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• W4309165769 abstract "As outlined in a recent editorial in this journal authored by members of a British Equine Veterinary Association (BEVA) and British Equestrian (BEF) working group, the United Kingdom and European equine and equestrian industry has recently faced the challenge of a significant shortage of equine influenza (EI) vaccine.1 As vaccine supply returns to normal, the pre-existing enhanced EI vaccination schedules introduced in several countries after the 2019 EI epidemic need to be promptly re-implemented to restore and then maintain optimal protective immunity within the horse population. After all, the equine industry must surely remain resolute and guided by scientific principles, as, in the words of the father of modern science, Galileo himself, ‘by denying scientific principles one may maintain any paradox’. In this article, the science behind the enhanced EI vaccination schedules, in particular the replacement of annual boosters with a mandatory bi-annual vaccination programme, is reviewed. The clear evidence from experimental, epidemiological and mathematical modelling studies indicates the benefit of bi-annual boosters, and in this editorial, we explore and explain this evidence. Equine influenza is a highly contagious respiratory disease which remains endemic in horse populations across numerous countries and is characterised by rapid spread and significant morbidity in the immunologically naive. With the introduction of mandatory EI vaccination by most competitive equestrian disciplines after the early 1980s, the scale and number of outbreaks, and corresponding economic losses, have in most years been relatively small. However, disease events such as those experienced in the United Kingdom in 1989,2 20033, 4 (Figure 1), and most recently in 20195 are portents of EI's epidemic potential, even in vaccinated horse populations. Across Europe during early 2019, an EI epidemic started to emerge with sufficient speed, magnitude and apparent potential for disruption that UK racing was pre-emptively cancelled for 6 days in February, to allow the industry to take stock but thereby incurring significant costs on itself.1, 5-7 Even before racing's shutdown, the British Horseracing Authority (BHA) had already in 2019 recommended booster vaccination of any racehorses that had not been administered EI vaccine in the preceding 6 months. The BHA subsequently increased the frequency of EI booster vaccinations on resumption of racing, with this policy now formally adopted as 6-monthly booster vaccinations by several racing jurisdictions internationally, including the BHA. These rules now align more closely with the long-established International Equestrian Federation (FEI) requirement for horses to be vaccinated within 6 months and 21 days of competition, albeit this may not always translate to bi-annual vaccination in all horses where some equestrian sports have relatively short competition seasons. Vaccination aims to both ameliorate, or ideally prevent, the clinical signs of disease but also to minimise viral shedding and associated onward transmission.8-10 The currently available EI vaccines achieve this principally through stimulating production of antibodies to the haemagglutinin (HA) glycoprotein of the influenza virus, and different levels of antibody are required to achieve these two aims. Antibody levels ≥85 mm2, as measured by single radial haemolysis (SRH), confer clinical protection but levels ≥150 mm2 are required to provide virological protection11, 12 and there is a general trend for higher antibody levels being associated with a reduced risk of infection.4 Ideally vaccination would induce life-long immunity but EI vaccines suffer from antibody decay13; antibody levels declining with time since last vaccination and requiring repeated booster administration to restore levels above protective thresholds. This identifies the rationale behind the requirement for booster vaccination but why should bi-annual rather than annual vaccine administration be preferred? Epidemiological data from previous natural EI outbreaks have repeatedly demonstrated the impermanent nature of the protection provided by vaccination. In 1995 investigations of an EI outbreak in Newmarket, UK, not only identified that the affected racehorses had been vaccinated more than 6 months previously but also confirmed the appropriateness of the virological protective antibody thresholds established experimentally by Mumford and Wood.11, 14 In 2003, clinical EI occurred again among vaccinated racing Thoroughbreds in Newmarket, but unusually it was observed that older horses, >3 years of age, were at increased risk of infection and suffered from greater disease severity.3 This could be explained by the fact that younger horses had been vaccinated more recently on their arrival into the training yards; statistical analysis demonstrating an increased risk and prevalence of EI infection in horses vaccinated more than 3 months prior to the outbreak.4 Similarly, analyses of outbreaks in Ireland between 2007 and 2010, highlighted that among clinical EI cases the average time since last vaccination was 7.7 months and 75% of individuals with signs of disease had not received a booster vaccination in the last 6 months.15 The same group also investigated EI outbreaks in Ireland in 2014 in which infection was confirmed in fully vaccinated horses on four premises and which had on average last been booster vaccinated 8.6 months before.16 These observational field studies repeatedly highlight the potential for 12-monthly boosters to leave a vulnerable immunity gap at both the individual animal and population level, and these phenomena are further ratified by results from mathematical models of EI transmission. The salient features of an EI epidemic can be simulated mathematically by compartmental (SEIR: susceptible—exposed—infected—recovered) models and these have demonstrated that effective vaccination is capable of reducing the size and incidence of epidemics9, 17; with <5% of a population becoming infectious in over 80% of modelling iterations.9 The advantage of mathematical modelling is that it can be used to assess the effect of changes in policy at the population level, without having any potential adverse impact on animal welfare. Park et al. demonstrated that in horses >2-years-old, reducing the booster interval from 1 year to 6 months reduced the risk of an outbreak developing on an equine premises through the introduction of an EI-infected horse.18 This work also showed that a 6-monthly vaccination strategy would reduce the risk of both large and small EI epidemics, having a more significant effect if applied at certain times of year which coincided with peaks in racing activity and associated mixing and return to home yards.18 Additional risks posed by the practice of synchronising premises-wide EI vaccination annually were also proposed by Gildea et al. in discussing their observations on EI outbreaks in Ireland in 2014–2015.19 An important consideration for disease transmission in racing and other equestrian sports is the extent of the connectivity that exists through competition attendance, between sub-populations that otherwise appear quite distant and so whose importance may be underestimated. The network of contacts formed between UK racehorse training yards through animals attending race meetings in a single week in October 2001 has been described.20 In the 7-day period investigated, 466 UK racing yards with entries in 149 races on 18 racecourses were shown, without any direct connections, to be closely indirectly connected with all other yards in a single, so-called ‘small-world’ network. This type of contact network, compared to a homogeneously mixing population, would lead to increased likelihood of a disease, such as EI spreading.20 Furthermore, unpublished observations made following the 2003 UK EI outbreak confirm that in training centres such as Newmarket, where there are multiple yards (Figure 1), indirect contact networks also exist. The contact networks in question are created through personnel that have physical contact with horses, such as: veterinary surgeons, farriers, and other paraprofessionals, moving between yards. These movements thereby link horses in different training yards and in theory may, without adequate attention to biosecurity, contribute to indirect infectious disease transmission. Figure 2 represents a contact network linking Newmarket training yards through only vets and farriers and is derived from questionnaire data collected from surveys returned by 39 yards in the aftermath of the 2003 EI outbreak. These networks are in addition to the close geographical proximity of adjacent premises, and the sharing of open training gallops and horse walks used by horses to access the various training grounds around the town (Figure 1); all of which may contribute to direct transmission of EI.3 Although this published evidence is heavily centred around the UK Thoroughbred racing sector, a reflection of this industry's financial support of EI surveillance and research, the overarching principles can be safely extrapolated to other equestrian disciplines and situations. The close proximity of many horses with shared exercise facilities displayed in Figure 1, could equally be replicated at competition venues all over the country, and from affiliated FEI events to local Pony Club activities. Likewise, the potential for indirect transmission through personnel that have contact with horses, such as vets and farriers (Figure 2), does not have to be confined to a small geographical area; contact networks could be formed over hundreds of miles by such individuals travelling between different yards for their work. Given all these factors and that often equestrian gatherings involve highly connected athletic horses, it is considered critical that population level immunity to EI is established and maintained; as already outlined, this will be best achieved through 6-monthly rather than annual EI booster vaccination. With regard to maintaining EI antibody levels, there is clear evidence to support the benefits of 6-monthly, over annual booster vaccination. However, due to the imperfect nature of the EI vaccines currently available and individual immunological responses to them, there are further indirect benefits delivered by this type of enhanced vaccination schedule. After immunisation using an identical protocol, a population of horses will show a surprisingly wide range of circulating antibody levels,9 in part influenced by their serological antibody titres prior to vaccination.12 At the lower extremity of this distribution are, however, a proportion of the population that for whatever reason fail to mount an effective immune response to vaccination; leaving them with low SRH antibody levels and heightened susceptibility to clinical disease and viral shedding if they become infected.21, 22 Poor responders to vaccination have been recorded in all age groups of horses but seem particularly prevalent in the weanling/yearling population.23 In investigating the circumstances of the highly impactful introduction of EI into Australia in August 2007,24 it was noted that some of the vaccinated horses held in the quarantine station from where the infecting EI virus was considered to have originated, despite vaccination had unexpectedly very low SRH antibody levels at the time of entry into quarantine. This was highly significant as these horses were the most susceptible to EI infection and would have greatly amplified the amount of EI virus circulating in the quarantine station to a level that was likely to have overcome the suboptimal biosecurity in place at the time.24 There are several theories for this imperfect response to vaccination, most probably a result of the complex relationship between virus and the maturity and genetics of individual horses.9 The key point however, is that these individuals will only be protected from EI if sufficient herd immunity is obtained through vaccination of the remainder of the equine population and more frequent booster vaccination across the population is most likely to enhance this. In addition, although poor responders appear more prevalent in the younger age categories, as a result of immune senescence, geriatric horses (>20 years old) also show a reduced antibody response to vaccination25, 26 such that though they may be clinically protected, there is likely to be increased sub-clinical EI viral shedding. Again, this advocates the whole population approach to vaccination in order to create adequate herd immunity to optimise protection of all individuals; particularly poor vaccine responders of any age. As an RNA virus, EI virus is prone to a high mutation rate during replication.17 Although many of these mutations are apparently inconsequential, even single amino acid changes, if they occur in important antigenic sites in the HA viral surface protein, may affect vaccine efficacy.27, 28 The accumulation of viral genetic mutations over time results in antigenic drift away from vaccine strains, which can contribute to reduced vaccine efficacy.9 Figure 3, based on mathematical modelling of pony experimental data by Park et al., demonstrates how the probability of EI is particularly increased for ‘heterologous’ vaccine strains (i.e. those differing antigenically to infecting strains) for mid-range SRH antibody levels compared to closely related ‘homologous’ vaccine strains.13 The modelling also indicates negligible differences in infection probability between homologous or heterologous vaccine strains where antibody levels are either very low (neither prevent infection) or very high (both prevent infection).13 This further argues for strong benefit from bi-annual booster vaccinations to enhance antibody levels across the population, particularly during periods when there is evidence of failing vaccine efficacy but before EI vaccine viral strains have been updated. If there is a mismatch between viral strains in EI vaccines and those currently circulating in the equine population, although individuals are usually still afforded a degree of clinical protection, virological protection is reduced; resulting in increased viral shedding from subclinically infected cases.17, 27 This, in turn, increases the probability of disease transmission and mathematical models have shown that although strain heterology has a relatively small effect on protection of individuals, these effects combine to have a significant effect at the population level where the probability of a large outbreak developing is significantly increased.8, 13, 27 To prevent mismatch between the vaccine and circulating EI viral strains, effective surveillance is required and vaccine strains subsequently updated in a timely manner to ensure inclusion of the most epidemiologically-relevant strains. This function is conducted annually by the World Organisation for Animal Health (WOAH) expert surveillance panel on EI vaccine composition (ESP; https://bulletin.woah.org/?officiel=08-4-2-2020-1-panel&edition=12827&pdf=officiel&article=15169), with the caveat that vaccine strain substitution is a slow and expensive process for equine vaccine manufacturers.19 This means that most manufacturers have not updated their vaccines for many years; presently one EI vaccine in the UK is compliant with both the latest ESP recommended strains first recommended in 2010, one is partially compliant with a strain first recommended in 2004 and one remains non-compliant. In the absence of updated vaccine strains, the strategy to enhance protective immunity in individuals and across populations by bi-annual vaccination is strongly recommended to help compensate for antigenic drift between vaccine and circulating EI viral strains, that is, to combat the heterologous strain effect presented in Figure 3.7, 13 With surveys demonstrating greater compliance with competition vaccination schedules as opposed to datasheet advice,29 it is imperative to ensure that these regulations are based on firm scientific evidence. Schedules should afford optimal protection; otherwise, animal welfare and the economies of all those involved in the equestrian sector may be likely to suffer in the event of another 2019-like EI epidemic. Although the recent EI vaccine shortage has necessitated a temporary relaxation of competition vaccine schedules, it is now necessary to reverse this assertively and renew the message that 6-monthly boosters are optimal and necessary. Also timely in this message is that those horses that were already on 6-monthly vaccination regimes were best positioned for the vaccine shortage with a built-in tolerance in their vaccination schedule; their levels of immunological protection would not be expected to decline to susceptible levels, even with a slight delay before being re-vaccinated. All authors contributed to and gave their final approval of the manuscript. The authors declare no conflicts of interest." @default.
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• W4309165769 title "Equine influenza bi‐annual boosters: What does the evidence tell us?" @default.
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