Simulation modeling of zoonotic diseases between swine and human populations for informing policy decisions

Approximately 60% of human pathogens and emerging infectious diseases are zoonotic. Simulation models are increasingly being used to investigate the spread of diseases, evaluate intervention strategies and guide the decisions of policy makers. In this thesis a systematic review of modeling methods and approaches used for zoonotic influenza in animals and humans was conducted, and knowledge gaps were identified. Furthermore, the disease spread and intervention parameters used in these studies were summarized for ready reference in future work. Building on this review work, the research presented in this thesis evaluated the effects of transmissibility of the pandemic H1N1 2009 (pH1N1) virus at the swine- human interface and the control strategies against its spread in swine and human populations as a case study for zoonotic disease modeling. The feasibility of North American Animal Disease Spread Model (NAADSM) for modeling directly transmitted zoonoses was also assessed. Population data based on swine herds and households (categorized as rural households with or without swine workers, and urban households without swine workers) of a county in Ontario, Canada was used. The swine workers served as a bridging population for the spread of the virus between swine herds and households. Scenarios based on the combinations of the transmissibility of the virus (low (L), medium (M), and high (H)) from swine-to-human and human-to-swine (LL, ML, HL, MM, HM, LL), and targeted vaccination of swine worker households (0% to 60%) were evaluated. The results showed that lowering the influenza transmissibility at the interface to low level and providing higher vaccine coverage (60%) had significant beneficial effects on all outcome measures. However, these measures had little or negligible impact on the total number of rural and urban households infected. A set of models evaluating the combination of control strategies indicated that a moderate speed of the detection (within 5 to 10 days of the first infection), combined with the quarantine of detected units alone, contained the outbreak within the swine population in most simulations. However, a zone-based quarantine strategy was more effective when the detection was delayed until around three weeks after initial infection. Ring vaccination had no added beneficial effect. This work suggested that NAADSM can be used for modeling the directly transmitted zoonotic diseases under similar simplifying assumptions adopted in these studies. However, this needs to be evaluated further with more accurate parameters and influenza outbreak data. To fill in some of the gaps identified in the review study, network analyses of swine shipments among farms, and between farms and abattoirs were conducted. This provided network metrics and parameters necessary for disease modeling and risk-based disease management in swine in Ontario for the first time. Finally, agent-based network models assessing the spread and control of pH1N1 in swine established the importance of explicitly incorporating appropriate contact network structures into such models to increase their validity. It also demonstrated the benefits of targeted control strategies against highly connected farms. In conclusion, the modeling tools developed in this thesis can assist decision makers in preparedness and response of outbreaks of infectious diseases as more information become available for the parameterization of models

Quantifying the Effects of Measures to Control Highly Pathogenic Avian Influenza H5N1 in Poultry in Southeast Asia

Despite the ongoing efforts to contain its spread, H5N1 is now considered endemic within poultry in various settings worldwide, threatening both the livelihoods of those involved in poultry production in affected countries and posing a continuous public health risk. The reasons for the varying levels of success in controlling H5N1 in Southeast Asia need to be better understood. In this thesis, various different methods of quantifying the effects of individual control measures, using the types of data available in various different contexts, are discussed and applied. In the first half of this thesis a spatio-temporal survival model is fitted to H5N1 outbreak surveillance data from Vietnam and Thailand using a Bayesian framework in order to account for unobserved infection times. Following vaccination in Vietnam it was found that transmissibility had been successfully reduced but, during a wave of outbreaks in 2007, that this coincided with a reduction in the rate of at which outbreaks were reported following the introduction of infection, limiting the overall impact this reduction in transmissibility had on the total epidemic size. In Thailand, active surveillance was found to be successful in contributing to the control of infection. Furthermore, backyard producers, whilst responsible for the majority of outbreaks, were, on average, less likely to transmit infection than those involved in more intensive production. In the second half of the thesis, the use of final size methods to assess the effectiveness of vaccination from trial data is explored. This involved an investigation into the effects of different assumptions regarding the action by which vaccination confers immunity and fitting estimates of transmissibility to data collected from outbreak investigations in the context of a field trial of vaccination in Indonesia, where, making strong assumptions about the underlying infection process, a reduction in both within and between flock transmissibility was detected for outbreaks occurring in areas where vaccination was being carried out

Intra- and interspecies transmission of H7N7 highly pathogenic avian influenza virus during the avian influenza epidemic in the Netherlands in 2003

The poultry epidemic of H7N7 highly pathogenic avian influenza (HPAI) virus in the Netherlands in 2003 was probably the result of the introduction of an H7N7 low pathogenic avian influenza (LPAI) virus (by interspecies transmission from wild birds) and the subsequent intraspecies transmission of this virus in poultry. The intraspecies transmission of the ensuing H7N7 HPAI virus was very successful both within and between flocks. Consequently, in the two poultry-dense areas that were affected, the epidemic could only be stopped by eliminating all poultry in the region. According to the spatial models these are the only areas where this was the case in the Netherlands. There was also interspecies transmission to mammals, i.e. to pigs and to humans. For pigs it was shown that possible subsequent intraspecies transmission was negligible (R0 <1). With hindsight the same was probably also true for human

Detecting differential transmissibilities that affect the size of self-limited outbreaks.

Our ability to respond appropriately to infectious diseases is enhanced by identifying differences in the potential for transmitting infection between individuals. Here, we identify epidemiological traits of self-limited infections (i.e. infections with an effective reproduction number satisfying [0 < R eff < 1) that correlate with transmissibility. Our analysis is based on a branching process model that permits statistical comparison of both the strength and heterogeneity of transmission for two distinct types of cases. Our approach provides insight into a variety of scenarios, including the transmission of Middle East Respiratory Syndrome Coronavirus (MERS-CoV) in the Arabian peninsula, measles in North America, pre-eradication smallpox in Europe, and human monkeypox in the Democratic Republic of the Congo. When applied to chain size data for MERS-CoV transmission before 2014, our method indicates that despite an apparent trend towards improved control, there is not enough statistical evidence to indicate that R eff has declined with time. Meanwhile, chain size data for measles in the United States and Canada reveal statistically significant geographic variation in R eff, suggesting that the timing and coverage of national vaccination programs, as well as contact tracing procedures, may shape the size distribution of observed infection clusters. Infection source data for smallpox suggests that primary cases transmitted more than secondary cases, and provides a quantitative assessment of the effectiveness of control interventions. Human monkeypox, on the other hand, does not show evidence of differential transmission between animals in contact with humans, primary cases, or secondary cases, which assuages the concern that social mixing can amplify transmission by secondary cases. Lastly, we evaluate surveillance requirements for detecting a change in the human-to-human transmission of monkeypox since the cessation of cross-protective smallpox vaccination. Our studies lay the foundation for future investigations regarding how infection source, vaccination status or other putative transmissibility traits may affect self-limited transmission

Avian Influenza H5N1 Transmission in Households, Indonesia

BACKGROUND: Disease transmission patterns are needed to inform public health interventions, but remain largely unknown for avian influenza H5N1 virus infections. A recent study on the 139 outbreaks detected in Indonesia between 2005 and 2009 found that the type of exposure to sources of H5N1 virus for both the index case and their household members impacted the risk of additional cases in the household. This study describes the disease transmission patterns in those outbreak households. METHODOLOGY/PRINCIPAL FINDINGS: We compared cases (n = 177) and contacts (n = 496) in the 113 sporadic and 26 cluster outbreaks detected between July 2005 and July 2009 to estimate attack rates and disease intervals. We used final size household models to fit transmission parameters to data on household size, cases and blood-related household contacts to assess the relative contribution of zoonotic and human-to-human transmission of the virus, as well as the reproduction number for human virus transmission. The overall household attack rate was 18.3% and secondary attack rate was 5.5%. Secondary attack rate remained stable as household size increased. The mean interval between onset of subsequent cases in outbreaks was 5.6 days. The transmission model found that human transmission was very rare, with a reproduction number between 0.1 and 0.25, and the upper confidence bounds below 0.4. Transmission model fit was best when the denominator population was restricted to blood-related household contacts of index cases. CONCLUSIONS/SIGNIFICANCE: The study only found strong support for human transmission of the virus when a single large cluster was included in the transmission model. The reproduction number was well below the threshold for sustained transmission. This study provides baseline information on the transmission dynamics for the current zoonotic virus and can be used to detect and define signatures of a virus with increasing capacity for human-to-human transmission

Estimation of Transmission Parameters of H5N1 Avian Influenza Virus in Chickens

Despite considerable research efforts, little is yet known about key epidemiological parameters of H5N1 highly pathogenic influenza viruses in their avian hosts. Here we show how these parameters can be estimated using a limited number of birds in experimental transmission studies. Our quantitative estimates, based on Bayesian methods of inference, reveal that (i) the period of latency of H5N1 influenza virus in unvaccinated chickens is short (mean: 0.24 days; 95% credible interval: 0.099–0.48 days); (ii) the infectious period of H5N1 virus in unvaccinated chickens is approximately 2 days (mean: 2.1 days; 95%CI: 1.8–2.3 days); (iii) the reproduction number of H5N1 virus in unvaccinated chickens need not be high (mean: 1.6; 95%CI: 0.90–2.5), although the virus is expected to spread rapidly because it has a short generation interval in unvaccinated chickens (mean: 1.3 days; 95%CI: 1.0–1.5 days); and (iv) vaccination with genetically and antigenically distant H5N2 vaccines can effectively halt transmission. Simulations based on the estimated parameters indicate that herd immunity may be obtained if at least 80% of chickens in a flock are vaccinated. We discuss the implications for the control of H5N1 avian influenza virus in areas where it is endemic

One-health simulation modelling : assessment of control strategies against the spread of influenza between swine and human populations using NAADSM

Simulation models implemented using a range of parameters offer a useful approach to identifying effective disease intervention strategies. The objective of this study was to investigate the effects of key control strategies to mitigate the simultaneous spread of influenza among and between swine and human populations. We used the pandemic H1N1 2009 virus as a case study. The study population included swine herds (488 herds) and households-of-people (29 707 households) within a county in Ontario, Canada. Households were categorized as: (i) rural households with swine workers, (ii) rural households without swine workers and (iii) urban households without swine workers. Seventy-two scenarios were investigated based on a combination of the parameters of speed of detection and control strategies, such as quarantine strategy, effectiveness of movement restriction and ring vaccination strategy, all assessed at three levels of transmissibility of the virus at the swine-human interface. Results showed that the speed of detection of the infected units combined with the quarantine strategy had the largest impact on the duration and size of outbreaks. A combination of fast to moderate speed of the detection (where infected units were detected within 5-10 days since first infection) and quarantine of the detected units alone contained the outbreak within the swine population in most of the simulated outbreaks. Ring vaccination had no added beneficial effect. In conclusion, our study suggests that the early detection (and therefore effective surveillance) and effective quarantine had the largest impact in the control of the influenza spread, consistent with earlier studies. To our knowledge, no study had previously assessed the impact of the combination of different intervention strategies involving the simultaneous spread of influenza between swine and human populations

Analysis of CDC social control measures using an agent-based simulation of an influenza epidemic in a city

Background: the transmission of infectious disease amongst the human population is a complex process which requires advanced, often individual-based, models to capture the space-time details observed in reality.Methods: an Individual Space-Time Activity-based Model (ISTAM) was applied to simulate the effectiveness of non-pharmaceutical control measures including: (1) refraining from social activities, (2) school closure and (3) household quarantine, for a hypothetical influenza outbreak in an urban area.Results: amongst the set of control measures tested, refraining from social activities with various compliance levels was relatively ineffective. Household quarantine was very effective, especially for the peak number of cases and total number of cases, with large differences between compliance levels. Household quarantine resulted in a decrease in the peak number of cases from more than 300 to around 158 for a 100% compliance level, a decrease of about 48.7%. The delay in the outbreak peak was about 3 to 17 days. The total number of cases decreased to a range of 3635-5403, that is, 63.7%-94.7% of the baseline value.When coupling control measures, household quarantine together with school closure was the most effective strategy. The resulting space-time distribution of infection in different classes of activity bundles (AB) suggests that the epidemic outbreak is strengthened amongst children and then spread to adults. By sensitivity analysis, this study demonstrated that earlier implementation of control measures leads to greater efficacy. Also, for infectious diseases with larger basic reproduction number, the effectiveness of non-pharmaceutical measures was shown to be limited.Conclusions: simulated results showed that household quarantine was the most effective control measure, while school closure and household quarantine implemented together achieved the greatest benefit. Agent-based models should be applied in the future to evaluate the efficacy of control measures for a range of disease outbreaks in a range of settings given sufficient information about the given case and knowledge about the transmission processes at a fine scal