Epidemiology and evolution of Marek’s Disease virus

Marek’s disease (MD) is an oncogenic disease affecting chickens and is estimated to cost the worldwide poultry industry $1-2 billion annually. The causative agent of MD, Marek’s disease virus (MDV), provides a welldocumented example of virus virulence evolution occurring over a period of sixty years. The reason behind this evolution is unknown, although certain untested hypotheses have been suggested. These include vaccination (with increasingly potent vaccines) and other aspects of industrialisation, such as the decreased cohort duration of successive generations and an increased stocking density of the broiler flocks. In this thesis, four sections of work are undertaken. First, estimation of epidemiological parameters is tackled: virulence of MDV is quantified by looking at host mortality and virus shedding rates in vaccinated and unvaccinated birds. This is achieved via maximum likelihood estimation and Bayesian McMC techniques. Second, viral fitness is quantified by defining multiple lifetime fitness functions using the parameters previously estimated to understand the direction and force of virulence selection for different farm environments. Third, the impact of an outbreak of MDV on a broiler flock is examined by simulating a whole flock of birds. This provides an epidemiological understanding of the virus at the flock level and can help elucidate methods for disease control and surveillance and can also give a fitness measure to understand on-farm evolution of the virus. Fourth, a between-farm model is analysed to evaluate which MDV strains are able to persist in a network structure of farms and how this might be affected by biosecurity measures, different farm networks, farm size, bird lifespan and vaccination. This provides insights into how quickly a different strain can invade a farm network and the plausibility of it becoming endemic. Parameter estimation results show that the time to death for an infected bird decreases and its virus shedding rate increases with previous definitions of virulence in the literature. Model results suggest that the choice of fitness measure alters the conclusions reached. Increasing the amount of demographic structure introduced into the fitness measure shows that neither vaccine introduction nor decreasing a bird’s lifespan changes the ability of more virulent virus strains to outcompete less virulent strains. In any environment, more virulent strains are always selected for. Epidemiological results suggest that vaccination allows a low prevalence of virus on a farm although there are no deaths from the disease itself. Analogous results for between-farm spread suggest that if on-farm cleaning efficiency is low enough, a high prevalence of disease throughout a network of vaccinated flocks can exist but the farms themselves show no signs of increased mortality from the disease. The hypotheses for explaining the increase in virulence of MDV may not be consistent with the results of this work. Despite previous arguments that vaccines are driving the evolution of virulence ofMDV, this first quantitative work on the subject demonstrates that this might not be the case. This work also formulates new hypotheses to explain why MDV virulence has increased over the past sixty years which will pave the way for ongoing research in the area of virulence evolution in farm environments

Modelling Marek's Disease Virus (MDV) infection: parameter estimates for mortality rate and infectiousness

Background: Marek's disease virus (MDV) is an economically important oncogenic herpesvirus of poultry. Since the 1960s, increasingly virulent strains have caused continued poultry industry production losses worldwide. To understand the mechanisms of this virulence evolution and to evaluate the epidemiological consequences of putative control strategies, it is imperative to understand how virulence is defined and how this correlates with host mortality and infectiousness during MDV infection. We present a mathematical approach to quantify key epidemiological parameters. Host lifespan, virus latent periods and host viral shedding rates were estimated for unvaccinated and vaccinated birds, infected with one of three MDV strains. The strains had previously been pathotyped to assign virulence scores according to pathogenicity of strains in hosts. Results: Our analyses show that strains of higher virulence have a higher viral shedding rate, and more rapidly kill hosts. Vaccination enhances host life expectancy but does not significantly reduce the shedding rate of the virus. While the primary latent period of the virus does not vary with challenge strain nor vaccine treatment of host, the time until the maximum viral shedding rate is increased with vaccination. Conclusions: Our approach provides the tools necessary for a formal analysis of the evolution of virulence in MDV, and potentially simpler and cheaper approaches to comparing the virulence of MDV strains

Cost-Effectiveness of Rotavirus Vaccination in France-Accounting for Indirect Protection.

BACKGROUND: Vaccination against rotavirus has shown great potential for reducing the primary cause of severe childhood gastroenteritis. Previous economic evaluations of rotavirus vaccination in France have not modeled the potential impact of vaccines on disease burden via reduced transmission. OBJECTIVE: To determine the cost-effectiveness of the introduction of pentavalent rotavirus vaccination into the French infant vaccination schedule. METHODS: We developed an age-structured model of rotavirus transmission calibrated to 6 years of French gastroenteritis incidence and vaccine clinical trial data. We evaluated the cost-effectiveness of pentavalent rotavirus vaccination considering that 75% of infants would receive the three-dose vaccine course. RESULTS: Our model predicts that rotavirus vaccination will decrease rotavirus gastroenteritis incidence and associated clinical outcomes in vaccinated and unvaccinated individuals, delay the seasonal peak of infection, and increase the age of infection. From the societal perspective, our base-case scenario predicts that vaccination coverage would be cost-effective at €115 or €135 per vaccine course at €28,500 and €39,500/quality-adjusted life-year (QALY) gained, respectively, and suggests that almost 95% of the financial benefits will be recouped within the first 5 years following vaccination implementation. From the third-party payer perspective, incremental cost-effectiveness ratios ranged from €12,500 to €20,000/QALY, respectively. Our uncertainty analysis suggests that findings were sensitive to various assumptions including the number of hospitalizations, outpatient visits, and the extent of QALY losses per rotavirus episode. CONCLUSIONS: Introducing pentavalent rotavirus vaccination into the French infant vaccination schedule would significantly reduce the burden of rotavirus disease in children, and could be cost-effective under plausible conditions

Within-host dynamics shape antibiotic resistance in commensal bacteria

The spread of antibiotic resistance, a major threat to human health, is poorly understood. Simple population-level models of bacterial transmission predict that above a certain rate of antibiotic consumption in a population, resistant bacteria should completely eliminate non-resistant strains, while below this threshold they should be unable to persist at all. This prediction stands at odds with empirical evidence showing that resistant and non-resistant strains coexist stably over a wide range of antibiotic consumption rates. Not knowing what drives this long-term coexistence is a barrier to developing evidence-based strategies for managing the spread of resistance. Here, we argue that competition between resistant and sensitive pathogens within individual hosts gives resistant pathogens a relative fitness benefit when they are rare, promoting coexistence between strains at the population level. To test this hypothesis, we embed mechanistically explicit within-host dynamics in a structurally neutral pathogen transmission model. Doing so allows us to reproduce patterns of resistance observed in the opportunistic pathogens Escherichia coli and Streptococcus pneumoniae across European countries and to identify factors that may shape resistance evolution in bacteria by modulating the intensity and outcomes of within-host competition

Modeling the effect of vaccination on selection for antibiotic resistance in Streptococcus pneumoniae

Vaccines against bacterial pathogens can protect recipients from becoming infected with potentially antibiotic-resistant pathogens. However, by altering the selective balance between antibiotic-sensitive and antibiotic-resistant bacterial strains, vaccines may also suppress-or spread-antibiotic resistance among unvaccinated individuals. Predicting the outcome of vaccination requires knowing what drives selection for drug-resistant bacterial pathogens and what maintains the circulation of both antibiotic-sensitive and antibiotic-resistant strains of bacteria. To address this question, we used mathematical modeling and data from 2007 on penicillin consumption and penicillin nonsusceptibility in Streptococcus pneumoniae (pneumococcus) invasive isolates from 27 European countries. We show that the frequency of penicillin resistance in S. pneumoniae can be explained by between-host diversity in antibiotic use, heritable diversity in pneumococcal carriage duration, or frequency-dependent selection brought about by within-host competition between antibiotic-resistant and antibiotic-sensitive S. pneumoniae strains. We used our calibrated models to predict the impact of non-serotype-specific pneumococcal vaccination upon the prevalence of S. pneumoniae carriage, incidence of disease, and frequency of S. pneumoniae antibiotic resistance. We found that the relative strength and directionality of competition between drug-resistant and drug-sensitive pneumococcal strains was the most important determinant of whether vaccination would promote, inhibit, or have little effect upon the evolution of antibiotic resistance. Last, we show that country-specific differences in pathogen transmission substantially altered the predicted impact of vaccination, highlighting that policies for managing antibiotic resistance with vaccines must be tailored to a specific pathogen and setting

Changing socio-economic and ethnic disparities in influenza/A/H1N1 infection early in the 2009 UK epidemic:a descriptive analysis

BACKGROUND: Higher incidence of and risk of hospitalisation and death from Influenza A(H1N1)pdm09 during the 2009 pandemic was reported in ethnic minority groups in many high-income settings including in the United Kingdom (UK). Many of these studies rely on geographical and temporal aggregation of cases and can be difficult to interpret due to the spatial and temporal factors in outbreak spread. Further, it can be challenging to distinguish between disparities in health outcomes caused by variation in transmission risk or disease severity. METHODS: We used anonymised laboratory confirmed and suspected case data, classified by ethnicity and deprivation status, to evaluate how disparities in risk between socio-economic and ethnic groups vary over the early stages of the 2009 Influenza A(H1N1)pdm09 epidemic in Birmingham and London, two key cities in the emergence of the UK epidemic. We evaluated the relative risk of infection in key ethnic minority groups and by national and city level deprivation rank. RESULTS: We calculated higher incidence in more deprived areas and in people of South Asian ethnicity in both Birmingham and London, although the magnitude of these disparities reduced with time. The clearest disparities existed in school-aged children in Birmingham, where the most deprived fifth of the population was 2.8 times more likely to be infected than the most affluent fifth of the population. CONCLUSIONS: Our analysis shows that although disparities in reported cases were present in the early phase of the Influenza A(H1N1)pdm09 outbreak in both Birmingham and London, they vary substantially depending on the period over which they are measured. Further, the development of disparities suggest that clustering of social groups play a key part as the outbreak appears to move from one ethnic and socio-demographic group to another. Finally, high incidence and large disparities between children indicate that they may hold an important role in driving inequalities