Proliferation des Cellules T dans des Conditions Lymphopenique: Modelisation, Estimation des Parametres et Analyse Mathematique

T lymphocytes are a fundamental component of the immune system that can recognise and respond to foreign antigens by virtue of their clonally expressed T cell antigen receptor (TCR). T cells that have yet to encounter the antigen they recognise are termed 'naive' as they have not been activated to respond. Homeostatic mechanisms maintain the number of T cells at an approximately constant level by controling cell division and death. In normal replete hosts, cell turnover within the naive compartment is very low and naive cells are maintained in a resting state.However, disruption of the homeostatic balance can arise from a wide variety of causes (viral infection (e.g. HIV), or drugs used in peritransplant induction therapy or cancer chemotherapy) and can result in T cell deciency or T lymphopenia. Under conditions of T lymphopenia, naive T cells undergo cell division with a subtle change in the cell surface phenotype (CD44 expression), termed homeostatic proliferation or lymphopenia induced proliferation (LIP). In this thesis, our purpose is to understand the process of T cell homeostatic through mathematical approach. Atfirst, we build a new model that describes the proliferation of T cells in vitro under lymphopenic conditions. Our nonlinear model is composed of ordinary dierential equations and partial dierential equations structured by age (maturity of cell) and CD44 expression. To better understand the homeostasis of T cells, we identify the parameters that dene T cell division by using experimental data. Next, we consider an age-structured model system describing the T cell homeostatic in vivo, and we investigate its asymptotic behaviour. Finally, an optimal strategy is applied in thein vivo model to rebuild immunity under conditions of T lympopenia.Les lymphocytes T sont une composante essentielle du systeme immunitaire de l'organisme. Ils peuvent reconna^tre et repondre a un antigene etranger en vertu de leur recepteur d'antigene.Dans le cas normal, le renouvellement des cellules T naives est tres faible et ces derniers restent approximativement dans un etat de repos. Cependant, une perturbation de l'equilibre homeostatique peut resulter d'une grande variete de causes (infection virale, ou les traitements de chimiotherapie), et peut entrainer une lymphopenie (i.e. Une carence en lymphocytes T). Dans ces conditions lymphopeniques, les cellules T naives subissent la division cellulaire avec un changement de l'expression de CD44 sur leur surface cellulaire. Ce processus est appele "proliferation homeostatique" ou en anglais "lymphopenia induced proliferation" (LIP). Ainsi, le CD44 est un marqueur naturel qui caracterise la transition des cellules du phenotype naf (CD44-) au phenotype memoire (CD44+) durant LIP.L'objectif de cette these est de comprendre la relation complexe entre LIP et le passage du phenotype naif (CD44-) au phenotype memoire (CD44+) en utilisant des modeles mathematiques et des donnees experimentales. On s'interesse en plus au comportement asymptotique des cellules T durant le processus d'homeostasie in vivo

Characterizing the transitioning epidemiology of herpes simplex virus type 1 in the USA: model-based predictions.

BACKGROUND: Herpes simplex virus type 1 (HSV-1) is a prevalent lifelong infection that appears to be undergoing an epidemiologic transition in the United States (US). Using an analytical approach, this study aimed to characterize HSV-1 transitioning epidemiology and estimate its epidemiologic indicators, past, present, and future. METHODS: An age-structured mathematical model was developed to describe HSV-1 transmission through oral and sexual modes of transmission. The model was fitted to the National Health and Nutrition Examination Surveys, 1976-2016 data series. RESULTS: HSV-1 seroprevalence was projected to decline from 61.5% in 1970 to 54.8% in 2018, 48.5% in 2050, and 42.0% in 2100. In  30% for those aged 0-19 years, but  60. Meanwhile, the number of new infections per year (oral and genital) was persistent at 2,762,000 in 1970, 2,941,000 in 2018, 2,933,000 in 2050, and 2,960,000 in 2100. Of this total, genital acquisitions contributed 252,000 infections in 1970, 410,000 in 2018, 478,000 in 2050, and 440,000 in 2100-a quarter of which are symptomatic with clinical manifestations. For those aged 15-49 years, nearly 25% of incident infections are genital. Most genital acquisitions (> 85%) were due to oral-to-genital transmission through oral sex, as opposed to genital-to-genital transmission through sexual intercourse. CONCLUSION: HSV-1 epidemiology is undergoing a remarkable transition in the US, with less exposure in childhood and more in adulthood, and less oral but more genital acquisition. HSV-1 will persist as a widely prevalent infection, with ever-increasing genital disease burden

Epidemiological Impact of Novel Preventive and Therapeutic HSV-2 Vaccination in the United States: Mathematical Modeling Analyses.

This study aims to inform herpes simplex virus type 2 (HSV-2) vaccine development, licensure, and implementation by delineating the population-level impact of vaccination. Mathematical models were constructed to describe the transmission dynamics in presence of prophylactic or therapeutic vaccines assuming 50% efficacy, with application to the United States. Catch-up prophylactic vaccination will reduce, by 2050, annual number of new infections by 58%, incidence rate by 60%, seroprevalence by 21%, and avert yearly as much as 350,000 infections. Number of vaccinations needed to avert one infection was only 50 by 2050, 34 by prioritizing those aged 15-19 years, 4 by prioritizing the highest sexual risk group, 43 by prioritizing women, and 47 by prioritizing men. Therapeutic vaccination of infected adults with symptomatic disease will reduce, by 2050, annual number of new infections by 12%, incidence rate by 13%, seroprevalence by 4%, and avert yearly as much as 76,000 infections. Number of vaccinations needed to avert one infection was eight by 2050, two by prioritizing those aged 15-19 years, three by prioritizing the highest sexual risk group, seven by prioritizing men, and ten by prioritizing women. HSV-2 vaccination offers an impactful and cost-effective intervention to prevent genital herpes medical and psychosexual disease burden

Treatment as prevention for hepatitis C virus in the Middle East and North Africa: a modeling study

Background: Direct-acting antivirals opened an opportunity for eliminating hepatitis C virus (HCV) infection in the Middle East and North Africa (MENA), the region most affected by HCV infection. Impact of HCV treatment as prevention (HCV-TasP) was investigated in 19 MENA countries. Methods: An age-structured mathematical model was used to assess program impact using epidemiologic and programming measures. The model was fitted to a database of systematically gathered HCV antibody prevalence data. Two main scenarios were investigated for the treatment roll-out to achieve (i) 80% reduction in HCV incidence by 2030, and (ii) incidence rate < 1 per 100,000 person-years by 2030. Results: In the target-80%-incidence-reduction scenario, number of treatments administrated by 2030 ranged from 2,610 in Lebanon to 180,416 in Sudan with a median of 53,079, and treatment coverage ranged between 40.2 and 78.4% with a median of 60.4%. By 2030, prevalence of chronic infection ranged between 0.0 and 0.3% with a median of 0.1%, and incidence rate, per 100,000 person-years, ranged between 0.9 and 16.3 with a median of 3.2. Program-attributed reduction in incidence rate ranged between 47.8 and 81.9% with a median of 68.5%, and number of averted infections ranged between 401 and 68,499 with a median of 8,703. Number of treatments needed to prevent one new infection ranged from 1.7 in Oman to 25.9 in Tunisia with a median of 6.5. In the target incidence rate < 1 per 100,000 person-years scenario, number of treatments administrated by 2030 ranged from 3,470 in Lebanon to 211,912 in Sudan with a median of 54,479, and treatment coverage ranged between 55.5 and 95.9% with a median of 87.5%. By 2030, prevalence of chronic infection was less than 0.1%, and incidence rate, per 100,000 person-years, reached less than 1. Program-attributed reduction in incidence rate ranged between 61.0 and 97.5% with a median of 90.7%, and number of averted infections ranged between 559 and 104,315 with a median of 12,158. Number of treatments needed to prevent one new infection ranged from 1.3 in Oman to 25.9 in Tunisia with a median of 5.5. Conclusion: HCV-TasP is an effective and indispensable prevention intervention to control MENA's HCV epidemic and to achieve elimination by 2030.This publication was made possible by NPRP grant number 12S-0216-190094 from the Qatar National Research Fund (a member of Qatar Foundation; https://www.qnrf.org ). HHA acknowledges the support of Qatar University QUCG-CAS-23/24-114. The statements made herein are solely the responsibility of the authors. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. The authors alone are responsible for the views expressed in this publication and they do not necessarily represent the views, decisions, or policies of World Health Organization. The authors are also grateful for infrastructure support provided by the Biostatistics, Epidemiology, and Biomathematics Research Core at Weill Cornell Medicine-Qatar.Scopu

Hepatitis C virus infection spontaneous clearance: Has it been underestimated?

OBJECTIVES: Hepatitis C virus (HCV) clearance rate (fclearance) is defined as the proportion of infected persons who will spontaneously clear their infection after acute infection. We aimed to estimate fclearance using a novel approach that avoids limitations in existing estimates, and to clarify the link between fclearance and HCV viremic rate-the latter being the proportion of RNA positivity among those antibody positive. METHODS: A mathematical model was developed to describe HCV transmission. fclearance was estimated by fitting the model to probability-based and nationally representative population-based data for Egypt (Egypt 2008 and Egypt 2015) and USA (NHANES A and NHANES B). Uncertainty and sensitivity analyses were conducted. RESULTS: fclearance was estimated at 39.9% (95% uncertainty interval (UI): 34.3%-46.4%) and 33.5% (95% UI: 29.2%-38.3%) for Egypt 2008 and Egypt 2015 data, respectively; and at 29.6% (23.0%-37.1%) and 39.9% (31.2%-51.0%) for NHANES A and NHANES B data, respectively. fclearance was found related to HCV viremic rate through (approximately) the formula fclearance=1.16 (1-HCV viremic rate). HCV viremic rate was higher with higher risk of HCV exposure. Robustness of results was demonstrated in uncertainty and sensitivity analyses. CONCLUSION: One-third of HCV-infected persons clear their infection spontaneously, higher than earlier estimates-the immune-system capacity to clear HCV infection may have been underestimated

Characterizing the historical role of parenteral antischistosomal therapy in hepatitis C virus transmission in Egypt.

BACKGROUND: Egypt is the nation most affected by hepatitis C virus (HCV) infection, following an epidemic of historic proportions. We aimed to characterize the epidemic's historical evolution and to delineate the role of parenteral antischistosomal therapy (PAT) campaigns in transmission. METHODS: A mathematical model was constructed and analysed in order to understand HCV-transmission dynamics. The model was fitted to Egypt's Demographic and Health Survey data and to a systematic database of HCV-prevalence data. RESULTS: The incidence rate peaked in 1966 at 15.7 infections per 1000 person-years-a period of time that coincides with the PAT campaigns-and rapidly declined thereafter, beginning the mid-1990s. The annual number of new infections peaked in 1993 at 581 200 (with rapid demographic growth), leading to a high-incidence-cohort effect, and declined to 67 800 by 2018. The number of individuals ever infected (1950-2018) was 16.4 million, with HCV prevalence peaking in 1979. The number of individuals ever exposed to PAT was 8.3 million; however, of these individuals, 7.3 million were alive in 1980 and only 3.5 million alive in 2018. The number of individuals ever infected due to PAT exposure was 963 900, with 850 200 individuals alive in 1980 and only 389 800 alive in 2018. The proportion of PAT-attributed prevalent infections peaked at 19.9% in 1972, declining to 5.5% by 2018. CONCLUSIONS: PAT campaigns played an important role in HCV transmission, yet explain only 6% of infections-they appear to be a manifestation, rather than a cause, of the epidemic. A possible driver of the epidemic could be the mass expansion of inadequate-quality healthcare during PAT campaigns and subsequent decades. Despite a historic toll, the epidemic has been rapidly diminishing since the mid-1990s

Epidemiological Differences in the Impact of COVID-19 Vaccination in the United States and China.

This study forecasts Coronavirus Disease 2019 (COVID-19) vaccination impact in two countries at different epidemic phases, the United States (US) and China. We assessed the impact of both a vaccine that prevents infection (VES of 95%) and a vaccine that prevents only disease (VEP of 95%) through mathematical modeling. For VES of 95% and gradual easing of restrictions, vaccination in the US reduced the peak incidence of infection, disease, and death by >55% and cumulative incidence by >32% and in China by >77% and >65%, respectively. Nearly three vaccinations were needed to avert one infection in the US, but only one was needed in China. For VEP of 95%, vaccination benefits were half those for VES of 95%. In both countries, impact of vaccination was substantially enhanced with rapid scale-up, vaccine coverage >50%, and slower or no easing of restrictions, particularly in the US. COVID-19 vaccination can flatten, delay, and/or prevent future epidemic waves. However, vaccine impact is destined to be heterogeneous across countries because of an underlying "epidemiologic inequity" that reduces benefits for countries already at high incidence, such as the US. Despite 95% efficacy, actual vaccine impact could be meager in such countries if vaccine scale-up is slow, acceptance is poor, or restrictions are eased prematurely

Age could be driving variable SARS-CoV-2 epidemic trajectories worldwide.

Current geographic spread of documented severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infections shows heterogeneity. This study explores the role of age in potentially driving differentials in infection spread, epidemic potential, and rates of disease severity and mortality across countries. An age-stratified deterministic mathematical model that describes SARS-CoV-2 transmission dynamics was applied to 159 countries and territories with a population ≥1 million. Assuming worst-case scenario for the pandemic, the results indicate that there could be stark regional differences in epidemic trajectories driven by differences in the distribution of the population by age. In the African Region (median age: 18.9 years), the median R0 was 1.05 versus 2.05 in the European Region (median age: 41.7 years), and the median (per 100 persons) for the final cumulative infection incidence was 22.5 (versus 69.0), for severe and/or critical disease cases rate was 3.3 (versus 13.0), and for death rate was 0.5 (versus 3.9). Age could be a driver of variable SARS-CoV-2 epidemic trajectories worldwide. Countries with sizable adult and/or elderly populations and smaller children populations may experience large and rapid epidemics in absence of interventions. Meanwhile, countries with predominantly younger age cohorts may experience smaller and slower epidemics. These predictions, however, should not lead to complacency, as the pandemic could still have a heavy toll nearly everywhere

Estimates of global SARS-CoV-2 infection exposure, infection morbidity, and infection mortality rates in 2020

We aimed to estimate, albeit crudely and provisionally, national, regional, and global proportions of respective populations that have been infected with SARS-CoV-2 in the first year after the introduction of this virus into human circulation, and to assess infection morbidity and mortality rates, factoring both documented and undocumented infections. The estimates were generated by applying mathematical models to 159 countries and territories. The percentage of the world's population that has been infected as of 31 December 2020 was estimated at 12.56% (95% CI: 11.17–14.05%). It was lowest in the Western Pacific Region at 0.66% (95% CI: 0.59–0.75%) and highest in the Americas at 41.92% (95% CI: 37.95–46.09%). The global infection fatality rate was 10.73 (95% CI: 10.21–11.29) per 10,000 infections. Globally per 1000 infections, the infection acute-care bed hospitalization rate was 19.22 (95% CI: 18.73–19.51), the infection ICU bed hospitalization rate was 4.14 (95% CI: 4.10–4.18). If left unchecked with no vaccination and no other public health interventions, and assuming circulation of only wild-type variants and no variants of concern, the pandemic would eventually cause 8.18 million deaths (95% CI: 7.30–9.18), 163.67 million acute-care hospitalizations (95% CI: 148.12–179.51), and 33.01 million ICU hospitalizations (95% CI: 30.52–35.70), by the time the herd immunity threshold is reached at 60–70% infection exposure. The global population remained far below the herd immunity threshold by end of 2020. Global epidemiology reveals immense regional variation in infection exposure and morbidity and mortality rates.- Biostatistics, Epidemiology, and Biomathematics Research Core at Weill Cornell Medicine-Qatar - 12S-0216-190094, 9-040-3-008. - UK Research and Innovation - ES/P010873/1. - Qatar National Research Fund - Qatar National Library provided fund for open access

Analytic Characterization of the Herpes Simplex Virus Type 2 Epidemic in the United States, 1950-2050.

BACKGROUND: We analytically characterized the past, present, and future levels and trends of the national herpes simplex virus type 2 (HSV-2) epidemic in the United States. METHODS: A population-level mathematical model was constructed to describe HSV-2 transmission dynamics and was fitted to the data series of the National Health and Nutrition Examination Survey. RESULTS: Over 1950-2050, antibody prevalence (seroprevalence) increased rapidly from 1960, peaking at 19.9% in 1983 in those aged 15-49 years, before reversing course to decline to 13.2% by 2020 and 8.5% by 2050. Incidence rate peaked in 1971 at 11.9 per 1000 person-years, before declining by 59% by 2020 and 70% by 2050. Annual number of new infections peaked at 1 033 000 in 1978, before declining to 667 000 by 2020 and 600 000 by 2050. Women were disproportionately affected, averaging 75% higher seroprevalence, 95% higher incidence rate, and 71% higher annual number of infections. In 2020, 78% of infections were acquired by those 15-34 years of age. CONCLUSIONS: The epidemic has undergone a major transition over a century, with the greatest impact in those 15-34 years of age. In addition to 47 million prevalent infections in 2020, high incidence will persist over the next 3 decades, adding >600 000 new infections every year