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The challenge of equine influenza

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01 November 2011, at 12:00am

KEVIN WHELAN of Merial, discusses the prevalence and control of this disease and the need to be aware of the differences between vaccines, both in terms of strain composition and technology

EQUINE influenza is one of the most important respiratory diseases of horses. Outbreaks of influenza can have devastating effects on the equine population and associated industries when the disease is introduced into naïve animals. This was dramatically demonstrated during the outbreak of influenza which occurred in Australia during 2007 (Callinan, 2008). Approximately 8,000 properties and 75,000 animals were infected with an estimated cost of one billion Australian dollars to the equine industry. In most parts of the world, including the UK and Ireland, the disease is endemic, with sporadic small outbreaks reported. There have been several small scale outbreaks reported in the UK in the last few years, mainly in unvaccinated animals. A national equine influenza surveillance scheme is in place, funded by the racing industry and managed by the Animal Health Trust (AHT) (Elton and Bryant, 2011). In addition to this scheme, Merial has set up an influenza alert text message service (Tell Tail) in conjunction with the AHT, which provides notification of confirmed cases of influenza within 24 hours of diagnosis. Since March 2010, those who have signed up to the service have been alerted to 15 outbreaks of disease, with cases reported this year in Wiltshire, Surrey, Lanarkshire, South Wales and Gloucestershire.

Virus evolution

In common with human influenza, equine influenza virus tends to mutate over time, with the periodic emergence of new strains which may be antigenically distinct from older strains. This evolution occurs through a process known as antigenic drift, where the accumulation of point mutations in the viral RNA can result in changes in viral antigenic proteins, such as haemagglutinin (HA) (Mumford, 2007). This is of significance where there is a mismatch between field strains of virus and the strains in commercially available vaccines. This mismatch can result in less than optimal vaccine performance, particularly in terms of reduction of viral shedding postinfection, which may have consequences for the control of the disease (Daly et al, 2004; Mumford, 2007). An example of this phenomenon is highlighted by the Australian outbreak, where influenza was introduced into the country by a vaccinated thoroughbred horse, which was shedding virus despite the absence of obvious clinical signs (Callinan, 2008). 

Vaccination 

Control of the disease in those countries where it is endemic is largely achieved through vaccination, which is compulsory for horses in the UK competing under Jockey Club or FEI rules. Whilst vaccination is generally regarded as being vital to the successful control of this disease, there are many challenges to effective vaccination. These include the virus strain evolution mentioned above, the relatively shortlived immunity induced by vaccination, the inability of vaccines to induce sterilising immunity and, in young horses, interference from  aternallyderived antibody (MDA) (Minke et al, 2007; Minke et al, 2004). Despite the introduction of compulsory vaccination in 1981, there has been a number of reported outbreaks across Europe in which wellvaccinated animals have shown signs of disease. Outbreaks of influenza in vaccinated horses during 1989 (Livesay et al, 1993) and more recent reports in Newmarket in 2003 (Newton, 2006), Croatia in 2004 (Barbic et al, 2008) and Italy in 2005 (Martella et al, 2007) suggest that vaccine performance in the field should be evaluated on a regular basis. These outbreaks can be partly attributed to the evolution of influenza virus as a result of antigenic drift, with a resultant mismatch between infecting and vaccine strains. In response to concerns regarding possibly significant evolution of influenza virus, an Equine Influenza Expert Surveillance Panel was established by the OIE in the early 1990s (Mumford, 2009). This panel consists of members from different OIE and WHO Reference Laboratories around the world. Their role is to analyse data from reported outbreaks of influenza and determine whether significant antigenic drift has occurred which could impact on vaccine performance. Based on this analysis, the panel issues recommendations regarding the strains which should be included in vaccines. Some examples of the recommendations made by the panel include the 1995 recommendation to include representative strains from both the American and European lineage influenza viruses in vaccines, based on evidence that two distinct lineages of influenza had emerged in the mid/late 1980s, named the American and European lineages. This recommendation has been followed by
most vaccine manufacturers worldwide. In 2004, due to concerns of significant evolution of the American lineage viruses, a recommendation was made to update the American lineage virus strain used in vaccines. To date, only one vaccine
manufacturer in Europe has followed this recommendation.
Merial’s canarypox vectored vaccine (Proteqflu) was updated to include the Ohio/03 strain in 2008. In 2010 a new recommendation was made, based on evidence of further evolution of the American lineage. The panel advised that
vaccines should now contain two strains of virus from the American lineage, specifically strains representative of both Florida clade 1 and Florida clade 2 viruses (OIE, 2010). This highlights the importance of ongoing surveillance of this disease. The only vaccine which partially complies with this  recommendation and contains a clade 1 virus strain (Ohio/03) is again Proteqflu; all other vaccine brands available in the UK are now noncompliant with current recommendations. The 2011
recommendations are unchanged from 2010 but the conclusion of the report also noted that: “There was some evidence of a lack of vaccine efficacy against clade 2 viruses, i.e. that vaccines containing earlier viruses of the American lineage (such as A/eq/Newmarket/1/93) do not provide adequate protection against these viruses” (OIE, 2011).

Cross-protection studies

In response to the OIE recommendations on vaccine composition, several vaccine manufacturers have carried out challenge studies to demonstrate the cross protection afforded by older vaccine strains against more recent field isolates (Bryant et al, 2009: Paillot et al, 2008; Paillot et al, 2010). However, it should be noted that there are many limitations to such studies, which are performed under optimum conditions with challenge infection generally carried out two weeks after primary vaccination, a time when antibody levels are at their peak. It is unknown whether similar levels of protection would be observed if the vaccinated horses were challenged at a later stage, and the independent authors of recently published review papers (Cullinane et al, 2010; Elton and Bryant, 2011) have called for vets to use updated vaccines and support manufacturers who have responded to the OIE recommendations by investing in updating their vaccines. 

Vaccine technology

Historically, equine influenza vaccines have been based on inactivated whole virus or surface antigens and have been available since the 1960s. Many of these early vaccines provided relatively shortlived immunity and were poorly immunogenic (Minke et al, 2004). Conventional inactivated vaccines are heavily dependent on the generation of high levels of circulating antibody (Paillot et al, 2006a; Elton and Bryant, 2011), and in recent years the focus has been on the development of vaccines
which more closely mimic natural infection and generate a broad immune response (Paillot et al, 2006a). The introduction of subunit vaccines based on the integration of surface antigens into immunostimulating complexes (ISCOM) in the 1990s represents one such development, and these vaccines have been shown to induce both a humoral and cellular immune response (Paillot et al, 2008). These vaccines, however, are still based on inactivated antigens and it was the introduction of a live viral vector vaccine in Europe in 2003 (Proteqflu, Merial) that  represented an innovative new approach to vaccination. This vaccine is based on a recombinant canarypox virus vector which contains DNA encoding for the haemagglutinin (HA) surface protein of the equine influenza virus. HA is one of the key antigens of the influenza virus and an important difference between this vaccine and the traditional inactivated products is that the HA antigen is synthesised by the horse’s cells, thereby more closely mimicking natural infection (Minke et al, 2004). However, because the canarypox virus is non-pathogenic to mammals, reversion to virulence is not possible so the vaccine is safe for use in horses. The interaction between the live vector and the immune system means that the vaccine induces a strong cell mediated response as well as a humoral response (Paillot et al, 2006b; Adams et al, 2010). Cell mediated immunity is an
important component of the natural immune response to equine
influenza infection, and naturally exposed horses have been
shown to be protected from subsequent infection even in the
absence of high levels of circulating antibody (Daly et al, 2010).
Another advantage of this technology is the ability to prime the
immune system even in the face of maternally-derived antibody (MDA) (Minke et al, 2007). The presence of even low levels of MDA has been shown to profoundly interfere with response to vaccination with inactivated products in foals and it has been reported that repeat vaccination in the face of MDA can induce immune tolerance (Cullinane et al, 2001). During the outbreak of equine influenza in Australia in 2007, strategic vaccination of horses played a key role in helping to control the outbreak and
eradicate the disease (Garner et al, 2011). Following careful consideration by the authorities, the canarypox vectored vaccine was selected as the vaccine of choice, due to the advantages conferred by the vector technology. The reasons cited by the authorities for choosing this particular vaccine
include the ability of the vaccine to rapidly induce effective immunity, the history of successful use of this vaccine in controlling a large outbreak in South Africa in 2003, and the ability to differentiate infected from vaccinated horses (due to the very targeted immune response induced by this vaccine) (Perkins et al, 2011). In summary, equine influenza remains an important and prevalent disease. Vaccination offers the best option for controlling this disease in those countries where it is
endemic and it is important that vets are aware of the significant differences between available vaccines, both in terms of strain composition and technology. 

References

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