The daily updated Dutch national database on COVID-19 epidemiology, vaccination and sewage surveillance.

The Dutch national open database on COVID-19 has been incrementally expanded since its start on 30 April 2020 and now includes datasets on symptoms, tests performed, individual-level positive cases and deaths, cases and deaths among vulnerable populations, settings of transmission, hospital and ICU admissions, SARS-CoV-2 variants, viral loads in sewage, vaccinations and the effective reproduction number. This data is collected by municipal health services, laboratories, hospitals, sewage treatment plants, vaccination providers and citizens and is cleaned, analysed and published, mostly daily, by the National Institute for Public Health and the Environment (RIVM) in the Netherlands, using automated scripts. Because these datasets cover the key aspects of the pandemic and are available at detailed geographical level, they are essential to gain a thorough understanding of the past and current COVID-19 epidemiology in the Netherlands. Future purposes of these datasets include country-level comparative analysis on the effect of non-pharmaceutical interventions against COVID-19 in different contexts, such as different cultural values or levels of socio-economic disparity, and studies on COVID-19 and weather factors.

The impact of influenza vaccination on infection, hospitalisation and mortality in the Netherlands between 2003 and 2015.

Influenza epidemics annually cause substantial morbidity and mortality. For this reason, vaccination is offered yearly to persons with an elevated risk for complications. Assessments of the impact of vaccination are, however, hampered by year-to-year variation in epidemic size and vaccine effectiveness. We estimate the impact of the current vaccination programme comparing simulations with vaccination to counterfactual simulations without vaccination. The simulations rely on an age- and risk-structured transmission model that tracks the build-up and loss of immunity over successive seasons, and that allows the vaccine match to vary between seasons. The model parameters are estimated with a particle Monte Carlo method and approximate Bayesian computation, using epidemiological data on vaccine effectiveness and epidemic size in the Netherlands over a period of 11 years. The number of infections, hospitalisations and deaths vary greatly between years because waning of immunity and vaccine match may differ every season, which is in line with observed variation in influenza epidemic sizes. At an overall coverage of 21%, vaccination has averted on average 13% (7.2-19%, 95% range) of infections, 24% (16-36%) of hospitalisations, and 35% (16-50%) of deaths. This suggests that vaccination is mainly effective in protecting vaccinees from infection rather than reducing transmission. As the Dutch population continues to grow and age, the vaccination programme is projected (up to 2025) to gain in impact, despite a decreasing infection attack rate.

Vaccinating children against influenza increases variability in epidemic size.

Seasonal influenza causes a high disease burden. Many influenza vaccination programmes target the elderly and persons at high risk of complications. Some countries have recommended or even implemented a paediatric vaccination programme. Such a programme is expected to reduce influenza transmission in the population, offering direct protection to the vaccinated children and indirect protection to the elderly. We study the impact of a child vaccination programme with an age- and risk-structured transmission model, calibrated to data of 11 influenza seasons in the Netherlands. The model tracks the build-up of immunes and susceptibles in each age cohort over time, and it allows for seasonal variation in vaccine match and antigenic drift. Different vaccination strategies are evaluated for three target age groups (2-3, 2-12 and 2-16 year olds) over the full range of vaccination coverages (0-100%). The results show that the paediatric vaccination programme has only a limited impact on the elderly age groups, which account for most influenza morbidity and mortality. This is due to two notable changes in infection dynamics. First, an age shift is observed: influenza infections are reduced in vaccinated children, but are increased in young adults with limited natural immunity after years of vaccination. These young adults assume the role of driving the epidemic. Second, a year with low influenza activity can be followed by a large epidemic due to build-up of susceptibles. This variation of the infection attack rate increases with increasing vaccination coverage. The increased variability in the infection attack rate implies that health care facilities should be prepared for rare but larger peaks in influenza patients. Moreover, vaccinating the group with the highest transmission potential, results in a larger dependency on a secure vaccine supply. These arguments should be taken into account in the decision to introduce mass vaccination of school-aged children against influenza.

Modelling the Innate Immune Response against Avian Influenza Virus in Chicken.

At present there is limited understanding of the host immune response to (low pathogenic) avian influenza virus infections in poultry. Here we develop a mathematical model for the innate immune response to avian influenza virus in chicken lung, describing the dynamics of viral load, interferon-α, -ß and -γ, lung (i.e. pulmonary) cells and Natural Killer cells. We use recent results from experimentally infected chickens to validate some of the model predictions. The model includes an initial exponential increase of the viral load, which we show to be consistent with experimental data. Using this exponential growth model we show that the duration until a given viral load is reached in experiments with different inoculation doses is consistent with a model assuming a linear relationship between initial viral load and inoculation dose. Subsequent to the exponential-growth phase, the model results show a decline in viral load caused by both target-cell limitation as well as the innate immune response. The model results suggest that the temporal viral load pattern in the lungs displayed in experimental data cannot be explained by target-cell limitation alone. For biologically plausible parameter values the model is able to qualitatively match to data on viral load in chicken lungs up until approximately 4 days post infection. Comparison of model predictions with data on CD107-mediated degranulation of Natural Killer cells yields some discrepancy also for earlier days post infection.

Analysis of Q fever in Dutch dairy goat herds and assessment of control measures by means of a transmission model.

Between 2006 and 2009 the largest human Q fever epidemic ever described occurred in the Netherlands. The source of infection was traced back to dairy goat herds with abortion problems due to Q fever. The first aim of control measures taken in these herds was the reduction of human exposure. To analyze Q fever dynamics in goat herds and to study the effect of control measures, a within-herd model of Coxiella burnetii transmission in dairy goat herds was developed. With this individual-based stochastic model we evaluated six control strategies and three herd management styles and studied which strategy leads to a lower Q fever prevalence and/or to disease extinction in a goat herd. Parameter values were based on literature and on experimental work. The model could not be validated with independent data. The results of the epidemiological model were: (1) Vaccination is effective in quickly reducing the prevalence in a dairy goat herd. (2) When taking into account the average time to extinction of the infection and the infection pressure in a goat herd, the most effective control strategy is preventive yearly vaccination, followed by the reactive strategies to vaccinate after an abortion storm or after testing BTM (bulk tank milk) positive. (3) As C. burnetii in dried dust may affect public health, an alternative ranking method is based on the cumulative amount of C. burnetii emitted into the environment (from disease introduction until extinction). Using this criterion, the same control strategies are effective as when based on time to extinction and infection pressure (see 2). (4) As the bulk of pathogen excretion occurs during partus and abortion, culling of pregnant animals during an abortion storm leads to a fast reduction of the amount of C. burnetii emitted into the environment. However, emission is not entirely prevented and Q fever will not be eradicated in the herd by this measure. (5) A search & destroy (i.e. test and cull) method by PCR of individual milk samples with a detection probability of 50% of detecting and culling infected goats - that excrete C. burnetii intermittently - will not result in eradication of Q fever in the herd. This control strategy was the least effective of the six evaluated strategies. Subject to model limitations, our results indicate that only vaccination is capable of preventing and controlling Q fever outbreaks in dairy goat farms. Thus, preventive vaccination should be considered as an ongoing control measure.

Economic aspects of Q fever control in dairy goats.

This paper presents an economic analysis of Q fever control strategies in dairy goat herds in The Netherlands. Evaluated control strategies involved vaccination strategies (being either preventive or reactive) and reactive non-vaccination strategies (i.e., culling or breeding prohibition). Reactive strategies were initiated after PCR positive bulk tank milk or after an abortion storm (abortion percentage in the herd of 5% or more). Preventive vaccination eradicates Q fever in a herd on average within 2 and 7 years (depending on breeding style and vaccination strategy). Economic outcomes reveal that preventive vaccination is always the preferred Q fever control strategy on infected farms and this even holds for a partial analysis if only on-farm costs and benefits are accounted for and human health costs are ignored. Averted human health costs depend to a large extend on the number of infected human cases per infected farm or animal. Much is yet unknown with respect to goat-human transmission rates. When the pathogen is absent in both livestock and farm environment then the "freedom of Q fever disease" is achieved. This would enable a return to non-vaccinated herds but more insight is required with respect to the mechanisms and probability of re-infection.

Controlling highly pathogenic avian influenza outbreaks: An epidemiological and economic model analysis.

Outbreaks of highly pathogenic avian influenza (HPAI) can cause large losses for the poultry sector and for animal disease controlling authorities, as well as risks for animal and human welfare. In the current simulation approach epidemiological and economic models are combined to compare different strategies to control highly pathogenic avian influenza in Dutch poultry flocks. Evaluated control strategies are the minimum EU strategy (i.e., culling of infected flocks, transport regulations, tracing and screening of contact flocks, establishment of protection and surveillance zones), and additional control strategies comprising pre-emptive culling of all susceptible poultry flocks in an area around infected flocks (1 km, 3 km and 10 km) and emergency vaccination of all flocks except broilers around infected flocks (3 km). Simulation results indicate that the EU strategy is not sufficient to eradicate an epidemic in high density poultry areas. From an epidemiological point of view, this strategy is the least effective, while pre-emptive culling in 10 km radius is the most effective of the studied strategies. But these two strategies incur the highest costs due to long duration (EU strategy) and large-scale culling (pre-emptive culling in 10 km radius). Other analysed pre-emptive culling strategies (i.e., in 1 km and 3 km radius) are more effective than the analysed emergency vaccination strategy (in 3 km radius) in terms of duration and size of the epidemics, despite the assumed optimistic vaccination capacity of 20 farms per day. However, the total costs of these strategies differ only marginally. Extending the capacity for culling substantially reduces the duration, size and costs of the epidemic. This study demonstrates the strength of combining epidemiological and economic model analysis to gain insight in a range of consequences and thus to serve as a decision support tool in the control of HPAI epidemics.

Evaluating vaccination strategies to control foot-and-mouth disease: a model comparison study.

Simulation models can offer valuable insights into the effectiveness of different control strategies and act as important decision support tools when comparing and evaluating outbreak scenarios and control strategies. An international modelling study was performed to compare a range of vaccination strategies in the control of foot-and-mouth disease (FMD). Modelling groups from five countries (Australia, New Zealand, USA, UK, The Netherlands) participated in the study. Vaccination is increasingly being recognized as a potentially important tool in the control of FMD, although there is considerable uncertainty as to how and when it should be used. We sought to compare model outputs and assess the effectiveness of different vaccination strategies in the control of FMD. Using a standardized outbreak scenario based on data from an FMD exercise in the UK in 2010, the study showed general agreement between respective models in terms of the effectiveness of vaccination. Under the scenario assumptions, all models demonstrated that vaccination with 'stamping-out' of infected premises led to a significant reduction in predicted epidemic size and duration compared to the 'stamping-out' strategy alone. For all models there were advantages in vaccinating cattle-only rather than all species, using 3-km vaccination rings immediately around infected premises, and starting vaccination earlier in the control programme. This study has shown that certain vaccination strategies are robust even to substantial differences in model configurations. This result should increase end-user confidence in conclusions drawn from model outputs. These results can be used to support and develop effective policies for FMD control.

Transmission rate of African swine fever virus under experimental conditions.

African swine fever (ASF) is a highly lethal, viral disease of swine. No vaccine is available, so controlling an ASF outbreak is highly dependent on zoosanitary measures, such as stamping out infected herds and quarantining of affected areas. Information on ASF transmission parameters could allow for more efficient application of outbreak control measures. Three transmission experiments were carried out to estimate the transmission parameters of two ASF virus isolates: Malta'78 (in two doses) and Netherlands'86. Different criteria were used for onset of infectiousness of infected pigs and moment of infection of contact pigs. The transmission rate (ß), estimated by a Generalized Linear Model, ranged from 0.45 to 3.63 per day. For the infectious period, a minimum as well as a maximum infectious period was determined, to account for uncertainties regarding infectiousness of persistently infected pigs. While the minimum infectious period ranged from 6 to 7 days, the average maximum infectious period ranged from approximately 20 to nearly 40 days. Estimates of the reproduction ratio (R) for the first generation of transmission ranged from 4.9 to 24.2 for the minimum infectious period and from 9.8 to 66.3 for the maximum infectious period, depending on the isolate. A first approximation of the basic reproduction ratio (R0) resulted in an estimate of 18.0 (6.90-46.9) for the Malta'78 isolate. This is the first R0 estimate of an ASFV isolate under experimental conditions. The estimates of the transmission parameters provide a quantitative insight into ASFV epidemiology and can be used for the design and evaluation of more efficient control measures.

Vaccination against foot-and-mouth disease I: epidemiological consequences.

An epidemic of foot-and-mouth disease (FMD) can have devastating effects on animal welfare, economic revenues, the export position and society as a whole, as occurred during the 2001 FMD epidemic in the Netherlands. Following the preemptive culling of 260,000 animals during this outbreak, the Dutch government adopted emergency vaccination as preferred control policy. However, a vaccination-to-live strategy has not been applied before, posing unprecedented challenges for effectively controlling the epidemic, regaining FMD-free status and minimizing economic losses. These three topics are covered in an interdisciplinary model analysis. In this first part we evaluate whether and how emergency vaccination can be effectively applied to control FMD epidemics in the Netherlands. For this purpose we develop a stochastic individual-based model that describes FMD virus transmission between animals and between herds, taking heterogeneity between host species (cattle, sheep and pigs) into account. Our results in a densely populated livestock area with >4 farms/km(2) show that emergency ring vaccination can halt the epidemic as rapidly as preemptive ring culling, while the total number of farms to be culled is reduced by a factor of four. To achieve this reduction a larger control radius around detected farms and a corresponding adequate vaccination capacity is needed. Although sufficient for the majority of simulated epidemics with a 2 km vaccination zone, the vaccination capacity available in the Netherlands can be exhausted by pig farms that are on average ten times larger than cattle herds. Excluding pig farms from vaccination slightly increases the epidemic, but more than halves the number of animals to be vaccinated. Hobby flocks - modelled as small-sized sheep flocks - do not play a significant role in propagating the epidemic, and need not be targeted during the control phase. In a more sparsely populated livestock area in the Netherlands with about 2 farms/km(2) the minimal control strategy of culling only detected farms seems sufficient to control an epidemic.

Vaccination against foot-and-mouth disease II: Regaining FMD-free status.

An epidemic of foot-and-mouth disease (FMD) can have devastating effects on animal welfare, economic revenues, the export position and society as a whole. The preferred control strategy in the Netherlands has recently changed to vaccination-to-live, but - not have been applied before - this poses unprecedented challenges for effectively controlling an epidemic, regaining FMD-free status and minimizing economic losses. These three topics are addressed in an interdisciplinary model analysis. In this second part we evaluate whether vaccination-to-live poses a higher risk for regaining FMD-free status than non-vaccination strategies and whether the final screening can be improved to reduce this risk. The FMD transmission model that was developed in the first part, predicted the prevalence of infected animals in undetected herds for 1000 hypothetical epidemics per control strategy. These results serve as input for the final screening model that was developed in this part. It calculates the expected number of undetected infected herds and animals per epidemic after final screening, as well as the number of herds and animals to be tested. Our results show that vaccination strategies yield a larger number of undetected infected animals in the whole country per epidemic before final screening than preemptive culling (median values and 5-95% interval): 8 (0-42) animals for 1 km preemptive culling, 50 (7-148) for 2 km vaccination and 35 (6-99) for 5 km vaccination. But the final screening reduced these to comparably low numbers: 1.0 (0-9.1) for 1 km preemptive culling, 3.5 (0.3-15) for 2 km vaccination and 2.1 (0.3-9.4) for 5 km vaccination. Undetected infected animals were mainly found in non-vaccinated sheep herds and vaccinated cattle and sheep herds. As a consequence, testing more non-vaccinated cattle and pig herds will not reduce the expected number of undetected infected animals after the final screening by much, while the required testing resources drastically increase. However, testing only a sample instead of all animals in vaccinated pig herds will not increase the expected number of undetected infected animals by much, while the required testing resources reduce by half. In conclusion, vaccination and preemptive culling strategies yield comparable numbers of undetected infected animals after final screening and the final screening costs can be reduced by testing a sample instead of all vaccinated pigs.

Transmission dynamics of hepatitis E virus in pigs: estimation from field data and effect of vaccination.

Hepatitis E is a viral disease that causes serious concerns for public health. Hepatitis E virus (HEV) genotype 3 is endemic in commercial pig farms worldwide that act as a reservoir. Pig-to-human transmission may occur when infectious animals enter the food chain at slaughter, through consumption of contaminated meat, direct exposure or use of by-products. To reduce the fraction of infectious animals at slaughter age and thus the risk for public health, it is important to understand the transmission dynamics of HEV in pig populations. In this study, we estimate the transmission rate parameter and mean infectious period of HEV in pigs from field data, using a Bayesian analysis. The data were collected in ten commercial pig herds that are each divided into three different age groups. Two transmission models were compared, assuming that animals are infected either locally by their group mates or globally by any infectious animal regardless of its group. For local and global transmission, the transmission rate parameters were 0.11 (posterior median with 95% credible interval: 0.092-0.14 day(-1)) and 0.16 (0.082-0.29 day(-1)), the mean infectious periods were 24 (18-33) days and 27 (20-39) days and the reproduction numbers were 2.7 (2.2-3.6) and 4.3 (2.8-6.9). Based on these results, global transmission is considered to be the more conservative model. Three effects of vaccination were explored separately. When vaccination is not sufficient to eliminate the virus, a shorter mean infectious period decreases the fraction of infectious animals at slaughter age, whereas a reduced transmission rate parameter adversely increases it. With a reduced susceptibility, vaccination of animals at a later age can be a better strategy than early vaccination. These effects should be taken into account in vaccine development.

Using mortality data for early detection of Classical Swine Fever in The Netherlands.

Early detection of the introduction of an infectious livestock disease is of great importance to limit the potential extent of an outbreak. Classical Swine Fever (CSF) often causes non-specific clinical signs, which can take considerable time to be detected. Currently, the disease can be detected by three main routes, that are all triggered by clinical signs. To improve the early detection of CSF an additional program, based on mortality data, aims to routinely perform PCR tests on ear notch samples from herds with a high(er) mortality. To assess the effectiveness of this new early detection system, we have developed a stochastic model that describes the virus transmission within a pig herd, the development of disease in infected animals and the different early detection programs. As virus transmission and mortality (by CSF and by other causes) are different for finishing pigs, piglets and sows, a distinction is made between these pig categories. The model is applied to an extensive database that contains all unique pig herds in The Netherlands, their herd sizes and their mortality reports over the CSF-free period 2001-2005. Results from the simulations suggest that the new early detection system is not effective in piglet sections, due to the high mortality from non-CSF causes, nor in sow sections, due to the low CSF-mortality. In finishing herds, the model predicts that the new early detection system can improve the detection time by two days, from 38 (27-53) days to 36 (24-51) days after virus introduction, when assuming a moderately virulent virus strain causing a 50% CSF mortality. For this result up to 5 ear notch samples per herd from 8 (0-13) finishing herds must be tested every workday. Detecting a source herd two days earlier could considerably reduce the number of initially infected herds. However, considering the variation in outcome and the uncertainty in some model assumptions, this two-day gain in detection time is too small to demonstrate a substantial effect of the new early detection system based on mortality data. But when the alertness of herd-owners and veterinarians diminishes during long CSF-free periods, the new early detection system might gain in effectiveness.

Poiseuille flow to measure the viscosity of particle model fluids.

The most important property of a fluid is its viscosity, it determines the flow properties. If one simulates a fluid using a particle model, calculating the viscosity accurately is difficult because it is a collective property. In this article we describe a new method that has a better signal to noise ratio than existing methods. It is based on using periodic boundary conditions to simulate counter-flowing Poiseuille flows without the use of explicit boundaries. The viscosity is then related to the mean flow velocity of the two flows. We apply the method to two quite different systems. First, a simple generic fluid model, dissipative particle dynamics, for which accurate values of the viscosity are needed to characterize the model fluid. Second, the more realistic Lennard-Jones fluid. In both cases the values we calculated are consistent with previous work but, for a given simulation time, they are more accurate than those obtained with other methods.

Combined length scales in dissipative particle dynamics.

When a particle model simulates fluid behavior, the calculation of all particle interactions causes long computation times. Especially in mesoscale simulations, the bulk areas can be computationally demanding. To reduce the time spent on such regions, we propose a model that combines different length scales in one system. This is a particle analog to mesh refinement in, for instance, finite-element methods. To this end, we define particles of a coarse-grained scale within the framework of dissipative particle dynamics. These particles have a lower number density, but the same mass density, pressure, temperature, and viscosity as the original description. Furthermore, the coarse-grained particles can directly interact with the "normal" particles. The two length scales are combined in one system, coupled by an overlap region. At the edges of this region, particles transform into the other scale, through local refining or coarse graining. The resulting combined system adequately reproduces the properties and flow behavior of a normal system. When half the system is coarse grained, the computation time reduces by a factor of two. Thus, computational efficiency can be greatly increased for a variety of mesoscale applications.