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.

Risk of introducing African horse sickness virus into the Netherlands by international equine movements.

African horse sickness (AHS) is a vector-borne viral disease of equines that is transmitted by Culicoides spp. and can have severe consequences for the horse industry in affected territories. A study was performed to assess the risk of introducing AHS virus (AHSV) into the Netherlands (P_AHS) by international equine movements. The goal of this study was to provide more insight into (a) the regions and equine species that contribute most to this risk, (b) the seasonal variation in this risk, and (c) the effectiveness of measures to prevent introduction of AHSV. Countries worldwide were grouped into three risk regions: (1) high risk, i.e., those countries in which the virus is presumed to circulate, (2) low risk, i.e., those countries that have experienced outbreaks of AHS in the past and/or where the main vector of AHS, Culicoides imicola, is present, and (3) very low risk, i.e., all other countries. A risk model was constructed estimating P_AHS taking into account the probability of release of AHSV in the Netherlands and the probability that local vectors will subsequently transmit the virus to local hosts. Model calculations indicated that P_AHS is very low with a median value of 5.1×10(-4)/year. The risk is highest in July and August, while equine movements in the period October till March pose a negligible risk. High and low risk regions contribute most to P_AHS with 31% and 53%, respectively. Importations of donkeys and zebras constitute the highest risk of AHSV release from high risk regions, while international movements of competition horses constitute the highest risk of AHSV release from low and very low risk regions. Preventive measures currently applied reduce P_AHS by 46% if compared to a situation in which no preventive measures are applied. A prolonged and more effective quarantine period in high risk regions and more stringent import regulations for low risk regions could further reduce P_AHS. Large uncertainty was involved in estimating model input parameters. Sensitivity analysis indicated that uncertainty about the probability of non-notified presence of AHS in low and very low risk regions, the protective effect of quarantine and the vector-host ratio had most impact on the estimated risk. Furthermore, temperature values at the time of release of AHSV largely influenced the probability of onward spread of the virus by local vectors to local hosts.

Design and analysis of small-scale transmission experiments with animals.

Interactions between pathogens and hosts at the population level should be considered when studying the effectiveness of control measures for infectious diseases. The advantage of doing transmission experiments compared to field studies is that they offer a controlled environment in which the effect of a single factor can be investigated, while variation due to other factors is minimized. This paper gives an overview of the biological and mathematical aspects, bottlenecks and solutions of developing and executing transmission experiments with animals. Different methods of analysis and different experimental designs are discussed. Final size methods are often used for analysing transmission data, but have never been published in a refereed journal; therefore, they will be described in detail in this paper. We hope that this information is helpful for scientists who are considering performing transmission experiments.

Quantification of the transmission of bovine herpesvirus 1 among red deer (Cervus elaphus) under experimental conditions.

Bovine herpesvirus 1 (BHV1) is endemically present in a cattle population that lives in a nature reserve in the Netherlands. Red deer (Cervus elaphus), living in the same nature reserve, can come into contact with the BHV1-infected cattle and could then become infected with BHV1. For the eradication of BHV1 in cattle, it is, therefore, important to know whether red deer alone can play a role in the transmission of BHV1. For that reason, we quantified the transmission of BHV1 among farmed red deer under experimental conditions. Two groups of ten animals were formed. In each group, five of these animals were inoculated with BHV1 and the other five served as contact animals. Three inoculated animals in each transmission experiment became infected and none of the contact animals became infected. The one-sided 95% confidence interval for R [0.0-0.94] showed that limited transmission might occur among red deer. Based on these results, we would expect only minor outbreaks of BHV1 to occur in red deer populations. We concluded that BHV1 will probably not survive longer than a few decades (several times the mean deer lifetime) in red deer populations. Consequently, it is not necessary for the eradication of BHV1 in cattle to eradicate BHV1 in red deer populations as well.

A review of porcine reproductive and respiratory syndrome virus in Dutch breeding herds: population dynamics and clinical relevance.

Understanding the spread of porcine reproductive and respiratory syndrome virus (PRRSV) in pig populations is essential to the development of effective PRRS prevention and control strategies. Moreover, knowledge of the field dynamics of PRRSV in pigs will provide insights into the clinical relevance of PRRS, and will enable the targeting of interventions. This review of PRRSV includes discussion on the occurrence of outbreaks, the persistence of infection and the fade-out of infection in Dutch breeding herds. The dynamic character of PRRSV infections in endemically infected herds and the relevance of the disease under Dutch field conditions are also highlighted. Furthermore, several strategies aimed at controlling the spread of PRRSV are discussed.

Estimating the incidence of influenza-virus infections in Dutch weaned piglets using blood samples from a cross-sectional study.

A cross-sectional study was carried out on 32 Dutch breeding herds to estimate the incidence of influenza-virus infections in piglets before the start of the finishing period, at the age of approximately 10 weeks. Longitudinal studies on two herds (8 and 10 litters, respectively) were done to obtain an average decay function for maternal antibodies.Each participating farm in the cross-sectional study was visited twice within 5 months; each time, blood samples were taken randomly from one compartment (a separate room with separate air flow) of 4-5-week-old piglets and one compartment of 8-9-week-old piglets. These blood samples (a total of 2598; 16-23 per compartment, depending on its size) were tested in a haemagglutination inhibition test for antibodies against influenza-virus subtypes H1 and H3. Samples from 8-9-week-old piglets from the first sampling period (n=660) were also tested in an IgM ELISA. For each individual herd and each influenza-virus subtype separately, the decay function derived from the longitudinal studies was used to calculate an expected seroprevalence in 8-9-week-old piglets, which was then compared to the observed seroprevalence. Depending on subtype and sampling period, between 10 and 15 of the 32 herds were suspected of virus circulation during the weaning period because the observed seroprevalence was significantly higher than the expected seroprevalence (P<0.05). In the first sampling period the IgM ELISA confirmed six of these outbreaks. However, due to the small window of detection of the IgM ELISA (compared to the length of the weaning period), it will always underestimate the number of infections. Infections in the first half of the weaning period will no longer be detectable because IgM antibodies have already disappeared. In individual pigs, an incidence of 16-17% was estimated for each subtype over a 4-week period between the age of 4-5 and 8-9 weeks. For each influenza subtype, 80% of the piglets will enter the finishing facilities without antibodies or with decaying maternal antibodies. These piglets may be susceptible to an infection with influenza virus.

Porcine reproductive and respiratory syndrome (PRRS) with special reference to clinical aspects and diagnosis. A review.

After a short introduction on Porcine Reproductive and Respiratory Syndrome (PRRS) regarding the history, the first occurrence in several countries, and the causal virus, designated Lelystad virus, a description is given of the clinical aspects and several diagnostic methods. After some general remarks on the clinical aspects, the epidemic and the endemic phase of the disease are described. Regarding the diagnosis, special attention is paid to the detection of antibodies and of the PRRS Virus (PRRSV). Regarding the detection of antibodies, a description is given of three tests: the immunoperoxidase monolayer assay, the enzyme-linked immunosorbent assay, and the serum neutralization test. Concerning the detection of PRRSV, attention is paid to the isolation of the virus, the demonstration of PRRSV antigens in frozen or fixed tissue using immunohistochemistry or immunofluorescence, the in situ hybridisation technique and the Polymerase Chain Reaction (PCR).

Quantification of transmission in one-to-one experiments.

We study the statistical inference from data on transmission obtained from one-to-one experiments, and compare two algorithms by which the reproduction ratio can be quantified. The first algorithm, the transient state (TS) algorithm, takes the time course of the epidemic into account. The second algorithm, the final size (FS) algorithm, does not take time into account but is based on the assumption that the epidemic process has ended before the experiment is stopped. The FS algorithm is a limiting case of the TS algorithm for the situation where time tends to infinity. So far quantification of transmission has relied almost exclusively on the FS algorithm, even if the TS algorithm would have been more appropriate. Its practical use, however, is limited to experiments with only a few animals. Here, we quantify the error made when the FS algorithm is applied to data of one-to-one experiments not having reached the final size. We conclude that given the chosen tests, the FS algorithm underestimates the reproduction ratio R0, is liberal when testing H0: R0 > or = 1 against H1: R0 < 1, is conservative when testing H0: R0 < or = 1 against H1: R0 > 1 and calculates the same probability as the TS algorithm when testing H0: R(0-control) = R(0-treatment) against H1: R(0-control) > R(0-treatment) We show how the power of the test depends on the duration of the experiments and on the number of replicates. The methods are illustrated by an application to porcine reproductive and respiratory syndrome virus (PRRSV).

A quantitative assessment of the effectiveness of PRRSV vaccination in pigs under experimental conditions.

This paper presents a quantitative approach to evaluate effectiveness of vaccination under experimental conditions. We used two consecutive experimental designs to investigate whether PRRSV transmission among vaccinated pigs was reduced compared to control pigs and to estimate the reproduction parameter R. Based upon data analysis and power calculations the series of small-scale vaccination-challenge experiments ended with multiple one-to-one experiments. This new experimental design has considerable power to detect the effect of vaccination on transmission if R is close to but still above one in vaccinated pigs. The last experiment showed that transmission was not significantly reduced and the R for vaccinated pigs was estimated to be larger than 4.9. This is remarkable because duration and level of viremia were significantly reduced by vaccination.

Introduction, persistence and fade-out of porcine reproductive and respiratory syndrome virus in a Dutch breeding herd: a mathematical analysis.

The objective of this study was to investigate the dynamics of PRRSV infection and to quantify transmission within a breeding herd, and its impact on herd performance. For this purpose a longitudinal study was performed in a closed breeding herd of 115 sows. Statistical methods and Monte Carlo simulations based on stochastic SIR models were used to analyse the observational data. Moreover, a case-control study was performed to determine whether seroconversion of sows during gestation was associated with aberrant litters. The transmission parameter R was estimated to be 3.0 (95% confidence interval 1.5-6.0) for the model version based on the most plausible assumptions that the infectious period lasts 56 days and no lifelong immunity exists after infection. Based on simulations using a breeding herd of equal size the average time-to-extinction was estimated to be 6 years; using a herd of twice the size, it was 80 years. Furthermore, in contrast to the epidemic phase of the disease, the endemic phase was not detrimental to herd performance.

Seroprevalence of porcine reproductive and respiratory syndrome virus in Dutch weaning pigs.

To determine whether under Dutch field conditions PRRSV infection occurs in weaning pigs before the finishing period, a cross-sectional study was performed on 32 breeding farms to estimate the seroprevalence of antibodies directed against PRRSV in 4- to 5-week-old and 8- to 9-week-old pigs. Farms were visited twice within 5 months, and during each sampling an average of 20 sera were randomly collected from a unit of 4- to 5-week-old and a unit of 8- to 9-week-old pigs. The sera (n = 2568) were tested in the IDEXX-ELISA for the presence of antibodies directed against PRRSV. The seroprevalence of PRRSV in 4- to 5-week-old pigs and 8- to 9-week-old pigs varied between both samplings for each farm. The seroprevalence in the younger pigs was significantly higher than in the older pigs for both samplings (p < 0.05), suggesting the presence of maternal antibodies. In addition, a longitudinal study was performed to evaluate the IDEXX-ELISA in detecting maternal antibodies directed against PRRSV and to determine the rate of decline of these antibodies in field sera. From serological results of eight litters, an average decay function was computed to quantify the maternal immunity to PRRSV. A seroprevalence in 8- to 9-weeks-old pigs of > or = 0.20 was calculated to indicate an active immune response to PRRSV. In the cross-sectional study in the pigs twenty-three percent of the units with 8- to 9-week-old pigs were considered to have an active serological response against PRRSV. We conclude that most Dutch pigs are seronegative for PRRSV at the start of the finishing period, since the results of this study showed that 77% of the units with 8- to 9-week-old pigs had a seroprevalence < 0.20.

Comparison of a commercial ELISA and an immunoperoxidase monolayer assay to detect antibodies directed against porcine respiratory and reproductive syndrome virus.

A commercially available enzyme-linked immunosorbent assay (ELISA) for the detection of antibodies against porcine respiratory and reproductive syndrome virus (PRRSV) was compared to an immunoperoxidase monolayer assay (IPMA). Serum samples used were collected from pigs experimentally infected with either the American or European antigenic type of PRRSV, and also from piglets born to sows that had been experimentally infected with the European antigenic type of PRRSV. In addition, three sets of European field sera (n = 275, n = 68, n = 349) were tested and evaluated using the IPMA as the gold standard. Results showed that both the IPMA and the ELISA were able to detect antibodies against the two antigenic types of PRRSV. When sera of experimentally infected pigs were tested, the IPMA with homologous antigen detected antibodies 2 to 3 days earlier than the ELISA, and was more sensitive in detecting maternal antibodies. The ELISA was slightly more sensitive for detecting antibodies against the American type than for the European type. When sets of field sera were tested, the relative sensitivity of the ELISA ranged between 0.68 and 0.91, and the relative specificity ranged between 0.75 and 0.97. However, in two of these sets (n = 275, n = 349) we determined that a decrease of the threshold value of ELISA (from 0.4 to 0.3) increased sensitivity without loss of specificity. We concluded that the ELISA is an easy, quick and reliable test to diagnose PRRSV infection in swine herds.