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Archive: 1999 Session - Appendix 16

1999 Session of the Research Group of the Standing Technical Committee of EuFMD



Implementation of emergency FMD vaccines Does current knowledge support the use of suppressive vaccination?


P. V. Barnett, R. J. Statham and R. P. Kitching
Institute for Animal Health, Pirbright Laboratory, Ash Road, Pirbright, Woking, Surrey GU24 0NF, UK


Foot-and-mouth disease (FMD) is a highly contagious viral disease of wild and domesticated cloven-hoofed animals. A combination of wide host range, low infectious dose susceptibility and the capacity for airborne spread, especially in areas of high livestock density in temperate climates, are factors which predispose to explosive epidemics of FMD. Such outbreaks can have a devastating effect upon the agricultural economies of developed, and particularly FMD-free countries, due to the cost of disease control measures and trade embargos. FMD-free countries, whose livestock are highly susceptible to FMD, have contingency plans to deal rapidly with confirmed FMD outbreaks. In the first instance a ístamping outÎ (by slaughter) policy would be instigated, together with associated zoosanitory measures including the imposition of movement restrictions. However, if an outbreak threatened to overwhelm these control measures, emergency ring-vaccination could be implemented in an attempt to prevent further spread of FMD virus (FMDV). Immediate access to high quality FMD vaccines would be required and for this reason, FMD-free states have established FMD vaccine banks, which primarily store concentrated, inactivated FMDV antigen at ultra-low temperatures. Antigen is highly stable during this form of storage and so vaccine can be rapidly formulated, as and when required. The International FMD Vaccine Bank (IVB) at Pirbright is a good example of this approach.

Swine pose the main threat for amplification and rapid dissemination of airborne FMDV due to the speciesÎ unique ability to excrete vast quantities of airborne virus, and the practice of having them in large numbers (Sellers and Parker, 1969; Donaldson and Doel, 1992). If an outbreak were to occur in a single large pig unit, logistical problems might delay the slaughter and disposal of animals thereby allowing the continued dispersal of plumes of airborne FMDV. An increasing environmental awareness has also lead to difficulties regarding carcass disposal as many local authorities will not permit burial of animals. Burning of carcasses would result in both stench and smoke pollution, and rendering requires complete containment for transportation and the close proximity of a suitable facility for large throughput to decrease the risk of virus dispersal. Media attention and public scrutiny together with heightened awareness of environmental and welfare issues would also result in every action being questioned, not least the wholesale slaughter of animals in order to eradicate a disease non-pathogenic to man, of low mortality, and which can be controlled by prophylaxis.

Taking into account these concerns a possible option which has gained more prominence in recent years is the use of íemergencyÎ vaccines within an infected area, in an attempt to reduce the amount of virus circulating and spreading beyond the restricted area. This so-called ísuppressionÎ or ídampening downÎ vaccination regime is now on the agenda of a European Commission working group set up to assist the Animal Health and Animal Welfare (AHAW) Committee in establishing criteria for the eradication of certain infectious diseases including FMD (Panina and Ahl, 1998).

To be of practical benefit ísuppressiveÎ vaccination is very much dependant upon the quality and efficacy of íemergencyÎ vaccines. Their application therefore raises key questions about the rate of development of protection in target species, and the extent to which such vaccines could be expected to prevent the spread of disease if effective viral challenge occurred immediately after immunisation. The most extensively examined íemergencyÎ vaccines are those stored in the International Vaccine Bank.



Current Knowledge

Using infected pigs in an indirect contact (airborne) challenge, initial studies demonstrated that both oil and Al(OH)3/saponin-adjuvanted monovalent vaccines containing either O1 Lausanne or C1 Oberbayern were capable of protecting cattle at 4 or more days after vaccination (Doel et al., 1994). This was achieved in the absence of significant quantities of neutralising antibody, total virus-specific antibodies, IgM, IgG1 or IgG2 as measured by ELISA. Doel also explored the level of virus persistence in vaccinated and non-vaccinated cattle and concluded that animals challenged a few days after vaccination appeared more likely to become ícarriersÎ. A repeat experiment using the same animals but another antigen (C1 Oberbayern), resulted in far fewer animals becoming persistently infected. Although this may have been related to the ability of the individual strains to establish a persistent state, it was felt more likely to be the result of pre-existing immunity to the previous vaccine. Another factor also not taken into account at the time was the extremely high potency of the C1 Oberbayern vaccine (PD50 ­112). In 1995, Salt expanded on these earlier cattle studies and showed that oil íemergencyÎ vaccines, and in particular those adjuvanted with Montanide ISA 206, íoutperformedÎ the aqueous formulation and protected cattle at two and three days post vaccination. Again, in the absence of detectable specific neutralising serum antibody. SaltÎs results also supported the observation by Doel that virus excretion was reduced more effectively by íemergencyÎ vaccines, particularly Al(OH)3/saponin based formulations, administered at the earliest possible time prior to challenge and suggested this may be the result of the presence in the upper respiratory tract secretions of humoral antibody.

Emergency vaccination of sheep produced similar rapid protection against an airborne challenge within 3 days of immunisation (Cox et al., 1999). Again, these studies were expanded to examine the effect of such vaccination on local virus replication and excretion, and the establishment of carriers. Both oil and aqueous vaccine formulations reduced the incidence of virus replication, and the number of animals infected, up to 28 days post challenge, when compared to non-vaccinated animals. There were examples in all the groups immunised 5 or more days prior to challenge, of sheep remaining free of virus in the oesophageal-pharyngeal tract for the duration of the trial. Indeed, comparison using O1 Lausanne or C1 Oberbayern in both oil and aqueous formulation (Cox et al., 1998) supported the previous observations in cattle that vaccines administered at the earliest possible time prior to challenge were most effective at reducing virus excretion and persistence. However, in contrast to the cattle results, both adjuvants were equally efficient at reducing the level of virus excretion. There was also evidence in support of a relationship between potency and the incidence of virus replication in the oropharynx. Inclusion of susceptible in-contact sheep following challenge of vaccinated sheep (Cox et al., 1999), also showed evidence of transmission, even from animals vaccinated 10 days before challenge, this time utilising Asia1 India antigen. These results were supported by the subsequent isolation of virus from probang samples of immunised donor animals. However, none of the in-contacts showed clinical signs, suggesting the level of transmission was insufficient to initiate disease.

Results from early trials in swine appeared to contradict those using cattle and sheep with protection being rarely observed before 21 days post vaccination (Doel et al., 1994). This inconsistency may have been due to the lower level of humoral neutralizing antibodies. However, as the different vaccination groups were housed together it was more likely due to the overwhelming challenge conditions resulting from unprotected pigs re-challenging other íprotectedÎ vaccinates before isolation. This concept of overwhelming challenge has also been cited for cattle (Donaldson and Kitching 1989) and is particularly relevant with regard to high density farming practices.

In consideration of the disappointing early protection studies in pigs, further controlled trials were performed in which vaccination groups were housed separately in individually ventilated isolation boxes, before and after challenge. Pigs showing early clinical signs were removed from the groups as soon as was practicable to avoid the complication of over-challenge. Under these conditions a C1 Oberbayern íemergencyÎ vaccine was shown to protect pigs against airborne challenge no earlier than four days post-immunisation (Salt et al., 1998). In a subsequent pig trial, virus excretion monitored within the isolation boxes of individual vaccination groups indicated that immunisation at seven days prior to challenge reduced the airborne excretion of virus from these pigs to such a degree as to prevent contact transmission to susceptible animals. However, there were some conflicting observations. Despite the apparent absence of excreted virus from íprotectedÎ pigs in the 4 day vaccination group, transmission to susceptible animals still occurred. In addition, protection was not conferred in all the 5 day vaccinates, resulting in high levels of virus excretion and rapid transmission to the susceptible contact pigs. Perhaps the most interesting result of this trial however, was the íprotectedÎ 4 day vaccinates eventually succumbing to disease as a result of communal housing with the now infected contact pigs. This not only reinforced the theory of overwhelming challenge proposed by Doel and others but also highlighted the intensity of direct challenge, even in the presence of íadequateÎ protective immunity. The severity of contact challenge had previously been shown to be greater than oral swabbing with, or needle inoculation of, live virus (De Leeuw et al.,1979) and protection required higher levels of neutralising antibody. A more recent íearly protectionÎ study by the author, employing a modified 2 hour direct contact challenge, as opposed to the indirect aerosol method, would also support the severity of this mode of challenge as no overall protection in any of the vaccination groups was observed (unpublished results).




The use of ÎemergencyÎ FMD vaccines has two clear objectives. Firstly to provide protective immunity as rapidly as possible to susceptible stock, and secondly to reduce the amount of virus released and thereby limit the spread of disease. During a ring vaccination campaign the most likely method of virus dissemination, once the control measures have been fully implemented and movement around the infected premises has ceased, is via airborne dispersal. It is clear from the authorsÎ studies that under such challenge conditions IVB íemergencyÎ vaccines are capable of conferring protective immunity against homologous strain challenge in target species within 4 days of vaccination. However, such experiments cannot mirror all variables and therefore such early protection is undoubtedly dependant, for example, on the weight of the challenge resulting from duration and route of exposure, virulence, or predilection for a certain host. Furthermore, early protection does not necessarily equate with the abolishment of local virus replication, since, in our experience, this appears to be reliant on a greater interval between vaccination and challenge as well as the potency of the vaccine used (Doel et al., 1994; Salt et al.,1995,1998; Cox et al.,1998, 1999).

Pigs have a particularly important role in the airborne spread of FMD and results to date suggest that vaccination at least 7 days prior to natural airborne exposure minimises the risk of virus excretion and further transmission (Salt et al.,1998). Indeed, this same high potency antigen (C1 Oberbayern, PD50 ­112), requires a similar time period in sheep (Cox et al.,1998). However, lower potency vaccine, such as Asia1 India (PD50 = 61), require longer to prevent local virus replication, taking up to 10 days post vaccination or even longer in cattle (Salt et al.,1995). Direct contact between housed and infected animals is the severest form of challenge and, for pigs, results in two phases of airborne FMDV emission (Davidson., 1997). The first, shortly after contact and lasting up to 24 hours, regardless of immune status, and a second more prolonged phase in which FMDV is produced in high concentrations, and which is coincident with viraemia and the development of clinical disease occurring in the absence of specific humoral immunity. Therefore, regardless of vaccination status, the early emission phase may play an important role in the rapid dissemination of virus within a group of susceptible pigs and in doing so amplify the initial challenge. Our studies appear to endorse this since íearly protectedÎ pigs did excrete sufficient amounts of virus to infect in-contacts which, in turn, would appear to have re-compromised the health status of these íearly protectedÎ vaccinates through communal existence. Such an early phase of airborne virus excretion after contact exposure has also been shown in cattle and sheep (Gibbs et al 1975; Sellers et al., 1977). Whether the excreted virus is the result of replication within the mucous membranes of the host, rather than one of íphysical recyclingÎ, is not clear. However, in the sheep experiments, transmission from early íprotectedÎ to susceptible animals did not result in the occurrence of diseased in-contacts, suggesting that the level of virus was insufficient to initiate clinical signs. While such virus transmission levels may be influenced by vaccination, it is important to note that, experimentally, direct transmission events within this species are notoriously inconsistent, even in the absence of specific immunity.

The need to ring vaccinate as early as possible is not in question; however, suppressive vaccination within an already infected area, even in the absence of clinical disease raises additional problems. In an infected area, high density livestock, and particularly those in enclosed housing, may or may not have been exposed to virus prior, or during vaccination. Even immediately following vaccination, animals could be subject to a challenge of the severest form encompassing aerosol and direct contact. No FMD vaccine, regardless of potency, has ever been shown to be protective under these circumstances, although there would be some value in examining such direct contact challenge in all the target species. However, protection would not be the only objective in instigating a suppressive vaccination campaign but also the reduction of the amount of virus circulating and spreading beyond the restricted area. Although íemergencyÎ vaccines are capable of reducing virus replication and transmission, the time is longer than that needed to confer protection. In consideration of the early phase of virus emission; 24 hours after vaccination, animals could still become infected in the absence of clinical signs and continue spreading virus. The rate at which this transmission would occur is very much dependent on a number of factors including climatic, environmental (e.g. are animals housed), densities of stock, species, vector and virulence of the outbreak strain. Seven days after vaccination, some animals, particular pigs, are still likely to show full clinical signs. This would amplify transmission and compromise any protected animals that, although unlikely, may still not have contracted the virus. Suppressive íemergencyÎ vaccination is therefore more likely to be effective under conditions supporting low rate transmission and perhaps should only be considered as a supporting measure where these conditions prevail. For example, physical segregation from infected stock in separate housed units or on different farms, or vaccination of all target species in a mixed husbandry area harbouring a virus naturally adapted to one host. However, low rate transmission is difficult to predict, even with the assistance of computer models, and a greater understanding of the pathogenesis of the disease is therefore essential.

Undoubtedly, confidence in the use of suppressive vaccination as a practical additional or alternative control measure to current policy requires further studies with íemergencyÎ vaccines, encompassing severer challenge conditions, additional serotypes, and further quantification of excretion and transmission events. However, since the natural route of FMDV infection and site of primary replication is the oropharynx, the first line of defence must begin at these mucosal surfaces. The development of vaccines that stimulate local mucosal responses and confer sterile immunity through the inhibition of local virus replication, is also fundamental to suppressive vaccination becoming a more acceptable option.

An assured method of suppressing the release of airborne virus is a rapid cull of the infected herd or flock. Slaughtering infected pigs can decrease the amount of airborne virus twenty-five fold or more after an hour and 5000 fold after 24 hours (Sellers et al., 1971). Slaughter without delay and disposal of the carcases at a later stage when circumstances permit would be an alternative option to the application of vaccine in the face of disease.




The more affluent nations and those with an economically significant live animal and animal product export trade, would primarily rely on the slaughter of all affected and in-contact susceptible animals to control outbreaks of FMD. Such measures might also extend to preemptively slaughtering other herds in which there is no clinical evidence of disease, but which have been epidemiologically linked with an outbreak, and may therefore contain infected animals. The success of ístamping outÎ is recognized by the OIE in its guidelines on re-establishing trade following an outbreak and the immediate slaughter of all infected and in-contact susceptible animals remains the recommended policy. However, political pressure may require that vaccination be introduced earlier than the veterinary authorities would prefer, or conversely, the need to initiate vaccination may be due to the failure of slaughter to halt an outbreak or difficulties involved in killing large numbers of animals and subsequent carcass disposal.

Without exception, all FMD free countries retain the option to vaccinate and have access to one or more banks of FMD virus antigen or formulated vaccine should it be required. However, the circumstances under which vaccination would be employed is far from clear and for EU countries is currently the subject of a separate committee within DG24.

If used, protective vaccination would only be effective in animals not already exposed to FMD virus. It would therefore be employed outside the 3 Km protection zone, and outside any predicted aerosol spread of virus from the infected premise. All vaccinates would be naive to FMD antigen, and would require a minimum of 3-4 days (see above) to develop protective immunity. This protective vaccination would thus form a ring around the infected area, preventing disease spread and allow the outbreak to expire within the protection zone, where infected herds would quickly be identified and slaughtered.

Nevertheless, the pressure to reduce or stop further slaughter may be such that additional suppressive vaccination would be introduced within the protection zone and aerosol dispersion contour, or even on infected premises. While the introduction of suppressive vaccination may achieve the short term objective of reducing the number of animals slaughtered, the disadvantages of this policy would include:

  1. Animals incubating the disease would probably be vaccinated, and these would still develop disease and produce infectious FMD virus.
  2. Vaccinating within an infected herd would increase the risk of virus spread.
  3. The clinical signs of disease would be less severe or absent after vaccination, so FMD virus could persist and circulate unobserved in the vaccinated animals, predisposing to further spread, and extend the duration of the outbreak.
  4. Animals vaccinated in a suppressive vaccination area should be slaughtered as soon as possible, but if this does not occur, surveillance of vaccinated pigs will be required for at least 3 months, and vaccinated cattle and sheep for their lifetime.
  5. While the objective of suppressive vaccination may initially be to reduce the pressure on the carcase disposal system, there may be a temptation, as the outbreak appears to subside, not to continue with the planned destruction of an infected herd, on the basis that it no longer appears to be infected.
  6. It will be difficult to maintain the distinction between the protectively vaccinated animals (low risk) and those given suppressive vaccination (high risk) and to justify the application of different follow-up procedures to the live animals and their products in the two groups.

Even though suppressive vaccination and its possible use in Europe has been written into the proposed new legislation on controlling FMD within the EU, it can only be recommended when political pressure makes it unavoidable, or logistical problems with slaughtering large numbers of animals and disposing of their carcases makes it necessary. It cannot be considered a desirable option from a disease control point of view.

Should suppressive vaccination be used, its distinction from protective vaccination must not be forgotten, and the follow up surveillance and control of animals given suppressive vaccination must be rigorous. Ultimately, whatever control measures are taken, much will be dependant on the speed with which the initial decision to vaccinate is taken.



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