Maquinaria principal o maquinaria propulsora

The passing of FMDV between animals depends on 1) shedding of infectious virus from an infected animal; 2) transfer of virus to the tissues of another animal; and 3) infection of the other animal.

Periods of shedding of infectious virus

Conventionally, the length of the latent period (exposure to infectiousness) was estimated from the length of time from experimental exposure to first detection of FMDV in infected animals’ secretions. Figure 1.2 summarises meta-analyses of 19 experiments measuring the FMD latent period, incubation period (from exposure to clinical signs), and period of virus shedding (termed “infectiousness”) (Mardones et al., 2010).

Figure 1.2: Latent, subclinical, incubation and virus shedding (“infectious”) periods

of FMD.

The plot is based on 19 experiments with serotype O. Frequency distributions and probability density functions fit to continuous (grey boxes) and discrete (red) data for

experimental animals and FMD stage. Non-parametric density estimation using the kernel standard deviation (dashed line) was estimated for smoothing the distribution.

N= 19 experiments, 295 animals (64 cattle, 149 sheep, 72 pigs, and 10 goats). From (Mardones et al., 2010).

Levels of virus shedding

Levels of virus shedding may be measured by quantifying FMDV in secretions and excretions of infected animals. Meta-analysis of 32 experiments suggests that most FMDV is found in upper respiratory secretions from cattle, followed by the breath of pigs, probang samples from cattle and blood from pigs (Bravo de Rueda et al., 2014) (Figure 1.3). The amount of FMDV released into the environment is also species-dependent (e.g. pigs excrete higher amounts of FMDV by the airborne route than cattle). Virus excretion levels are positively associated with the presence of clinical signs. Higher levels are excreted around the onset of clinical signs as opposed to later in the course of disease. When variation due to different experiments was taken into account, (Bravo de Rueda et al., 2014) reported that FMDV serotype or route of infection did not help explain the quantities of FMDV shed.

Figure 1.3: Boxplot of FMDV amounts in secretions and excretions.

Cattle are represented by blue, swine by red and small ruminants by green. In airborne excretion (*), ¹⁰log TCID50/animal/day is reported. When applicable, each column contains the extreme of the lower whisker, the lower hinge, the median, the upper hinge and the extreme of the upper whisker for one plot. N = of 32 experiments

involving 220 cattle, 71 pigs and 36 small ruminants. URT = upper respiratory tract secretions and excretions. From (Bravo de Rueda et al., 2014).

The association between virus shedding, clinical signs and infectiousness

Whilst FMDV levels in secretions have been reported in multiple experiments, infectiousness is more difficult to measure, and carefully structured transmission studies are required. A recent study with serotype O (N = 9 infected cattle, 28 transmission attempts, and 8 transmission events), showed that, whilst virus is present in secretions prior to clinical signs, transmission events are most likely to occur in the first two days after onset of clinical signs (Charleston et al., 2011). However, in contrast to this study (Charleston et al., 2011), which allowed eight-hour transmission windows only, studies of animals in contact for extended periods of time showed that transmission is possible also prior to observation of clinical signs (Orsel et al., 2007, 2009).

Transfer of virus and infection of another animal

FMDV can be transferred from an infected animal in close proximity, but can also survive in the environment for up to 14 weeks (for example in manure) (Bøtner & Belsham, 2012;

products, such as untreated meat or milk, which may then be ingested by susceptible animals (Donaldson, 1997; Hartnett et al., 2007). FMDV can also be mechanically transferred via people, non-susceptible animals and objects.

Infection routes in different species have been determined using experiments and field observations, with inhalation of aerosols infected with virus being most common for cattle and small ruminants, and ingestion of contaminated material for swine (Alexandersen et al., 2003). These infection routes suggest that FMDV will be transmitted more rapidly in denser host populations, where more animals will be exposed to high levels of infectious virus from an infected individual. Transmission can also occur through insemination with semen from an infected animal (Cottral et al., 1968) and intra-mammary inoculation (Burrows et al., 1971). Transfer is theoretically possible thorough injection with FMDV contaminated materials and incisions with FMDV contaminated instruments (expert opinion from Prof. David Paton). The ability of FMDV to survive in biting flies has been recently demonstrated, but this potential route of transmission has never been proven (University of Edinburgh & Pirbright Institute, 2016).

Long-term FMD transmission cycles

Transmission from acutely infected animals has been relatively well documented, and extensive studies have investigated outbreaks occurring in countries that are normally FMD free (Boender et al., 2010; Bouma et al., 2003; Cottam et al., 2008a, b; Gibbens &

Wilesmith, 2002; Gibbens et al., 2001; Haydon et al., 2004). Conversely, many questions remain about long-term transmission cycles of FMDV in endemic regions. For example, FMDV is reported to have a high reproduction ratio (secondary cases for each infected unit), and, after infection, animals are immune to the variant of FMDV that infected them for several years (Doel, 1996, 2005). Therefore, it would be expected that a high level of herd immunity would cause extinction of FMDV variants after they have circulated through a large enough proportion of the population. However, this does not always happen, and very similar variants have been observed to recur over many decades.

Potential explanations for these observations include that:

• There is a large enough connected community of susceptible hosts capable of maintaining a pathogen in the long term. In other words, as a portion of the community reaches a high level of immunity, the FMDV variant is maintained by

the other susceptible hosts within the community. Once immunity decays in the initial section (due to birth of naïve animals and possibly loss of acquired immunity), the variant can cause disease again in this original subset. The concept of a maintenance community (Haydon et al., 2002; Viana et al., 2014) is more fully described in Section 1.7.

• FMDV may have a lower reproduction rate in partially immune populations, particular species or populations with lower density or contact rates. This might result in slower development of herd immunity and longer persistence of the FMDV variant in the population.

• The FMDV variant remains in persistently infected animals long enough for the immunity levels in the population to decay. Transmission may then be achieved from the persistently infected host to a susceptible animal, causing the variant to continue circulating.

In relation to explanation 2, the estimated reproduction ratio of FMDV in a partially immune (vaccinated) population of cattle is lower than in unvaccinated cattle (Gonzales et al., 2014). Similarly, a sheep transmission experiment suggested, that, whilst FMD can potentially persist in a sheep population, the reproduction ratio is relatively low (1.14, 95%

CI: 0.3-3.0)), which might result in slower development of herd immunity (Orsel et al., 2007). Research is ongoing to understand transmission parameters and persistence mechanisms of FMDV in African buffalo populations, that may also have lower reproduction ratios compared to cattle (Maree et al., 2016). These populations potentially allow particular strains of FMDV to persist for longer, through lower transmission rates and subsequently slower development of protective immunity.

For explanation 3, there is scant evidence of FMD transmission from persistently infected animals. Milk and semen have respectively been demonstrated to contain FMDV, or at least its genome, for as long as 51 days (Burrows et al., 1971) and five months (Sharma et

foetuses and fluids many months after initial infection (Ryan et al., 2007). Despite these experiments showing that animals can shed FMDV after clinical signs have subsided, no unequivocal reports of transmission from persistently infected livestock exist (Thomson, 1996). As discussed in more detail in Section 1.6, out of seven different experiments attempting to achieve transmission through protracted contact between persistently infected African buffalo and uninfected cattle, only two were successful (Dawe et al., 1994; Vosloo et al., 1996), whereas the other five did not demonstrate transmission (Anderson et al., 1979; Bengis et al., 1986; Condy & Hedger, 1974; Gainaru et al., 1986;

Maree et al., 2016). Therefore, the role of persistently infected livestock and wildlife in FMDV transmission has yet to be fully understood.

As well as persistence mechanisms that may be employed by individual variants of FMDV, a further mechanism that might explain persistence is antigenic variation.

Pathogens that have high reproduction rates may persist in the face of rapid development of herd immunity by antigenic variation to circumvent the immune response of the host population. As an RNA virus, the FMDV genome has a high replication error rate (Domingo et al., 2006), facilitating rapid evolution of antigenic variants. This is reflected by the large number of FMDV serotypes and variants within serotypes. However, FMDV antigenic variance has a limit. Human rhinovirus for example, a related picornavirus, appears to have relatively more antigenic variation, comprising at least 102 serotypes (Savolainen et al., 2002). This limit to antigenic variation in FMDV may possibly reflect the balance between the benefit of antigenic variation, and the cost of loss of important functions through changes in essential viral genes that may be unique for the ecological niche of each pathogen (Eigen, 2002; Grande-Pérez et al., 2002). This might explain why only seven serotypes of FMDV have been identified.