Understanding foot-and-mouth disease virus transmission biology: identification of the indicators of infectiousness.

The control of foot-and-mouth disease virus (FMDV) outbreaks in non-endemic countries relies on the rapid detection and removal of infected animals. In this paper we use the observed relationship between the onset of clinical signs and direct contact transmission of FMDV to identify predictors for the onset of clinical signs and identify possible approaches to preclinical screening in the field. Threshold levels for various virological and immunological variables were determined using Receiver Operating Characteristic (ROC) curve analysis and then tested using generalized linear mixed models to determine their ability to predict the onset of clinical signs. In addition, concordance statistics between qualitative real time PCR test results and virus isolation results were evaluated. For the majority of animals (71%), the onset of clinical signs occurred 3-4 days post infection. The onset of clinical signs was associated with high levels of virus in the blood, oropharyngeal fluid and nasal fluid. Virus is first detectable in the oropharyngeal fluid, but detection of virus in the blood and nasal fluid may also be good candidates for preclinical indicators. Detection of virus in the air was also significantly associated with transmission. This study is the first to identify statistically significant indicators of infectiousness for FMDV at defined time periods during disease progression in a natural host species. Identifying factors associated with infectiousness will advance our understanding of transmission mechanisms and refine intra-herd and inter-herd disease transmission models.

Modelling the within-host dynamics of the foot-and-mouth disease virus in cattle.

In this paper we investigate the within-host dynamics of the foot-and-mouth disease virus (FMDV) in cattle using previously published data for 8 experimentally infected cows. An 8-compartment, 14-parameter differential equation model was fitted to data collected from each cow every 24 h over the course of an infection on: (i) the concentration of FMDV genomes in the blood, (ii) the concentration of infectious virus in the blood, (iii) antibody levels, and (iv) interferon levels. Model parameters were estimated using maximum-likelihood methods. The likelihood surface was sampled using Markov chain Monte Carlo methods giving credible intervals for each of the model parameters. The model was able to capture the within-host dynamics well for 6 of the infections, with both the innate (type 1 interferon) and antibody responses playing key roles in determining the height and duration of peak levels of virus. There was considerable variation between virus dynamics in individual cattle which was only partly accounted for by inferred differences in the dose of virus received. A better understanding of the within-host dynamics also provides insights into the dynamics of infectiousness and the transmission of virus to new hosts.

Evaluation of the solid phase competition ELISA for detecting antibodies against the six foot-and-mouth disease virus non-O serotypes.

The solid-phase competition ELISA (SPCE) has been evaluated in both screening and titration assay formats for detecting antibodies against foot-and-mouth disease virus (FMDV) for the six non-O serotypes A, C, SAT 1, SAT 2, SAT 3 and Asia 1. Cut-off values were determined as a percentage inhibition of 40 for the SAT serotypes and 50 for serotypes A, C and Asia 1, which gave rise to specificity values ranging from 99.41% to 99.9% for the different serotypes. The relative sensitivity between the SPCE and LPBE/virus neutralisation test was 100%/109%. Antiserum titres derived by the SPCE for samples of serotypes O, A(22) and Asia 1 were more than 11, 1 and 5 times of those determined by virus neutralisation test, respectively. This study indicated that the non-type O SPCEs have sufficient sensitivities and specificities for use as serological diagnostic tests for the qualitative and quantitative detection of antibodies against FMDV.

Cattle remain immunocompetent during the acute phase of foot-and-mouth disease virus infection.

Infection of cattle with foot-and-mouth disease virus (FMDV) results in the development of long-term protective antibody responses. In contrast, inactivated antigen vaccines fail to induce long-term protective immunity. Differences between susceptible species have also been observed during infection with FMDV, with cattle often developing persistent infections whilst pigs develop more severe symptoms and excrete higher levels of virus. This study examined the early immune response to FMDV in naïve cattle after in-contact challenge. Cattle exposed to FMDV were found to be viraemic and produced neutralising antibody, consistent with previous reports. In contrast to previous studies in pigs these cattle did not develop leucopenia, and the proliferative responses of peripheral blood mononuclear cells to either mitogen or third party antigen were not suppressed. Low levels of type 1 interferon and IL-10 were detected in the circulation. Taken together, these results suggest that there was no generalised immunosuppression during the acute phase of FMDV infection in cattle.

Relationship between clinical signs and transmission of an infectious disease and the implications for control.

Control of many infectious diseases relies on the detection of clinical cases and the isolation, removal, or treatment of cases and their contacts. The success of such "reactive" strategies is influenced by the fraction of transmission occurring before signs appear. We performed experimental studies of foot-and-mouth disease transmission in cattle and estimated this fraction at less than half the value expected from detecting virus in body fluids, the standard proxy measure of infectiousness. This is because the infectious period is shorter (mean 1.7 days) than currently realized, and animals are not infectious until, on average, 0.5 days after clinical signs appear. These results imply that controversial preemptive control measures may be unnecessary; instead, efforts should be directed at early detection of infection and rapid intervention.

Foot-and-mouth disease virus (O/UKG/2001) is poorly transmitted between sheep by the airborne route.

Foot-and-mouth disease virus (FMDV) can be spread by the airborne route and therefore atmospheric dispersion models have been developed to predict where the virus might spread during a disease outbreak. Airborne transmission between sheep of the FMDV strain involved in the outbreak in Europe in 2001 (O/UKG/2001) was studied experimentally. Recipient animals were exposed to two donor sheep excreting virus for 2, 4, 6, 8 or 24 h. Although FMDV was detected in air samples collected during challenge, none of the recipient sheep became infected. These data suggest that O/UKG/2001 is not efficiently transmitted by the airborne route between sheep.

Bovine serum panel for evaluating foot-and-mouth disease virus nonstructural protein antibody tests.

A panel of 36 sera has been assembled from experimental cattle that had been infected by inoculation or contact exposure with 4 serotypes of foot-and-mouth disease virus (FMDV) with or without prior vaccination. Virus replication and persistence had been characterized in all of the animals. The proportion of the sera scored positive by 5 tests for antibodies to the nonstructural proteins of FMDV varied, suggesting that the panel can discriminate between the sensitivity with which such tests are able to identify infected cattle. Use of this panel will help in assessment of new tests and quality control of existing methods.