The effect of foot-and-mouth disease (FMD) vaccination on virus transmission and the significance for the field

Abstract

Vaccination against foot-and-mouth disease (FMD) might be one of the control measures used during an FMD epidemic depending on the local epidemiological situation, the status of the country, and the opinion of policy makers. A sound decision on vaccination can be made only if there is sufficient scientific knowledge on the effectiveness of vaccination in eliminating the virus from the population. An important question is whether a single vaccination applied as an emergency vaccine can contribute to the control of an epidemic. This paper presents the results of transmission experiments on vaccine efficacy in groups of cattle, pigs, and sheep and concludes that vaccination seemed to be effective in cattle and sheep, but was less effective in pigs. The possible implications for application to field conditions are discussed.

Introduction

Foot-and-mouth disease (FMD) is an economically important contagious viral disease that affects livestock species such as cattle, sheep, and pigs (Terrestrial code of the World Organisation for Animal Health, OIE). The United States, Canada, and many countries in Europe and Asia, although currently free of FMD virus, are at risk for new outbreaks, due to their non-vaccination policy, allowing the livestock population in these countries to become highly susceptible.

Factors such as the movement of animals and animal products, mobility of humans, and the interaction between domestic and wildlife populations may increase the risk of virus introduction (1). The risk of a new outbreak is not hypothetical as illustrated by the large epidemic of FMD in 2001 in Europe, which started in the United Kingdom, a country often considered to have a lower risk for virus introduction than mainland Europe. The virus spread to France, the Netherlands, and Ireland, and resulted in the slaughter of millions of animals.

The UK applied the regular EU measures, like culling of infected herds, pre-emptive culling of contiguous farms, and control of movement. These measures were also implemented in the Netherlands, but in addition, emergency vaccination of the whole susceptible livestock population in the affected area was applied, followed by culling of all vaccinated animals.

Whether or not vaccination is applied depends on the local epidemiological situation, export markets, and the opinion of policy makers in the country. If an outbreak were to occur in Canada, the FMD contingency plans provide for possible use of vaccination to combat the outbreak (2). The pre-emptive killing of mainly healthy non-infected animals either vaccinated or not, has triggered discussion about the control policy in the EU, and the use of a “vaccination-to-live” strategy as an additional intervention tool that could be used during a future epidemic. A logical decision on application of suppressive vaccination, an appropriate vaccination strategy, and a vaccination-to-live policy during an epidemic of FMD can be made only if there is sufficient scientific knowledge on the efficacy of vaccination in the most important, or most abundant, species in animal husbandry.

Emergency or suppressive vaccination can be applied using different strategies (3) and several papers on emergency vaccination using homologous vaccines have already been published (4–6). The efficacy of heterologous vaccination protocols has also been studied (7), as immediate availability of vaccine during an epidemic is an important issue especially with respect to antigenic matching of the field and vaccine virus strain.

Most studies have demonstrated that appropriate vaccines are capable of inducing clinical protection against infection with the FMD virus (FMDV). One of the questions that remains, however, is if a single vaccination could prevent horizontal transmission of virus, and ultimately eliminate the virus from the population. This is the ultimate goal for countries that face an outbreak after having been formerly free of infection. Various transmission experiments have been carried out to answer this question. The aim of this paper was to summarize some of the results of the transmission studies that were carried out in recent years.

Vaccine evaluation

Field versus experimental studies

Studies to evaluate FMD vaccines for their ability to reduce transmission in groups of animals can be carried out in the field or under experimental conditions. Field experience with vaccination against FMD has mainly been obtained in countries where FMD is endemic and mass vaccination is applied to prevent clinical disease (8,9). During an epidemic in a formerly free country, however, the aim of vaccination may be to eliminate the virus from the population. It is hardly possible to determine the efficacy of vaccination under field conditions with respect to eradication of the virus, as it is considered unethical to carry out a clinical trial with a vaccine group and control group under these circumstances.

An alternative is to determine vaccine efficacy under experimental conditions in a controlled environment in which the effect of one factor can be investigated, while variation due to other factors is minimized. A disadvantage is the difficulty in extrapolating the results to field situations (10). Most experimental studies are vaccination/challenges, in which the vaccine is evaluated for its ability to protect vaccinated animals against clinical signs after challenge infection. However, these experiments cannot determine if horizontal transmission can be prevented, as all animals in such an experiment are infected deliberately.

Transmission experiments

Transmission experiments are suitable for determining the effect of vaccination on horizontal transmission of infectious agents (11). The key parameter is the reproduction ratio, which is the expected number of secondary cases produced by a typical infected individual during its entire period of infectiousness in a completely susceptible population (12). The aim of vaccination is to reduce the reproduction ratio (R) to a level less than 1 (R < 1), as then only minor outbreaks will occur and the epidemic will fade out. When R > 1, the epidemic might not stop and major outbreaks can occur. In the case of FMD emergency vaccination, this parameter R is preferred over clinical protection as a measure of vaccine efficacy. Moreover, an infection may occur without clinical signs and therefore clinical protection is not a good parameter in determining if further spread of the infection has been prevented (13,14).

Transmission studies are designed to quantify this reproduction ratio R. For that goal, some animals within a group are infected through inoculation; the remaining animals are then contact-exposed to the inoculated ones. The infection chain can be monitored by determining the replication of the agent in the animals. This may be accomplished by measuring virus excretion and immune responses as indirect evidence of infection. The number of contact infections at the end of the infectious period is used for statistical analysis (11). The reproduction ratio can be calculated from this final size of infection. In addition, it can be determined if a particular measure such as vaccination has a significant effect on R and if R is significantly < 1.

Several transmission experiments with FMD vaccination have been carried out in the Netherlands (15–21) and the UK (4,22–24). Studies by the Institute for Animal Health in Pirbright, UK mainly focused on emergency application of vaccination in which animals are challenged close to the time of vaccination.

This paper gives an overview of experiments performed at the Central Veterinary Institute (CVI) in Lelystad, the Netherlands, on quantification of transmission of FMDV.

Foot-and-mouth disease transmission trials

Design

Animals

Species differ in susceptibility to a FMDV infection, and possibly also in infectivity (25,26). From field observations in 2001 and experimental work with the 2001 field strain in the Netherlands, it was noticed that veal calves did not show clear signs of FMD (21), whereas dairy cows did. Also in sheep, clinical signs seemed to have been rare or unclear (27), but nevertheless are assumed to have played an important role in the early stages of the 2001 FMD epidemic in the UK (28). Pigs are rather resistant to natural aerosols, but once infected they are considered to be potent emitters of airborne virus (29).

For targeted vaccination strategies, it is necessary to have scientific knowledge on vaccine efficacy in species that are economically important host species for FMD. Therefore, we studied transmission of FMDV in groups of calves (18), lambs (17), and piglets (16). The experiments were performed with animals that were approximately 10 wk of age, as they were easier to handle. As dairy cattle are also important, and as raw milk is an important route of FMDV transmission (30), experiments were also carried out with adult dairy cows (15).

Design

The trials were done with groups of vaccinated and unvaccinated animals (group size varied from 4 to 10 animals per group). Vaccination was applied once, with inactivated, purified O₁Manisa antigen using a mineral oil adjuvant in a double oil emulsion formulation.

When measuring transmission, an infection chain has to be started in part of the group. In general, challenge-inoculation was carried out 14 d after vaccination of the designated group with the FMDV field isolate O/NET/2001. This interval was chosen as these experiments were meant to provide a proof of principle: is a single vaccination able to reduce horizontal transmission at all? Moreover, this timeframe was also used in the outbreak in 2001 in the Netherlands to allow transportation of vaccinated animals to the slaughterhouse. It would provide scientific data on whether or not transmission can be expected from the vaccinated animals. Half of the animals in each group were challenged by intranasal application of the FMDV strain; the other half of the group was contact-exposed to the inoculated animals.

Clinical signs, virus excretion, and serological response were measured. Virus was detected by virus isolation on cell culture, and real-time polymerase chain reaction (RT-PCR) tests on heparinized blood, oro-pharyngeal fluid, and probang samples. The antibody response was determined using the virus neutralization test to detect neutralizing antibodies against field and vaccine virus, and by using an enzyme-linked immunosorbent assay (ELISA) for detection of nonstructural (NS) proteins of the FMD field virus. This NS-ELISA is able to differentiate between vaccinated and infected animals (31). If an animal tested positive in 1 of the above tests it was classified as infected. Based on the final size of infection (11) (the total number of contact-infected animals), we determined if the reproduction ratio in the vaccinated groups (R_v) was < 1, and if transmission in the vaccinated groups was significantly lower than transmission in the unvaccinated groups.

Results of the transmission trials

Calves

In the experiments with groups of unvaccinated calves, only mild clinical signs were observed in infected animals. Although not all contact-exposed calves in each group became infected, the reproduction ratio R_nv was significantly > 1. In the vaccinated groups, virus transmission occurred to 1 contact-exposed calf in 1 group, resulting in R_v significantly < 1. This estimate was significantly lower than R_nv (18). This result indicates that a single vaccination is able to reduce horizontal virus transmission among calves significantly to such a level that eradication should be possible.

Lambs

In the study with lambs, infection occurred without clear clinical signs. Virus excretion, measured as duration and mean daily virus titer in saliva samples, was significantly reduced in the vaccinated groups. Virus transmission, however, did not differ significantly between the vaccinated and unvaccinated groups of lambs (17). In both vaccinated [R_v 0.22 (range: 0.01 to 1.78)] and unvaccinated groups [R_nv 1.14 (range: 0.3 to 3.3)] the estimate of R was not significantly different from 1, indicating minor outbreaks to be most likely to occur.

Piglets

Challenge infections in piglets are usually established by intra-dermal injection with a high challenge dose, which results in high levels of virus excretion by inoculated pigs and severe clinical signs. Using this method, Eblé et al (20) demonstrated in similar experiments that vaccination was highly efficacious, as infection could not even be established in vaccinated pigs. Quantification of transmission is, however, only possible when at least some of the inoculated animals are infectious, and in their experiments this did not occur (20).

Therefore, in the transmission experiments described in Orsel et al (16), the infection chain was established differently. Instead of inoculation of vaccinated piglets by intradermal injection, unvaccinated piglets were inoculated using the same method, and these were used as “seeders.” Although the challenge dose cannot be controlled, seeders pigs are routinely used as a method of challenge (32).

Vaccinated piglets were placed in contact with the seeders to induce infectious vaccinated piglets by contact infection. After it was determined whether or not these piglets had become infected, the piglets were moved to another room with new vaccinated piglets, thereby preventing exposure to a high challenge dose. Transmission was studied from the infected vaccinated piglets to this 2nd group of vaccinated piglets.

Infection with FMDV in piglets using this method induced severe clinical signs and high virus excretion levels in both vaccinated and unvaccinated groups of piglets. Virus excretion was only slightly reduced in vaccinated piglets compared with unvaccinated piglets. In both groups, the reproduction ratio’s R_nv and R_v were significantly > 1, and, therefore, major outbreaks could be expected even in groups of vaccinated piglets. Consequently, vaccination would not be expected to be effective in preventing major outbreaks, when piglets were exposed to virus-shedding piglets in the same group. The number of new infections per day (rate of transmission) was, however, significantly lower in the vaccinated than in the unvaccinated groups of piglets. This implies that although transmission was not prevented by vaccination, the outbreak might be slowed by vaccination.

Dairy cows

Severe clinical signs of FMD were observed in unvaccinated dairy cows, which was consistent with previous studies (25,33). In unvaccinated groups of dairy cows, all cows, inoculated as well as contact-exposed, became infected and, for welfare reasons, some had to be euthanized before the end of the experiment. The reproduction ratio in these groups (R_nv) was significantly > 1. In the vaccinated groups, the inoculated cows did not show clinical signs, which was also consistent with other vaccine studies. In addition, no contact infections were detected as all test results remained negative. It was concluded that a single vaccination effectively reduced R_v < 1 in groups of dairy cattle (15).

Consequences for the field

Extrapolation of experimental results to the field is always difficult. First, vaccine efficacy determined under experimental conditions may differ from efficacy in the field for various, not always clear, reasons such as concurrent diseases, climate differences, and sub-optimal vaccination techniques. Indirectly, this has been shown for, for example, with Aujeszkys disease (34), infectious bovine rhinotracheitis (IBR) (35), and Newcastle disease (36). Secondly, we determined vaccine efficacy only when the vaccine was applied 14 d before challenge; these intervals will be different in the field. Thirdly, we used homogenous groups, either with respect to vaccination status or species, whereas farms often house more than 1 species (31). Finally, only “within group” transmission was determined; “between group” transmission has not been determined in experimental settings.

These general remarks are not specific for our experiments, but apply to nearly all experimental research, and uncertainties will always be present. So will each epidemic differ from the previous one, and experiments or scenario studies can never cover all situations or variations. The authors are, however, of the opinion that the experimental results do provide essential information about vaccine efficacy and can contribute to optimizing control programmes for future outbreaks, including vaccination strategies.

Although these experiments determined only “within group” transmission, de Jong et al (37) showed that if the “within group” R is < 1, it is unlikely that “between group” transmission will occur. Moreover, Van Nes et al (38) showed that the contact rate between farms is generally lower than the rate within farms. Consequently, it seems reasonable to assume that the “between group” R will be lower than the “within group” R, not only because of the aforementioned reasons, but also as measures other than just vaccination are implemented. These may include hygienic measures and initiation of a stand still. A single vaccination may also be effective under field conditions, even in pigs, and eradication of the virus may be possible by using the whole set of control measures.

Vaccination in dairy cattle was highly effective, and the experimental results are supported by field experiences, as most European countries gained the freedom-from-disease status with an intensive routine mass vaccination protocol focussing on adult cattle during 1953–1992. The main difference between these 2 situations is that during the former mass vaccination campaigns, vaccines were applied yearly, and vaccination during an outbreak would likely be applied only once.

The vaccination of cattle seemed to have been effective in the Netherlands (39), but it may remain questionable as to whether or not an outbreak in pigs would also have been successfully controlled by vaccination. Although the first outbreak in the UK in 2001 occurred on a pig farm, and was detected at the slaughterhouse (28), no outbreaks on other pig farms were reported. Worldwide, however, as in endemic areas in Asia, pigs can be the dominant species affected by FMD (40). In the transmission experiments, vaccination of piglets did not seem to be effective in preventing transmission when piglets were exposed to clinically affected pigs that were shedding the virus. It is, however, unlikely that incursion of FMDV into a herd will occur via introduction of a clinically affected pig. More likely, indirect contacts will be responsible for introduction of the virus, and the virus load will be much lower. Consequently, the effect of vaccination measured in these experimental studies might be an underestimation of vaccine effectiveness in the field.

The rate of transmission within the groups, expressed as the number of new infections per day, was significantly reduced within vaccinated piglet groups. Consequently, vaccination might help to slow an outbreak in piglets, but it seems highly advisable to implement additional measures like pre-emptive culling of in-contact pig herds (16).

In the Canadian contingency plan, vaccination is considered as a potentially important tool that could help Canadian authorities faced with impediments to rapid slaughter and disposal of susceptible animals to gain control of an outbreak. Prompt slaughter and disposal of vaccinated animals would ensure that Canada’s FMD-free status would be quickly regained, in accordance with current international standards (2). As clarified by Kahn et al (2), this would mean that vaccination would be carried out with the objective of slowing the spread of infection until it is possible to slaughter and dispose of all infected animals and animals at risk (2). This effect can only be achieved if vaccine is available in sufficient amounts and the genetic relatedness of the vaccine strain and circulating field isolate is close enough for the vaccine to be effective.

Recently, Whiting (41) stressed the severe consequences for animal welfare that might occur during an outbreak in Canada. Welfare slaughter is not part of the Canadian contingency plans and should be considered as an important part of the total management of the outbreak (41). If this policy were accepted by the international community, this could help to mitigate the economic losses associated with the use of vaccination and could provide for the maintenance of vaccinated animals.

Use of the DIVA (Differentiating Infected and Vaccinated Animals) principle by vaccination in combination with differentiating tests as the NS-ELISA, could contribute to this policy. These NS-ELISA’s have shown their usefulness, although still not officially accepted in all outbreak situations (42).

More knowledge on various aspects of FMD control will help to reduce the risk of major outbreaks in the future. The transmission experiments described in this paper, mathematical models and analysis of epidemics, and the local epidemiological situation will contribute to optimizing control strategies. Moreover, because of trade of live-animal and animal products all over the world, FMD control should be considered more and more in a global perspective (1,43).