervical cancer can be prevented by primary (vaccination) and secondary (screening) interventions. To reduce the burden of this disease, we need to consider both the cost and effectiveness of the various prevention options that are relevant to the Lao context. Objectives: The main objective of this thesis is to simulate the cost-effectiveness of prevention strategies against cervical cancer in Lao PDR. The thesis is based on three studies. The first study aimed to determine the average sensitivity and specificity of combined Visual Inspection with Acetic Acid (VIA) and cytology testing. Theses parameters were used for the third study. The second study aimed to determine the cost-effectiveness of various vaccination modalities. The third study aimed to determine the cost-effectiveness of screening strategies. Methodology: A systematic review and a meta-analysis were conducted for the first study. For the second and third studies, a population-based compartment and dynamic model of the natural history of cervical cancer was built. The model was calibrated to the age structure of the Vientiane capital population, and the incidence and mortality rates of cervical cancer in Lao PDR. The main outcome of interest was the incremental cost per Disability-Adjusted Life Year (DALY) averted, under a public health care system perspective. The threshold for declaring an option very cost-effective was an Incremental cost-effectiveness ratio (ICER) lower than one GDP per capita per DALY averted, based on WHO recommendations. Results: The pooled estimates of the sensitivity and specificity of the combined VIA and cytology testing (with a positive result in at least one of them) were 0.87 (95% CI: 0.83-0.90) and 0.79 (95% CI: 0.63-0.89), respectively. The second study showed that a 10-year-old girl vaccination program is very cost-effective. Adding a catch-up vaccination element for 11-25 year old women to a girl vaccination program was more cost-effective than adding a boy vaccination component. However, the catch-up should be extended to a higher age if vaccination coverage is lower than 50% or if the duration of the natural immunity or the duration of vaccine protection is no longer than 10 years or if the incidence of cervical cancer is higher than 40% of the Globocan estimates, i.e 17.5 cases per 100 000 women. Additionally, adding a screening strategy to a girl vaccination program is more cost-effective than vaccination alone. Among the screening strategies, a three-yearly VIA screening program for 30-65 year-old women is the most cost-effective strategy, followed by the three-yearly rapid HPV DNA testing option and the five-yearly combined VIA and conventional cytology option, respectively. The probability of cost-effectiveness for these strategies is around 73%. Conclusion: Decision makers should consider expanding the girl vaccination program currently implemented in Vientiane capital nationwide and adding a catch-up vaccination element and a VIA or rapid HPV DNA testing program as appropriate

Human Papillomavirus and Related Diseases

Cervical cancer is the second most prevalent cancer among women worldwide, and infection with Human Papilloma Virus (HPV) has been identified as the causal agent for this condition. The natural history of cervical cancer is characterized by slow disease progression, rendering the condition in essence preventable and even treatable when diagnosed in early stages. Pap smear and the recently introduced prophylactic vaccines are the most prominent prevention options, but despite the availability of these primary and secondary screening tools, the global burden of disease is unfortunately still very high This book will focus on the clinical and diagnostic aspects of HPV and related disease, highlighting the latest developments in this field