Modelling the performance of isoniazid preventive therapy for reducing tuberculosis in HIV endemic settings: the effects of network structure

Individuals living with HIV experience a much higher risk of progression from latent M. tuberculosis infection to active tuberculosis (TB) disease relative to individuals with intact immune systems. A several-month daily course of a single drug during latent infection (i.e. isoniazid preventive therapy (IPT)) has proved in clinical trials to substantially reduce an HIV-infected individual''s risk of TB disease. As a result of these findings and ongoing studies, the World Health Organization has produced strong guidelines for implementing IPT on a community-wide scale for individuals with HIV at risk of TB disease. To date, there has been limited use of IPT at a community-wide level. In this paper, we present a new co-network model for HIV and TB co-epidemics to address questions about how the population-level impact of community-wide IPT may differ from the individual-level impact of IPT offered to selected individuals. In particular, we examine how the effect of clustering of contacts within high-TB incidence communities may affect the rates of re-infection with TB and how this clustering modifies the expected population-level effects of IPT. We find that populations with clustering of respiratory contacts experience aggregation of TB cases and high numbers of re-infection events. While, encouragingly, the overall population-level effects of community-wide IPT appear to be sustained regardless of network structure, we find that in populations where these contacts are highly clustered, there is dramatic heterogeneity in the impact of IPT: in some sub-regions of these populations, TB is nearly eliminated, while in others, repeated re-infection almost completely undermines the effect of IPT. Our findings imply that as IPT programmes are brought to scale, we should expect local heterogeneity of effectiveness as a result of the complex patterns of disease transmission within communities.     

Rates of coalescence for common epidemiological models at equilibrium

Coalescent theory provides a mathematical framework for quantitatively interpreting gene genealogies. With the increased availability of molecular sequence data, disease ecologists now regularly apply this body of theory to viral phylogenies, most commonly in attempts to reconstruct demographic histories of infected individuals and to estimate parameters such as the basic reproduction number. However, with few exceptions, the mathematical expressions at the core of coalescent theory have not been explicitly linked to the structure of epidemiological models, which are commonly used to mathematically describe the transmission dynamics of a pathogen. Here, we aim to make progress towards establishing this link by presenting a general approach for deriving a model''s rate of coalescence under the assumption that the disease dynamics are at their endemic equilibrium. We apply this approach to four common families of epidemiological models: standard susceptible-infected-susceptible/susceptible-infected-recovered/susceptible-infected-recovered-susceptible models, models with individual heterogeneity in infectivity, models with an exposed but not yet infectious class and models with variable distributions of the infectious period. These results improve our understanding of how epidemiological processes shape viral genealogies, as well as how these processes affect levels of viral diversity and rates of genetic drift. Finally, we discuss how a subset of these coalescent rate expressions can be used for phylodynamic inference in non-equilibrium settings. For the ones that are limited to equilibrium conditions, we also discuss why this is the case. These results, therefore, point towards necessary future work while providing intuition on how epidemiological characteristics of the infection process impact gene genealogies.     

Eliminating human tuberculosis in the twenty-first century.

Recognizing that tuberculosis (TB) is still the leading cause of human death from a curable infection, the international health community has set ambitious targets for disease control. One target is to eliminate TB by 2050; that is, to cut the annual incidence of new cases to less than 1 per million population. National TB control programmes are working to eliminate TB mainly by intensifying efforts to find and cure patients with active disease. Here, we use mathematical modelling to show that, while most TB patients can be cured with present drug regimens, the 2050 target is far more likely to be achieved with a combination of diagnostics, drugs and vaccines that can detect and treat both latent infection and active disease. We find that the coupling of control methods is particularly effective because treatments for latent infection and active disease act in synergy. This synergistic effect offers new perspectives on the cost-effectiveness of treating latent TB infection and the impact of possible new TB vaccines. Our results should be a stimulus to those who develop, manufacture and implement new technology for TB control, and to their financial donors.     

Social encounter networks: collective properties and disease transmission

A fundamental challenge of modern infectious disease epidemiology is to quantify the networks of social and physical contacts through which transmission can occur. Understanding the collective properties of these interactions is critical for both accurate prediction of the spread of infection and determining optimal control measures. However, even the basic properties of such networks are poorly quantified, forcing predictions to be made based on strong assumptions concerning network structure. Here, we report on the results of a large-scale survey of social encounters mainly conducted in Great Britain. First, we characterize the distribution of contacts, which possesses a lognormal body and a power-law tail with an exponent of −2.45; we provide a plausible mechanistic model that captures this form. Analysis of the high level of local clustering of contacts reveals additional structure within the network, implying that social contacts are degree assortative. Finally, we describe the epidemiological implications of this local network structure: these contradict the usual predictions from networks with heavy-tailed degree distributions and contain public-health messages about control. Our findings help us to determine the types of realistic network structure that should be assumed in future population level studies of infection transmission, leading to better interpretations of epidemiological data and more appropriate policy decisions.     

Networks and epidemic models.

Networks and the epidemiology of directly transmitted infectious diseases are fundamentally linked. The foundations of epidemiology and early epidemiological models were based on population wide random-mixing, but in practice each individual has a finite set of contacts to whom they can pass infection; the ensemble of all such contacts forms a 'mixing network'. Knowledge of the structure of the network allows models to compute the epidemic dynamics at the population scale from the individual-level behaviour of infections. Therefore, characteristics of mixing networks-and how these deviate from the random-mixing norm-have become important applied concerns that may enhance the understanding and prediction of epidemic patterns and intervention measures. Here, we review the basis of epidemiological theory (based on random-mixing models) and network theory (based on work from the social sciences and graph theory). We then describe a variety of methods that allow the mixing network, or an approximation to the network, to be ascertained. It is often the case that time and resources limit our ability to accurately find all connections within a network, and hence a generic understanding of the relationship between network structure and disease dynamics is needed. Therefore, we review some of the variety of idealized network types and approximation techniques that have been utilized to elucidate this link. Finally, we look to the future to suggest how the two fields of network theory and epidemiological modelling can deliver an improved understanding of disease dynamics and better public health through effective disease control.     

Stochastic amplification in epidemics

The role of stochasticity and its interplay with nonlinearity are central current issues in studies of the complex population patterns observed in nature, including the pronounced oscillations of wildlife and infectious diseases. The dynamics of childhood diseases have provided influential case studies to develop and test mathematical models with practical application to epidemiology, but are also of general relevance to the central question of whether simple nonlinear systems can explain and predict the complex temporal and spatial patterns observed in nature outside laboratory conditions. Here, we present a stochastic theory for the major dynamical transitions in epidemics from regular to irregular cycles, which relies on the discrete nature of disease transmission and low spatial coupling. The full spectrum of stochastic fluctuations is derived analytically to show how the amplification of noise varies across these transitions. The changes in noise amplification and coherence appear robust to seasonal forcing, questioning the role of seasonality and its interplay with deterministic components of epidemiological models. Childhood diseases are shown to fall into regions of parameter space of high noise amplification. This type of "endogenous" stochastic resonance may be relevant to population oscillations in nonlinear ecological systems in general.     

Disease transmission in territorial populations: the small-world network of Serengeti lions

Territoriality in animal populations creates spatial structure that is thought to naturally buffer disease invasion. Often, however, territorial populations also include highly mobile, non-residential individuals that potentially serve as disease superspreaders. Using long-term data from the Serengeti Lion Project, we characterize the contact network structure of a territorial wildlife population and address the epidemiological impact of nomadic individuals. As expected, pride contacts are dominated by interactions with neighbouring prides and interspersed by encounters with nomads as they wander throughout the ecosystem. Yet the pride–pride network also includes occasional long-range contacts between prides, making it surprisingly small world and vulnerable to epidemics, even without nomads. While nomads increase both the local and global connectivity of the network, their epidemiological impact is marginal, particularly for diseases with short infectious periods like canine distemper virus. Thus, territoriality in Serengeti lions may be less protective and non-residents less important for disease transmission than previously considered.     

Rotavirus within day care centres in Oxfordshire, UK: characterization of partial immunity

Repeated measures data for rotavirus infection in children within 14 day care centres (DCCs) in the Oxfordshire area, UK, are used to explore aspects of rotavirus transmission and immunity. A biologically realistic model for the transmission of infection is presented as a set of probability models suitable for application to the data. Two transition events are modelled separately: incidence and recovery. The complexity of the underlying mechanistic model is reflected in the choice of the fixed variables in the probability models. Parameter estimation was carried out using a Bayesian Markov chain Monte Carlo method. We use the parameter estimates obtained to build a profile of the natural history of rotavirus reinfection in an individual child. We infer that rotavirus transmission in children in DCCs is dependent on the DCC prevalence, with symptomatic infection of longer duration, but no more infectious per day of infectious period, than asymptomatic infection. There was evidence that a recent previous infection reduces the risk of disease and, to a lesser extent, reinfection, but not duration of infection. The results provide evidence that partial immunity to rotavirus infection develops over several time scales.     

Dissecting the determinants of malaria chronicity: why within-host models struggle to reproduce infection dynamics

The duration of infection is fundamental to the epidemiological behaviour of any infectious disease, but remains one of the most poorly understood aspects of malaria. In endemic areas, the malaria parasite Plasmodium falciparum can cause both acute, severe infections and asymptomatic, chronic infections through its interaction with the host immune system. Frequent superinfection and massive parasite genetic diversity make it extremely difficult to accurately measure the distribution of infection lengths, complicating the estimation of basic epidemiological parameters and the prediction of the impact of interventions. Mathematical models have qualitatively reproduced parasite dynamics early during infection, but reproducing long-lived chronic infections remains much more challenging. Here, we construct a model of infection dynamics to examine the consequences of common biological assumptions for the generation of chronicity and the impact of co-infection. We find that although a combination of host and parasite heterogeneities are capable of generating chronic infections, they do so only under restricted parameter choices. Furthermore, under biologically plausible assumptions, co-infection of parasite genotypes can alter the course of infection of both the resident and co-infecting strain in complex non-intuitive ways. We outline the most important puzzles for within-host models of malaria arising from our analysis, and their implications for malaria epidemiology and control.     

Campylobacter jejuni colonization and transmission in broiler chickens: a modelling perspective.

Campylobacter jejuni is one of the most common causes of acute enteritis in the developed world. The consumption of contaminated poultry, where C. jejuni is believed to be a commensal organism, is a major risk factor. However, the dynamics of this colonization process in commercially reared chickens is still poorly understood. Quantification of these dynamics of infection at an individual level is vital to understand transmission within populations and formulate new control strategies. There are multiple potential routes of introduction of C. jejuni into a commercial flock. Introduction is followed by a rapid increase in environmental levels of C. jejuni and the level of colonization of individual broilers. Recent experimental and epidemiological evidence suggest that the celerity of this process could be masking a complex pattern of colonization and extinction of bacterial strains within individual hosts. Despite the rapidity of colonization, experimental transmission studies exhibit a highly variable and unexplained delay time in the initial stages of the process. We review past models of transmission of C. jejuni in broilers and consider simple modifications, motivated by the plausible biological mechanisms of clearance and latency, which could account for this delay. We show how simple mathematical models can be used to guide the focus of experimental studies by providing testable predictions based on our hypotheses. We conclude by suggesting that competition experiments could be used to further understand the dynamics and mechanisms underlying the colonization process. The population models for such competition processes have been extensively studied in other ecological and evolutionary contexts. However, C. jejuni can potentially adapt phenotypically through phase variation in gene expression, leading to unification of ecological and evolutionary time-scales. For a theoretician, the colonization dynamics of C. jejuni offer an experimental system to explore these 'phylodynamics', the synthesis of population dynamics and evolutionary biology.     

Role of high-dose exposure in transmission hot zones as a driver of SARS-CoV-2 dynamics

Epidemiological data about SARS-CoV-2 spread indicate that the virus is not transmitted uniformly in the population. The transmission tends to be more effective in select settings that involve exposure to relatively high viral dose, such as in crowded indoor settings, assisted living facilities, prisons or food processing plants. To explore the effect on infection dynamics, we describe a new mathematical model where transmission can occur (i) in the community at large, characterized by low-dose exposure and mostly mild disease, and (ii) in so-called transmission hot zones, characterized by high-dose exposure that can be associated with more severe disease. The model yields different types of epidemiological dynamics, depending on the relative importance of hot zone and community transmission. Interesting dynamics occur if the rate of virus release/deposition from severely infected people is larger than that of mildly infected individuals. Under this assumption, we find that successful infection spread can hinge upon high-dose hot zone transmission, yet the majority of infections are predicted to occur in the community at large with mild disease. In this regime, residual hot zone transmission can account for continued virus spread during community lockdowns, and the suppression of hot zones after community interventions are relaxed can cause a prolonged lack of infection resurgence following the reopening of society. This gives rise to the notion that targeted interventions specifically reducing virus transmission in the hot zones have the potential to suppress overall infection spread, including in the community at large. Epidemiological trends in the USA and Europe are interpreted in light of this model.     

Metapopulation dynamics of Escherichia coli O157 in cattle: an exploratory model.

Livestock movement is thought to be a risk factor for the transmission of infectious diseases of farm animals. Simple mathematical models were constructed for the transmission of Escherichia coli serogroup O157 between Scottish cattle farms, and the models were used in a preliminary exploration of factors contributing to the levels of infection reported in the field. The results suggest that cattle movement can make a significant contribution to the observed prevalence of E. coli O157-positive farms, but is not by itself sufficient for the persistence of E. coli O157. The results also suggest that cattle movements involving infected farms with cattle shedding an exceptional amount of E. coli O157, 'super-shedders', also make a substantial contribution to the prevalence of infected farms. Simulations indicate that E. coli O157 could have reached the currently observed prevalence levels in less than a decade. Implications and findings from our models are discussed in relation to possible control of E. coli O157 in Scottish cattle.     

Time-dependent spectral analysis of epidemiological time-series with wavelets.

In the current context of global infectious disease risks, a better understanding of the dynamics of major epidemics is urgently needed. Time-series analysis has appeared as an interesting approach to explore the dynamics of numerous diseases. Classical time-series methods can only be used for stationary time-series (in which the statistical properties do not vary with time). However, epidemiological time-series are typically noisy, complex and strongly non-stationary. Given this specific nature, wavelet analysis appears particularly attractive because it is well suited to the analysis of non-stationary signals. Here, we review the basic properties of the wavelet approach as an appropriate and elegant method for time-series analysis in epidemiological studies. The wavelet decomposition offers several advantages that are discussed in this paper based on epidemiological examples. In particular, the wavelet approach permits analysis of transient relationships between two signals and is especially suitable for gradual change in force by exogenous variables.     

Evolution of an asymptomatic first stage of infection in a heterogeneous population

Pathogens evolve different life-history strategies, which depend in part on differences in their host populations. A central feature of hosts is their population structure (e.g. spatial). Additionally, hosts themselves can exhibit different degrees of symptoms when newly infected; this latency is a key life-history property of pathogens. With an evolutionary-epidemiological model, we examine the role of population structure on the evolutionary dynamics of latency. We focus on specific power-law-like formulations for transmission and progression from the first infectious stage as a function of latency, assuming that the across-group to within-group transmission ratio increases if hosts are less symptomatic. We find that simple population heterogeneity can lead to local evolutionarily stable strategies (ESSs) at zero and infinite latency in situations where a unique ESS exists in the corresponding homogeneous case. Furthermore, there can exist more than one interior evolutionarily singular strategy. We find that this diversity of outcomes is due to the (possibly slight) advantage of across-group transmission for pathogens that produce fewer symptoms in a first infectious stage. Thus, our work reveals that allowing individuals without symptoms to travel can have important unintended evolutionary effects and is thus fundamentally problematic in view of the evolutionary dynamics of latency.     

Interactions between serotypes of dengue highlight epidemiological impact of cross-immunity

Dengue, a mosquito-borne virus of humans, infects over 50 million people annually. Infection with any of the four dengue serotypes induces protective immunity to that serotype, but does not confer long-term protection against infection by other serotypes. The immunological interactions between serotypes are of central importance in understanding epidemiological dynamics and anticipating the impact of dengue vaccines. We analysed a 38-year time series with 12 197 serotyped dengue infections from a hospital in Bangkok, Thailand. Using novel mechanistic models to represent different hypothesized immune interactions between serotypes, we found strong evidence that infection with dengue provides substantial short-term cross-protection against other serotypes (approx. 1–3 years). This is the first quantitative evidence that short-term cross-protection exists since human experimental infection studies performed in the 1950s. These findings will impact strategies for designing dengue vaccine studies, future multi-strain modelling efforts, and our understanding of evolutionary pressures in multi-strain disease systems.     

Mechanistic movement models reveal ecological drivers of tick-borne pathogen spread

Identifying ecological drivers of tick-borne pathogen spread has great value for tick-borne disease management. However, theoretical investigations into the consequences of host movement behaviour on pathogen spread dynamics in heterogeneous landscapes remain limited because spatially explicit epidemiological models that incorporate more realistic mechanisms governing host movement are rare. We built a mechanistic movement model to investigate how the interplay between multiple ecological drivers affects the risk of tick-borne pathogen spread across heterogeneous landscapes. We used the model to generate simulations of tick dispersal by migratory birds and terrestrial hosts across theoretical landscapes varying in resource aggregation, and we performed a sensitivity analysis to explore the impacts of different parameters on the infected tick spread rate, tick infection prevalence and infected tick density. Our findings highlight the importance of host movement and tick population dynamics in explaining the infected tick spread rate into new regions. Tick infection prevalence and infected tick density were driven by predictors related to the infection process and tick population dynamics, respectively. Our results suggest that control strategies aiming to reduce tick burden on tick reproduction hosts and encounter rate between immature ticks and pathogen amplification hosts will be most effective at reducing tick-borne disease risk.     

Face masking and COVID-19: potential effects of variolation on transmission dynamics

Face masks do not completely prevent transmission of respiratory infections, but masked individuals are likely to inhale fewer infectious particles. If smaller infectious doses tend to yield milder infections, yet ultimately induce similar levels of immunity, then masking could reduce the prevalence of severe disease even if the total number of infections is unaffected. It has been suggested that this effect of masking is analogous to the pre-vaccination practice of variolation for smallpox, whereby susceptible individuals were intentionally infected with small doses of live virus (and often acquired immunity without severe disease). We present a simple epidemiological model in which mask-induced variolation causes milder infections, potentially with lower transmission rate and/or different duration. We derive relationships between the effectiveness of mask-induced variolation and important epidemiological metrics (the basic reproduction number and initial epidemic growth rate, and the peak prevalence, attack rate and equilibrium prevalence of severe infections). We illustrate our results using parameter estimates for the original SARS-CoV-2 wild-type virus, as well as the Alpha, Delta and Omicron variants. Our results suggest that if variolation is a genuine side-effect of masking, then the importance of face masks as a tool for reducing healthcare burdens from COVID-19 may be under-appreciated.     

Analytical methods for quantifying environmental connectivity for the control and surveillance of infectious disease spread

The sustained transmission and spread of environmentally mediated infectious diseases is governed in part by the dispersal of parasites, disease vectors and intermediate hosts between sites of transmission. Functional geospatial models can be used to quantify and predict the degree to which environmental features facilitate or limit connectivity between target populations, yet typical models are limited in their geographical and analytical approach, providing simplistic, global measures of connectivity and lacking methods to assess the epidemiological implications of fine-scale heterogeneous landscapes. Here, functional spatial models are applied to problems of surveillance and control of the parasitic blood fluke Schistosoma japonicum and its intermediate snail host Oncomelania haupensis in western China. We advance functional connectivity methods by providing an analytical framework to (i) identify nodes of transmission where the degree of connectedness to other villages, and thus the potential for disease spread, is higher than is estimated using Euclidean distance alone and (ii) (re)organize transmission sites into disease surveillance units based on second-order relationships among nodes using non-Euclidean distance measures, termed effective geographical distance (EGD). Functional environmental models are parametrized using ecological information on the target organisms, and pair-wise distributions of inter-node EGD are estimated. A Monte Carlo rank product analysis is presented to identify nearby nodes under alternative distance models. Nodes are then iteratively embedded into EGD space and clustered using a k-means algorithm to group villages into ecologically meaningful surveillance groups. A consensus clustering approach is taken to derive the most stable cluster structure. The results indicate that novel relationships between nodes are revealed when non-Euclidean, ecologically determined distance measures are used to quantify connectivity in heterogeneous landscapes. These connections are not evident when analysing nodes in Euclidean space, and thus surveillance and control activities planned using Euclidean distance measures may be suboptimal. The methods developed here provide a quantitative framework for assessing the effectiveness of ecologically grounded surveillance systems and of control and prevention strategies for environmentally mediated diseases.     

Timing and severity of immunizing diseases in rabbits is controlled by seasonal matching of host and pathogen dynamics

Infectious diseases can exert a strong influence on the dynamics of host populations, but it remains unclear why such disease-mediated control only occurs under particular environmental conditions. We used 16 years of detailed field data on invasive European rabbits (Oryctolagus cuniculus) in Australia, linked to individual-based stochastic models and Bayesian approximations, to test whether (i) mortality associated with rabbit haemorrhagic disease (RHD) is driven primarily by seasonal matches/mismatches between demographic rates and epidemiological dynamics and (ii) delayed infection (arising from insusceptibility and maternal antibodies in juveniles) are important factors in determining disease severity and local population persistence of rabbits. We found that both the timing of reproduction and exposure to viruses drove recurrent seasonal epidemics of RHD. Protection conferred by insusceptibility and maternal antibodies controlled seasonal disease outbreaks by delaying infection; this could have also allowed escape from disease. The persistence of local populations was a stochastic outcome of recovery rates from both RHD and myxomatosis. If susceptibility to RHD is delayed, myxomatosis will have a pronounced effect on population extirpation when the two viruses coexist. This has important implications for wildlife management, because it is likely that such seasonal interplay and disease dynamics has a strong effect on long-term population viability for many species.     

The long and winding road to inhaled TB therapy: not only the bug’s fault

Not all of the issues impacting the success of tuberculosis (TB) treatment arise from pathogen-related disease characteristics. Nowadays, there is an increasing awareness that antibiotic treatment is not the only answer to the TB problem, promoting the search for alternative administration strategies and host-directed therapies. Among all the administration routes, being the lungs the main TB focus, inhalation is conceptually a logical solution to enhance treatment effectiveness and compliance. Nevertheless, research efforts and funding are almost entirely conveyed to conventional approaches. This review will critically evaluate the reasons constraining research in this field, providing some future perspectives. The most recent advances in inhalation approaches for TB will be discussed, either at the preclinical or clinical phase, illustrating the risk of failure and chances of success.