Cross-serotype interactions and disease outcome prediction of dengue infections in Vietnam.

Dengue pathogenesis is extremely complex. Dengue infections are thought to induce life-long immunity from homologous challenges as well as a multi-factorial heterologous risk enhancement. Here, we use the data collected from a prospective cohort study of dengue infections in schoolchildren in Vietnam to disentangle how serotype interactions modulate clinical disease risk in the year following serum collection. We use multinomial logistic regression to correlate the yearly neutralizing antibody measurements obtained with each infecting serotype in all dengue clinical cases collected over the course of 6 years (2004-2009). This allowed us to extrapolate a fully discretised matrix of serotype interactions, revealing clear signals of increased risk of clinical illness in individuals primed with a previous dengue infection. The sequences of infections which produced a higher risk of dengue fever upon secondary infection are: DEN1 followed by DEN2; DEN1 followed by DEN4; DEN2 followed by DEN3; and DEN4 followed by DEN3. We also used this longitudinal data to train a machine learning algorithm on antibody titre differences between consecutive years to unveil asymptomatic dengue infections and estimate asymptomatic infection to clinical case ratios over time, allowing for a better characterisation of the population's past exposure to different serotypes.

Refined efficacy estimates of the Sanofi Pasteur dengue vaccine CYD-TDV using machine learning.

CYD-TDV is the first licensed dengue vaccine for individuals 9-45 (or 60) years of age. Using 12% of the subjects enroled in phase-2b and phase-3 trials for which baseline serostatus was measured, the vaccine-induced protection against virologically confirmed dengue during active surveillance (0-25 months) was found to vary with prior exposure to dengue. Because age and dengue exposure are highly correlated in endemic settings, refined insight into how efficacy varies by serostatus and age is essential to understand the increased risk of hospitalisation observed among vaccinated individuals during the long-term follow-up and to develop safe and effective vaccination strategies. Here we apply machine learning to impute the baseline serostatus for subjects with post-dose 3 titres but missing baseline serostatus. We find evidence for age dependence in efficacy independent of serostatus and estimate that among 9-16 year olds, CYD-TDV is protective against serotypes 1, 3 and 4 regardless of baseline serostatus.

Transmission scenarios for Middle East Respiratory Syndrome Coronavirus (MERS-CoV) and how to tell them apart.

Detection of human cases of Middle East Respiratory Syndrome Coronavirus (MERS-CoV) infection internationally is a global public health concern. Rigorous risk assessment is particularly challenging in a context where surveillance may be subject to under-ascertainment and a selection bias towards more severe cases. We would like to assess whether the virus is capable of causing widespread human epidemics, and whether self-sustaining transmission is already under way. Here we review possible transmission scenarios for MERS-CoV and their implications for risk assessment and control. We discuss how existing data, future investigations and analyses may help in reducing uncertainty and refining the public health risk assessment and present analytical approaches that allow robust assessment of epidemiological characteristics, even from partial and biased surveillance data. Finally, we urge that adequate data be collected on future cases to permit rigorous assessment of the transmission characteristics and severity of MERS-CoV, and the public health threat it may pose. Going beyond minimal case reporting, open international collaboration, under the guidance of the World Health Organization and the International Health Regulations, will impact on how this potential epidemic unfolds and prospects for control.

Discrepancy between minimal inhibitory concentration to enrofloxacin and mutations present in the quinolone-resistance determining regions of Mycoplasma gallisepticum field strains.

Molecular characterization of the quinolone-resistance determining regions (QRDRs) of DNA gyrase and topoisomerase IV in 93 Mycoplasma gallisepticum field strains isolated in different geographic regions revealed discrepancies between minimal inhibitory concentration values and presence of amino acid substitutions within the QRDRs of GyrA and ParC in 9/93 (10%) strains. This may delimitate applicability of a gene-based assay to detect fluoroquinolone resistance in this avian pathogen.

Threshold parameters for a model of epidemic spread among households and workplaces.

The basic reproduction number R0 is one of the most important concepts in modern infectious disease epidemiology. However, for more realistic and more complex models than those assuming homogeneous mixing in the population, other threshold quantities can be defined that are sometimes more useful and easily derived in terms of model parameters. In this paper, we present a model for the spread of a permanently immunizing infection in a population socially structured into households and workplaces/schools, and we propose and discuss a new household-to-household reproduction number RH for it. We show how RH overcomes some of the limitations of a previously proposed threshold parameter, and we highlight its relationship with the effort required to control an epidemic when interventions are targeted at randomly selected households.

Transmission dynamics and mechanisms of endemicity of scrapie in the UK sheep population.

SUMMARYScrapie is a fatal neurological disease of sheep which is endemic in the United Kingdom. It is one of the family of transmissible spongiform encephalopathies (TSEs) that includes BSE. In this paper, we developed a micro-simulation model for scrapie in the UK sheep population, incorporating the genetic and structural diversity of the population and infectious contact between flocks through trading. The simulation was fitted to epidemiological data from a range of sources. We found a detection/reporting probability of 16% (95% CI 12-17) for animals dying of scrapie. Prevalence of infected animals in the population was about 0.15%. Infected individuals were found in 9% of flocks overall, rising to 60% in Shetland and 75% in Swaledale flocks. Mean values of R0 for flocks varied with breed from 2.43 (Shetland) to 0.21 (Suffolk). We also examined the possible long-term persistence of scrapie in the UK flock in the absence of any intervention.

Control of scrapie in the UK sheep population.

Scrapie is a fatal transmissible spongiform encephalopathy (TSE) of sheep, endemic in the UK for centuries. Interest in the disease has been heightened over the last decade by the possibility of the related BSE being transmissible to and between sheep and a range of control interventions has been proposed and implemented. In this paper, we examined the effect of these policies and their components on observed case rate, susceptible allele frequency and R0 within the framework of a large simulation model of the British sheep population and its breeding and trading structure. We compared interventions with the natural fade-out of scrapie in the population through loss of susceptible genotypes in the absence of control. We compare the results of interventions with the natural course of the scrapie epidemic. Our model suggested that scrapie will persist in the national flock for 300-400 years with the impact on gene frequencies confined largely to high case-rate breeds, such as Shetland and Swaledale. We found the National Scrapie Plan (NSP) to be the most effective in terms of the removal of both susceptible genotypes and scrapie from the population. Complete eradication of scrapie can be achieved within 32 years (95% CI 23-43 years). The Compulsory Scrapie Flock Scheme (CSFS) is as effective as the NSP in reducing the observed case rate but has a limited impact on the frequencies of susceptible genotypes in the population overall. In combination with the NSP, eradication of scrapie is achieved >10 years faster. Of the components of the CSFS, the breeding and culling aspects are each almost as effective as the full policy, with trading restrictions contributing little. We have speculated on the impact of control measures on the possibility BSE infection within the national flock by examining their effect on flock R0 for BSE across different breeds.

Interactions of multiple strain pathogen diseases in the presence of coinfection, cross immunity, and arbitrary strain diversity.

A model for coinfection in multiple strain infectious diseases is developed to incorporate coinfection statuses, immune and infection history, and cross immunity. It is solved for the symmetric interior equilibrium through the use of a ladder operator formalism inspired by quantum mechanical methods. We find that coinfection can fundamentally affects transmission dynamics with important epidemiologic and evolutionary consequences. It can significantly shift the distribution of age at infection for highly antigenically diverse pathogens so that in small host populations, an evolutionary strategy maximizing individual strain transmissibility might be less optimal than one which maximizes the total prevalence of all strains in the system. Alternatively, mechanisms which inhibit coinfection and thus increase total infection prevalence may be evolutionarily advantageous.

Analytic approximation of spatial epidemic models of foot and mouth disease.

The effect of spatial heterogeneity in epidemic models has improved with computational advances, yet far less progress has been made in developing analytical tools for understanding such systems. Here, we develop two classes of second-order moment closure methods for approximating the dynamics of a stochastic spatial model of the spread of foot and mouth disease. We consider the performance of such 'pseudo-spatial' models as a function of R(0), the locality in disease transmission, farm distribution and geographically-targeted control when an arbitrary number of spatial kernels are incorporated. One advantage of mapping complex spatial models onto simpler deterministic approximations lies in the ability to potentially obtain a better analytical understanding of disease dynamics and the effects of control. We exploit this tractability by deriving analytical results in the invasion stages of an FMD outbreak, highlighting key principles underlying epidemic spread on contact networks and the effect of spatial correlations.

Approximate disease dynamics in household-structured populations.

We argue that the large-dimensional dynamical systems which frequently occur in biological models can sometimes be effectively reduced to much smaller ones. We illustrate this by applying projection operator techniques to a mean-field model of an infectious disease spreading through a population of households. In this way, we are able to accurately approximate the dynamics of the system in terms of a few key quantities greatly reducing the number of equations required. We investigate linear stability in this framework and find a new way of calculating the familiar threshold criterion for household systems.

Seroprevalence of IgG antibodies to SARS-coronavirus in asymptomatic or subclinical population groups.

We systematically reviewed the current understanding of human population immunity against SARS-CoV in different groups, settings and geography. Our meta-analysis, which included all identified studies except those on wild animal handlers, yielded an overall seroprevalence of 0.10% [95% confidence interval (CI) 0.02-0.18]. Health-care workers and others who had close contact with SARS patients had a slightly higher degree of seroconversion (0.23%, 95% CI 0.02-0.45) compared to healthy blood donors, others from the general community or non-SARS patients recruited from the health-care setting (0.16%, 95% CI 0-0.37). When analysed by the two broad classes of testing procedures, it is clear that serial confirmatory test protocols resulted in a much lower estimate (0.050%, 95% CI 0-0.15) than single test protocols (0.20%, 95% CI 0.06-0.34). Potential epidemiological and laboratory pitfalls are also discussed as they may give rise to false or inconsistent results in measuring the seroprevalence of IgG antibodies to SARS-CoV.

Epidemiological analysis of data for scrapie in Great Britain.

In recent years, the control or eradication of scrapie and any other transmissible spongiform encephalopathies (TSEs) possibly circulating in the sheep population has become a priority in Britain and elsewhere in Europe. A better understanding of the epidemiology of scrapie would greatly aid the development and evaluation of control and eradication strategies. Here we bound the range of key epidemiological parameters using a combination of relatively detailed pathogenesis and demography data, more limited data on susceptibility and incubation times, and recent survey data on scrapie incidence in Great Britain. These data are simultaneously analysed using mathematical models describing scrapie transmission between sheep and between flocks. Our analysis suggests that occurrence of scrapie in a flock typically provokes changes in flock management that promote termination of the outbreak, such as the adoption of selective breeding, and that a large fraction of cases (possibly over 80%) goes undetected. We show that the data analysed are consistent with the within-flock reproduction number of scrapie lying in the range 1.5-6, consistent with previous epidemiological studies.

Density dependence and overdispersion in the transmission of helminth parasites.

The influence of density-dependent processes on the transmission of parasitic helminths is determined by both the severity of the regulatory constraints and the degree of parasite overdispersion among the host population. We investigate how overdispersed parasite distributions among humans influence transmission levels in both directly- and indirectly-transmitted nematodes (Ascaris lumbricoides and Onchocerca volvulus). While past work has assumed, for simplicity, that density dependence acts on the average worm load, here we model density-dependence as acting on individual parasite burdens before averaging across hosts. A composite parameter, which we call the effective transmission contribution, is devised to measure the number of transmission stages contributed by a given worm burden after incorporating over-dispersion in adult worm mating probabilities and other density-dependent mechanisms. Results indicate that the more overdispersed the parasite population, the greater the effect of density dependence upon its transmission dynamics. Strong regulation and parasite overdispersion make the relationship between mean worm burden and its effective contribution to transmission highly non-linear. Consequently, lowering the intensity of infection in a host population using chemotherapy may produce only a small decline in transmission (relative to its initial endemic level). Our analysis indicates that when parasite burden is low, intermediate levels of parasite clustering maximize transmission. Implications are discussed in relation to existing control programmes and the spread of anthelmintic resistance.

Characterizing the symmetric equilibrium of multi-strain host-pathogen systems in the presence of cross immunity.

We investigate the population dynamics of host-pathogen systems in which the pathogen has a potentially arbitrary number of antigenically distinct strains interacting via cross-immunity. The interior equilibrium configuration of the symmetric multiple strain SIR model with cross-immunity is characterized. We develop an efficient iterative method for numerically solving the equilibrium equation together with a number of informative analytical approximations to the full solution. Equilibrium properties are studied as a function of the number of strains, reproduction number, infectious period, and cross immunity profile. We establish that the prevalence in the system increases monotonically with the number of strains and the reduction in cross immunity. Moreover, we demonstrate the existence of a phase transition separating high prevalence and low prevalence parameter regions, with the critical point being defined by sigmaR0 congruent with1, where sigma is the level of cross-immunity and R0 is the reproduction number. Above the threshold, prevalence saturates with increasing numbers of strains as a result of the inclusion of prohibition of co-infection in the model. Below the threshold, prevalence saturates much more rapidly as the number of strains increases--indicating that when cross-protection is sufficiently intense, the selective advantage for a pathogen to increase its diversity is substantially less than in the threshold region. Similarly, there is limited benefit to increased transmissibility (or decreased cross-immunity) both for the high and low diversity pathogen systems compared with systems at the threshold sigmaR0 congruent with1 where small increase in transmissibility can result in significant increase in prevalence.

Adherence to antiretroviral therapy and its impact on clinical outcome in HIV-infected patients.

We analyse data on patient adherence to prescribed regimens and surrogate markers of clinical outcome for 168 human immunodeficiency virus infected patients treated with antiretroviral therapy. Data on patient adherence consisted of dose-timing measurements collected for an average of 12 months per patient via electronic monitoring of bottle opening events. We first discuss how such data can be presented to highlight suboptimal adherence patterns and between-patient differences, before introducing two novel methods by which such data can be statistically modelled. Correlations between adherence and subsequent measures of viral load and CD4+T-cell counts are then evaluated. We show that summary measures of short-term adherence, which incorporate pharmacokinetic and pharmacodynamic data on the monitored regimen, predict suboptimal trends in viral load and CD4+T-cell counts better than measures based on adherence data alone.

Spatial heterogeneity and the persistence of infectious diseases.

The endemic persistence of infectious diseases can often not be understood without taking into account the relevant heterogeneities of host mixing. Here, we consider spatial heterogeneity, defined as 'patchiness' of the host population. After briefly reviewing how disease persistence is influenced by population size, reproduction number and infectious period, we explore its dependence on the level of spatial heterogeneity. Analysis and simulation of disease transmission in a symmetric meta-population suggest that disease persistence typically becomes worse as spatial heterogeneity increases, although local persistence optima can occur for infections with oscillatory population dynamics. We obtain insight into the dynamics that underlie the observed persistence patterns by studying the infection prevalence correlation between patches and by comparing full-model simulations to results obtained using simplified patch-level descriptions of the interplay between local extinctions and between-patch transmissions. The observed patterns are interpreted in terms of rescue effects for strong spatial heterogeneity and in terms of between-patch coherence and synchronization effects at intermediate and weak levels of heterogeneity.

Safety and efficacy of the avirulent Mycoplasma gallisepticum strain K5054 as a live vaccine in poultry.

A Mycoplasma gallisepticum (MG) isolate from an atypically mild outbreak in turkey breeders was found to be similar to house finch isolates by DNA analyses. A preliminary study in turkeys showed that this isolate (K5054) caused very mild lesions and protected turkeys against subsequent challenge with a virulent MG strain. In this study, K5054 was further evaluated as a potential vaccine strain in commercial layer-type chickens and turkeys. The safety of K5054 was evaluated by aerosol challenge followed by evaluation of gross and histopathologic lesions as well as serologic reactions and isolation of MG from the trachea and air sacs. Infection of chickens (trial 1) and turkeys (trial 2) with K5054 resulted in little evidence of MG lesions. There was weak seroconversion, and K5054 was consistently reisolated from the tracheas of chickens and turkeys. The efficacy of K5054 as a vaccine was evaluated by aerosol challenge of vaccinated chickens (trial 3) and turkeys (trial 4) with virulent R strain. There was evidence of protection from lesions associated with MG.

Dynamics of a scrapie outbreak in a flock of Romanov sheep--estimation of transmission parameters.

Knowledge of epidemiological mechanisms and parameters underlying scrapie transmission in sheep flocks remains very limited at present. Here we introduce a method for fitting stochastic transmission models to outbreak data to estimate bounds on key transmission parameters. We apply this method to data describing an outbreak of scrapie in a closed flock of Romanov sheep. The main findings are that the relative infectiousness of infected animals in this outbreak becomes appreciable early into disease incubation and that the mean incubation period is less than 1.5 years. We also find that the data are consistent with a broad range of values for the basic reproduction number R0 and describe how the boundaries of this range depend on assumptions about the mean incubation period and the contribution to transmission of a long-lived environmental reservoir of infectivity.

Characterization of a naturally occurring infection of a Mycoplasma gallisepticum house finch-like strain in turkey breeders.

An outbreak of Mycoplasma gallisepticum (MG) in commercial turkeys involving very mild clinical signs was difficult to confirm by routine methods. In the first part of this study (trial A), we conducted a bioassay to increase the likelihood of detecting MG. Susceptible turkeys were inoculated with sinus exudates from four different affected commercial turkey flocks. Turkeys were evaluated for clinical signs, as well as by serology and culture of tracheal swabs, at 21 and 42 days postchallenge. An MG isolate from one of the sinus exudates used for inoculation, designated K5054, was very similar to isolates from house finches when characterized by random amplified polymorphic DNA analysis as well as DNA sequence analysis of portions of the phase-variable putative adhesin protein (pvpA) gene, a lipoprotein gene, and the cytadhesin gapA/mgc1 gene. The turkeys inoculated with the K5054 sinus exudate seroconverted in the absence of severe clinical signs. There was a single reisolation of K5054 from these turkeys 42 days postchallenge. Susceptible contact turkeys were commingled with the K5054-inoculated turkeys at 49 days postchallenge. We found no evidence of transmission of MG to the contacts by culture or serology at 7, 21, or 35 days after commingling. In the second part of this study (trial B), we challenged the contacts and K5054 sinus exudate-inoculated turkeys from trial A with virulent R strain 88 days after the K5054 sinus exudate inoculation. On necropsy 10 days postchallenge, the evaluation of gross and microscopic lesions, serology, and culture showed that the turkeys previously inoculated with K5054 sinus exudate were protected against disease and reinfection.

Extending backcalculation to analyse BSE data.

We review the origins of backcalculation (or back projection) methods developed for the analysis of AIDS (acquired immunodeficiency syndrome) incidence data. These techniques have been used extensively for >15 years to deconvolute clinical case incidence, given knowledge of the incubation period distribution, to obtain estimates of past HIV (human immunodeficiency virus) infection incidence and short-term predictions of future AIDS incidence. Adaptations required for the analysis of bovine spongiform encephalopathy (BSE) incidence included: stratification of BSE incidence by age as well as birth cohort; allowance for incomplete survival between infection and the onset of clinical signs of disease; and decomposition of the age- and time-related infection incidence into a time-dependent feed risk component and an age-dependent exposure/susceptibility function. The most recent methodological developments focus on the incorporation of data from clinically unaffected cattle screened using recently developed tests for preclinical BSE infection. Backcalculation-based predictions of future BSE incidence obtained since 1996 are examined. Finally, future directions of epidemiological analysis of BSE epidemics are discussed taking into account ongoing developments in the science of BSE and possible changes in BSE-related policies.