Don Klinkenberg

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.

Spatial and stochastic simulation to compare two emergency-vaccination strategies with a marker vaccine in the 1997/1998 Dutch Classical Swine Fever epidemic.

Two alternative emergency-vaccination strategies with a marker vaccine that could have been applied in the 1997/1998 Dutch Classical Swine Fever (CSF) epidemic were evaluated in a modified spatial, temporal and stochastic simulation model: InterCSF. In strategy 1, vaccination would be applied only to overcome a shortage in destruction capacities. Destruction of all pigs on vaccinated farms distinguishes this strategy from strategy 2, which assumes intra-Community trade of vaccinated pig meat. InterCSF simulates the spread of CSF between farms through local spread and three contact types. Disease spread is affected by control measures implemented through different mechanisms. Economic results were generated by a separate model that calculated the direct costs (including the vaccination costs) and consequential losses for farmers and related industries subjected to control measures. The comparison (using epidemiological and economic results) between the different emergency-vaccination strategies with an earlier simulated preventive-slaughter scenario led to some general conclusions on the Dutch CSF epidemic. Both emergency-vaccination strategies were hardly more efficient than the non-vaccination scenario. The intra-Community trade strategy (vaccination-strategy 2) was the least costly of all three scenarios.

Quantifying Transmission of Campylobacter jejuni in Commercial Broiler Flocks

ABSTRACT Since meat from poultry colonized with Campylobacter spp. is a major cause of bacterial gastroenteritis, human exposure should be reduced by, among other things, prevention of colonization of broiler flocks. To obtain more insight into possible sources of introduction of Campylobacter into broiler flocks, it is essential to estimate the moment that the first bird in a flock is colonized. If the rate of transmission within a flock were known, such an estimate could be determined from the change in the prevalence of colonized birds in a flock over time. The aim of this study was to determine the rate of transmission of Campylobacter using field data gathered for 5 years for Australian broiler flocks. We used unique sampling data for 42 Campylobacter jejuni-colonized flocks and estimated the transmission rate, which is defined as the number of secondary infections caused by one colonized bird per day. The estimate was 2.37 ± 0.295 infections per infectious bird per day, which implies that in our study population colonized flocks consisting of 20,000 broilers would have an increase in within-flock prevalence to 95% within 4.4 to 7.2 days after colonization of the first broiler. Using Bayesian analysis, the moment of colonization of the first bird in a flock was estimated to be from 21 days of age onward in all flocks in the study. This study provides an important quantitative estimate of the rate of transmission of Campylobacter in broiler flocks, which could be helpful in future studies on the epidemiology of Campylobacter in the field.

Quantifying Transmission of Campylobacter spp. among Broilers

ABSTRACT Campylobacter species are frequently identified as a cause of human gastroenteritis, often from eating or mishandling contaminated poultry products. Quantitative knowledge of transmission of Campylobacter in broiler flocks is necessary, as this may help to determine the moment of introduction of Campylobacter in broiler flocks more precisely. The aim of this study was to determine the transmission rate parameter in broiler flocks. Four experiments were performed, each with four Campylobacter-inoculated chicks housed with 396 contact chicks per group. Colonization was monitored by regularly testing fecal samples for Campylobacter. A mathematical model was used to quantify the transmission rate, which was determined to be 1.04 new cases per colonized chick per day. This would imply that, for example, in a flock of 20,000 broilers, the prevalence of Campylobacter would increase from 5% to 95% within 6 days after Campylobacter introduction. The model and the estimated transmission rate parameter can be used to develop a suitable sampling scheme to determine transmission in commercial broiler flocks, to estimate whether control measures can reduce the transmission rate, or to estimate when Campylobacter was introduced into a colonized broiler flock on the basis of the time course of transmission in the flock.

The effectiveness of contact tracing in emerging epidemics.

Background Contact tracing plays an important role in the control of emerging infectious diseases, but little is known yet about its effectiveness. Here we deduce from a generic mathematical model how effectiveness of tracing relates to various aspects of time, such as the course of individual infectivity, the (variability in) time between infection and symptom-based detection, and delays in the tracing process. In addition, the possibility of iteratively tracing of yet asymptomatic infecteds is considered. With these insights we explain why contact tracing was and will be effective for control of smallpox and SARS, only partially effective for foot-and-mouth disease, and likely not effective for influenza. Methods and Findings We investigate contact tracing in a model of an emerging epidemic that is flexible enough to use for most infections. We consider isolation of symptomatic infecteds as the basic scenario, and express effectiveness as the proportion of contacts that need to be traced for a reproduction ratio smaller than 1. We obtain general results for special cases, which are interpreted with respect to the likely success of tracing for influenza, smallpox, SARS, and foot-and-mouth disease epidemics. Conclusions We conclude that (1) there is no general predictive formula for the proportion to be traced as there is for the proportion to be vaccinated; (2) variability in time to detection is favourable for effective tracing; (3) tracing effectiveness need not be sensitive to the duration of the latent period and tracing delays; (4) iterative tracing primarily improves effectiveness when single-step tracing is on the brink of being effective.

Early epidemiological assessment of the virulence of emerging infectious diseases: a case study of an influenza pandemic.

Background The case fatality ratio (CFR), the ratio of deaths from an infectious disease to the number of cases, provides an assessment of virulence. Calculation of the ratio of the cumulative number of deaths to cases during the course of an epidemic tends to result in a biased CFR. The present study develops a simple method to obtain an unbiased estimate of confirmed CFR (cCFR), using only the confirmed cases as the denominator, at an early stage of epidemic, even when there have been only a few deaths. Methodology/Principal Findings Our method adjusts the biased cCFR by a factor of underestimation which is informed by the time from symptom onset to death. We first examine the approach by analyzing an outbreak of severe acute respiratory syndrome in Hong Kong (2003) with known unbiased cCFR estimate, and then investigate published epidemiological datasets of novel swine-origin influenza A (H1N1) virus infection in the USA and Canada (2009). Because observation of a few deaths alone does not permit estimating the distribution of the time from onset to death, the uncertainty is addressed by means of sensitivity analysis. The maximum likelihood estimate of the unbiased cCFR for influenza may lie in the range of 0.16–4.48% within the assumed parameter space for a factor of underestimation. The estimates for influenza suggest that the virulence is comparable to the early estimate in Mexico. Even when there have been no deaths, our model permits estimating a conservative upper bound of the cCFR. Conclusions Although one has to keep in mind that the cCFR for an entire population is vulnerable to its variations among sub-populations and underdiagnosis, our method is useful for assessing virulence at the early stage of an epidemic and for informing policy makers and the public.

Detecting emerging transmissibility of avian influenza virus in human households

Accumulating infections of highly pathogenic H5N1 avian influenza in humans underlines the need to track the ability of these viruses to spread among humans. A human-transmissible avian influenza virus is expected to cause clusters of infections in humans living in close contact. Therefore, epidemiological analysis of infection clusters in human households is of key importance. Infection clusters may arise from transmission events from (i) the animal reservoir, (ii) humans who were infected by animals (primary human-to-human transmission), or (iii) humans who were infected by humans (secondary human-to-human transmission). Here we propose a method of analysing household infection data to detect changes in the transmissibility of avian influenza viruses in humans at an early stage. The method is applied to an outbreak of H7N7 avian influenza virus in The Netherlands that was the cause of more than 30 human-to-human transmission events. The analyses indicate that secondary human-to-human transmission is plausible for the Dutch household infection data. Based on the estimates of the within-household transmission parameters, we evaluate the effectiveness of antiviral prophylaxis, and conclude that it is unlikely that all household infections can be prevented with current antiviral drugs. We discuss the applicability of our method for the detection of emerging human-to-human transmission of avian influenza viruses in particular, and for the analysis of within-household infection data in general.

Quantification of horizontal transmission of Salmonella enterica serovar Enteritidis bacteria in pair-housed groups of laying hens.

ABSTRACT An important source of human salmonellosis is the consumption of table eggs contaminated with Salmonella enterica serovar Enteritidis. Optimization of the various surveillance programs currently implemented to reduce human exposure requires knowledge of the dynamics of S. Enteritidis infection within flocks. The aim of this study was to provide parameter estimates for a transmission model of S. Enteritidis in laying-type chicken flocks. An experiment was carried out with 60 pairs of laying hens. Per pair, one hen was inoculated with S. Enteritidis and the other was contact exposed. After inoculation, cloacal swab samples from all hens were collected over 18 days and tested for the presence of S. Enteritidis. On the basis of this test, it was determined if and when each contact-exposed hen became colonized. A transmission model including a latency period of 1 day and a slowly declining infectivity level was fitted. The mean initial transmission rate was estimated to be 0.47 (95% confidence interval [CI], 0.30 to 0.72) per day. The reproduction number R0, the average number of hens infected by one colonized hen in a susceptible population, was estimated to be 2.8 (95% CI, 1.9 to 4.2). The generation time, the average time between colonization of a “primary” hen and colonization of contact-exposed hens, was estimated to be 7.0 days (95% CI, 5.0 to 11.6 days). Simulations using these parameters showed that a flock of 20,000 hens would reach a maximum colonization level of 92% within 80 days after colonization of the first hen. These results can be used, for example, to evaluate the effectiveness of control and surveillance programs and to optimize these programs in a cost-benefit analysis.

The correlation between infectivity and incubation period of measles, estimated from households with two cases.

The generation time of an infectious disease is the time between infection of a primary case and infection of a secondary case by the primary case. Its distribution plays a key role in understanding the dynamics of infectious diseases in populations, e.g. in estimating the basic reproduction number. Moreover, the generation time and incubation period distributions together characterize the effectiveness of control by isolation and quarantine. In modelling studies, a relation between the two is often not made specific, but a correlation is biologically plausible. However, it is difficult to establish such correlation, because of the unobservable nature of infection events. We have quantified a joint distribution of generation time and incubation period by a novel estimation method for household data with two susceptible individuals, consisting of time intervals between disease onsets of two measles cases. We used two such datasets, and a separate incubation period dataset. Results indicate that the mean incubation period and the generation time of measles are positively correlated, and that both lie in the range of 11-12 days, suggesting that infectiousness of measles cases increases significantly around the time of symptom onset. The correlation between times from infection to secondary transmission and to symptom onset could critically affect the predicted effectiveness of isolation and quarantine.

Influence of maternal antibodies on efficacy of a subunit vaccine: transmission of classical swine fever virus between pigs vaccinated at 2 weeks of age

This study shows the effectiveness of vaccination with an E2 subunit vaccine against classical swine fever (CSF) in 2-week-old piglets. Half of the piglets were carrying maternally derived antibodies (MDAs) at the time of vaccination. Three and 6 months later, antibody levels were compared between the two treatments. Moreover, reduction of virus transmission was investigated at 3 and 6 months by doing transmission experiments. The vaccine was found to be capable of reducing virus transmission significantly at both time intervals. Maternal immunity reduced vaccination-induced antibody levels after 3 and 6 months and possibly led to a less effective protection against virus transmission after 6 months.