Annotated Framework for Decisions



ENVIRONMENTAL RISK MANAGEMENT AUTHORITY DECISION

Date signed: 20 December 2007

|Application code: |NOQ07001 |

|Application category: |Import for release or release from containment a Qualifying New Organism under the |

| |Hazardous Substances and New Organisms (HSNO) Act 1996 |

|Applicant: |MAF Biosecurity New Zealand |

|Purpose: |To release Flu Avert® I.N., an intranasal vaccine to be used to prevent or combat an |

| |outbreak or in vaccination programmes against equine influenza |

|Date received: |30 November 2007 |

|Consideration date: |14 December 2007 |

|Considered by: |A Committee of the Environmental Risk Management Authority |

1. Summary of decision

1. Application NOQ07001 to import for release the cold-adapted equine influenza virus contained within the Flu Avert® I.N. vaccine is approved with controls (specified in Appendix 1 of this decision), having been considered in accordance with the relevant provisions of the Hazardous Substances and New Organisms (HSNO) Act 1996 (the Act) and of the HSNO (Methodology) Order 1998 (the Methodology).

2. Legislative criteria for application

1. The application was lodged by the Ministry of Agriculture and Forestry Biosecurity New Zealand (MAF BNZ) pursuant to section 34 of the Act. The decision was made in accordance with section 38I of the Act taking into account matters relevant to the purpose of the Act, as specified under Part II of the Act. Unless otherwise stated, references to section numbers in this decision refer to sections of the Act.

2. Consideration of the application followed the relevant provisions of the Methodology, as specified in more detail below. Unless otherwise stated, references to clauses in this decision refer to clauses of the Methodology.

3. Application Process

Application Receipt

1. The application was formally received on 30 November 2007.

Notification and consultation with government departments

2. In accordance with section 53, the application was not publicly notified.

3. In accordance with section 58(1) and clause 5, the Ministry of Agriculture and Forestry Biosecurity New Zealand (MAF BNZ) Facility and Approvals Group in the Borders Standards Directorate, the Agricultural Compounds and Veterinary Medicines (ACVM) Group of the New Zealand Food Safety Authority and the Department of Conservation (DOC) were notified and provided with the opportunity to comment on the application. The Committee reviewed the comments made and addressed specific comments where appropriate throughout this document.

4. The Committee noted that the Animal Response Group in the Post-Border Directorate of MAF BNZ will be responsible for the use of this vaccine and the Facility and Approvals Group in the Borders Standards Directorate of MAF BNZ will audit compliance with this approval. The Committee noted that these groups have distinctly separate roles within MAF BNZ, and the Committee considered that an impartial audit of compliance with this approval could be achieved. The Committee also noted that MAF BNZ is the lead Government Agency responsible for New Zealand’s biosecurity, and as such has a vested interest in complying with the controls on this approval.

Decision Making Committee

5. In accordance with section 19(2)(b) and clause 43 of the First Schedule to the Act, the Environmental Risk Management Authority (the Authority) appointed a Decision-making Committee (“the Committee”) to consider the application. The Committee comprised of: Dr Kieran Elborough (Chair), Dr Val Orchard and Dr Deborah Read.

Information available for the consideration

6. The information available for the consideration comprised of:

• The application for NOQ07001 (Form NO1Q);

• The references as listed in the application and memo to the Committee;

• A memo from the Agency to the Committee to assist and support the Committee’s decision making; and

• Comments received from DOC and MAF BNZ.

4. Associated approvals

1. The Committee noted that before an approval granted under section 38I can be used, the vaccine must have approval under the Agricultural Compounds and Veterinary Medicines (ACVM) Act 1997 and biosecurity clearance under the Biosecurity Act 1993.

2. The Committee also noted that, as the vaccine contains a cold-adapted attenuated strain of equine influenza (EI) which is an unwanted organism, under the Biosecurity Act 1993, exemption under sections 52 and 53 of that Act granted by a Chief Technical Officer, MAF BNZ is required before the vaccine EI strain can be communicated, released, offered for sale, exhibited or propagated.

5. Sequence of the consideration

1. In accordance with clause 8 and section 38I, the Committee considered the information provided in the sources listed above.

2. In accordance with section 38I, the Committee considered whether the Flu Avert® I.N. vaccine contains a qualifying organism.

3. The Committee considered that Flu Avert® I.N. vaccine falls under the criteria of a veterinary medicine as stated in Section 2 of the ACVM Act 1997 as it is a biological compound (a viral vaccine) that is intended for use in the direct management of an animal.

4. The Committee considered the potential conditions (controls) that may be set for the use of this veterinary medicine under the ACVM Act and identified conditions such as those that limit the use of the vaccine to veterinarians or require the veterinary medicine to be used as per the label instructions will mitigate the effects of the vaccine virus on public health and the environment.

5. Although the Committee expect similar types of ACVM controls will be imposed for the Flu Avert® I.N. vaccine, the Committee noted that the ACVM approval process will not be completed until after the HSNO Act approval process. Therefore, the Committee considered only HSNO Act controls in its consideration of Flu Avert® I.N. vaccine.

6. The Committee considered that if there are any inconsistencies between these controls and the controls imposed under the ACVM Act, a review (under section 38L) of the controls could be sought (control 1, Appendix 1 of this decision).

7. In accordance with clauses 21, 22 and 24 and section 38I, the Committee adopted the approach of first identifying and assessing any potentially significant adverse effects, with particular reference to the matters set out in section 38I (also covered by parts of clauses 9 and 10).

8. Also, the Committee considered the principles and matters relevant to the purpose of the Act as set out in sections 4, 5, 6 and 8. Identification and assessment of risk was in accordance with clause 12. Costs were assessed in accordance with clause 13.

9. In accordance with section 38I(4)(b), the Committee did not consider the effect of the Flu Avert® I.N. vaccine on the animal being treated with the vaccine.

10. The Committee considered the type of controls that may be imposed, including those listed in section 38K and imposed controls regarding the use, storage or disposal of the organism and, as referred to in section 38L, included a review requirement specifying the circumstances in which controls would be reviewed and the potential consequences of such a review. The controls imposed by the Committee are detailed in Appendix 1.

11. Section 7 and clauses 29 and 32 require the Committee to take into account the need for caution in managing adverse effects where there is scientific and technical uncertainty. The degree of uncertainty attached to the evidence was taken into account, as required by clauses 25, 29, 30 and 32.

12. The approach to the consideration followed the decision path as set out in the ERMA New Zealand publication “Decision Paths ERMA New Zealand Policy Series: Protocol 2”.

6. Application summary

1. MAF BNZ have applied to import for release Flu Avert® I.N. vaccine for use against equine influenza (EI) (an influenza A virus). The Flu Avert® I.N. vaccine contains a cold-adapted attenuated strain of equine influenza. MAF BNZ has stated that Flu Avert® I.N. vaccine may be used to help contain or prevent an outbreak of EI only once the disease is identified as being present in New Zealand and that pre-emptive vaccination using this vaccine is not currently considered an option.

7. Identification of the organism

Biological characteristics of influenza A

1. Influenza A (IA) belongs to the Family Orthomyxoviridae: Genus Influenzavirus A. IA viruses are single stranded RNA viruses. The genome consists of 8 separate segments which encode: Haemagglutinin (HA), Neuraminidase (NA), Polymerase A (PA), Polymerase B1 (PB1), Polymerase B2 (PB2), Nucleocapsid protein (NP), Matrix Protein (M1 and M2) and Non-structural protein (NS1 and NS2) (Gürtler, 2006; Webster et al, 1992).

2. Influenza virus strains are named for the influenza virus type, the location of initial virus isolation, the strain number, the year of isolation and the HA and NA serotype (eg A/Fujian/411/2002 (H3N2)). If the animal of origin of the virus is not human, this information is also included in the name for example, A/goose/Guangdong/1/96 (H5N1) (Werner and Harder, 2006; Gürtler, 2006).

3. IA strains are subtyped by the HA and NA proteins they contain. There are currently 16 HA (numbered H1-16) and 9 NA (numbered N1-9) subtypes (Werner and Harder, 2006). Each influenza virus contains one HA and one NA. HA and NA are the main antigenic determinants of influenza viruses.

4. HA is responsible for the binding of the virus to the target epithelial cell via specific sialic acid sugars on the cell surface and the entry of the viral genome into the cell (Gürtler, 2006; Werner and Harder, 2006). The HA subtype determines the host range of the virus.

5. NA is a glycosylated enzyme found on the surface of the influenza virus. NA enzyme activity facilitates the release of progeny viruses from infected cells by cleaving sugars that bind the mature viral particle to the host cell. NA is also thought to prevent viral aggregation and to assist the movement of the virus through the mucus layer of epithelial cells (Werner and Harder, 2006; Gürtler, 2006).

6. IAs are susceptible to antigenic drift and antigenic shift. Antigenic drift occurs when mutations occur at the antigenic (antibody binding) sites of HA or NA. When an infection occurs, the immune system produces neutralising antibodies against the virus strain. The appearance of viral strains that are mutated at the antigenic sites mean that antibodies which had been effective against the original viral strains are no longer effective and cannot prevent subsequent viral infections (Gürtler, 2006). Through antigenic drift, the host range, pathogenicity or infectivity of a virus may change.

7. Antigenic shift (or reassortment) is a rare event where different IA viruses exchange genetic segments during replication to form a new virus (Gürtler, 2006), for example a H1N1 and H2N2 virus could form a H1N2 or H2N1 virus through reassortment. Through antigenic shift, a virus may alter its host range, pathogenicity or infectivity.

Equine influenza (EI)

8. EI infects all species of the family Equidae which includes horses, donkeys, mules and zebras (Animal Health Australia, 2007). In this document, where the term “horse” is used, this includes all species of the family Equidae.

9. EI is endemic in Europe (except Iceland), North and South America, North Africa and Asia with Australia currently experiencing its first EI epidemic (Animal Health Australia, 2007). No cases of EI have been recorded in New Zealand to date.

10. EI has two main subtypes H7N7 (Equine-1) and H3N8 (Equine-2). The H7N7 subtype is not used in EI vaccines as it is not currently in circulation. (Paillot et al, 2006; Naylor, 2004; Daly et al, 2004).

11. EI is highly contagious. The virus infects and replicates in the ciliated cells of the upper and lower respiratory tract. The clinical signs of EI include a sudden increase in temperature (39-41°C), a deep dry hacking cough, a watery nasal discharge that may become mucopurulent (composed of mucus and pus), depression, loss of appetite, laboured breathing, muscle pain and stiffness (Animal Health Australia, 2007; Paillot et al, 2006).

12. The incubation period for EI is 1-3 days. The largest number of viral particles are shed in the early stages of infection when coughing is most pronounced. In naïve horses, virus is secreted for 7-10 days. (Animal Health Australia, 2007; Paillot et al, 2006). Horses in good health can recover from EI within 10 days although coughing may persist for longer.

13. The overall mortality rate of EI is between 1-8% with relatively high mortality observed in foals, animals in poor health and donkeys (Naylor, 2004). Death of adult horses as a result of EI is normally due to bacterial infections (Animal Health Australia, 2007). Infection results in the deciliation of large areas of the respiratory tract. This compromises the mucociliary clearance mechanism making the animal more susceptible to bacterial infections (Animal Health Australia, 2007; Paillot et al, 2006). There is no carrier state for EI (Animal Health Australia, 2007).

14. Horses have no innate immunity to EI and vaccination is used to limit the severity of disease in infected animals (Animal Health Australia, 2007).

15. The Committee noted that although the mutation rate for EI H3N8 (calculated at 2.5 nucleotide substitutions per year (0.8 amino acids per year)) (Daly et al, 1996) is slower that that of human influenza (7.9 nucleotide substitutions per year (3.4 amino acids per year)) (Bean et al, 1992), as a consequence of the mutation rate, it is necessary to periodically update the vaccine strains to reflect the circulating EI strains (Minke et al, 2004).

Flu Avert® I.N vaccine

16. The following describes the process used to produce the vaccine virus present in Flu Avert® I.N. vaccine.

17. Flu Avert® I.N. vaccine contains a cold-adapted EI virus derived from strain A/equine/Kentucky/1/91 (H3N8). The Committee noted that cold adaptation is considered to be a reliable technique to attenuate IA viruses (Maassab and Bryant, 1999).

18. The Committee noted that the gradual cold adaptation of a virus provides selective pressure favouring mutant viruses with cold-adapted and temperature-sensitive phenotypes. It is proposed that when viruses are grown in decreasing temperatures, there is reduced pressure for the virus to maintain heat stable proteins, this results in the temperature-sensitive phenotype. In addition, the use of hosts, other than the natural host of the virus, to produce the cold-adapted strain creates selective pressure that leads to the attenuation of viruses (Youngner et al, 2001).

19. The EI strain A/equine/Kentucky/1/91 (H3N8) was selected, to create the cold-adapted EI strain present in the Flu Avert® I.N. vaccine, due to its ability to reliably infect horses. The virus was subjected to repeated passage in embryonated chicken eggs at gradually reduced temperatures (34oC, 30oC, 28oC and 26oC) to select viruses with a cold-adapted and attenuated phenotype (Youngner et al, 2001).

20. Ten cold-adapted clones were then tested for stability by serial passage in cell lines and embryonated eggs at 34oC. It was shown that all clones were stable and clone P821 was chosen for further analysis. It was proposed that the stability of the clones was likely due to the stepwise selection of cold-adapted virus with multiple mutations, and that these multiple mutations would reduce the probability of reversion of the virus. It was shown that unlike the parental virus, P821 could not efficiently replicate at 39.5oC. Clone P821 was deemed to be sufficiently attenuated and was chosen as the basis of the Flu Avert® I.N. vaccine (Youngner et al, 2001). Cold-adapted viruses are suited to growing in the cooler upper respiratory tract, while replicating poorly or not at all in the lower respiratory tract.

21. As the EI virus in Flu Avert® I.N. vaccine was produced by serial passage at progressively lower temperatures, the Committee considers that this protocol does not fall under the definition of genetic modification under the Act.

Dose and administration of Flu Avert® I.N vaccine

22. The Committee noted that the dose and route of administration of Flu Avert® I.N. vaccine is described in the Flu Avert® I.N. vaccine instructions for the intranasal administration of the vaccine (called the “product label”) (Intervet, no date). The document describes how the lyophilized vaccine is to be mixed with sterile diluent prior to use and how the vaccine is to be administered intranasally. It is stated that this vaccine is to be used for horses over 11 months of age and is not to be given to pregnant horses.

23. The Committee also noted that the Flu Avert® I.N. vaccine Material Safety and Data Sheet (MSDS) (Intervet, 2003) lists handling and storage requirements and describes what should be done if the vaccine is spilled. For example, the vaccine is to be kept refrigerated, with containers to be protected from damage (point 7 in the MSDS) and if there is a spill of the vaccine, the spill should be sprayed with a mild disinfectant such as bleach, absorbent material should be used to wipe up the spill and this material placed in a secure container for disposal (point 6). In addition, veterinarians are instructed to wear splash protective eyewear, chemical resistant gloves, impervious long-sleeves and trousers when administering the vaccine (point 8) and to wash their hands after handling the live virus (point 3). It is also stated that pregnant women should not work with live virus (point 3).

24. The Committee noted that at the dose and route of administration used for Flu Avert® I.N. vaccine, the efficacy of the Flu Avert® I.N. vaccine has been evaluated. It has been shown that six months after a single dose of Flu Avert® I.N. vaccine, significant clinical protection with decreased concentration and duration of virus shed were observed when these animals were exposed to an abnormally large dose of wild type EI virus. In addition, when animals (12 months post-vaccination) were exposed to wild type EI virus, lower rectal temperatures, lower quantities of viral isolate and shorter duration of viral shedding were also observed (Townsend et al, 2001). As the post-vaccination trials were performed using an abnormally high dose of influenza, the protection against a natural EI infection may be expected to be better. The Committee noted that there is no information available on the potential effect this vaccine may have on a naïve horse population (horses that have not previously been exposed to EI).

8. Ability to form an undesirable self-sustaining population

1. In accordance with section 38I(3)(b) and clauses 10(e) and (f), the Committee firstly considered whether a self-sustaining population would be undesirable (sections 8.2 - 8.4 of this decision), and then considered the ability of the organism to form an undesirable self-sustaining population and the pathways by which a self-sustaining population could form. During the consideration of these pathways, the Committee imposed controls to prevent the formation of a self-sustaining population (sections 8.5 - 8.74 of this decision).

Undesirability of a self-sustaining population

2. The Committee first considered whether a self-sustaining population would be undesirable. In this consideration, the Committee noted the following points. Within a contained small group of horses (ie on a farm), the limited transfer of a vaccine virus from one animal to another may result in a low level infection and the “vaccination” of the recipient animals. However, the uncontrolled spread of the vaccine virus (even though it is an attenuated version of the virus) into the larger horse population of New Zealand cannot be desirable for the reasons discussed below (section 8.4 of this decision).

3. The Committee noted that EI has only a limited survival outside a host organism, with EI shown to persist in horse blood for 18 hours, horse urine for 5-6 days, in soil for 24 hour in the dark and 8 hours in sunlight and in water for up to 18 days (Animal Health Australia, 2007).

4. As previously noted in section 7.15 of this decision, the mutation rate for EI H3N8 was calculated at 0.8 amino acids per year (Daly et al, 1996). Therefore, due to the rapid mutation rate of the EI virus and the ability to exchange genetic material with other viruses, the spread of the vaccine virus through a population (ie formation of a self-sustaining population) would significantly increase the opportunities for mutations or reassortments to occur which could enhance the pathogenicity, virulence or infectivity of the vaccine virus (sections 7.6 – 7.7 of this decision). Such an event could have adverse effects on the health and safety of the public, on valued species, natural habitats or the environment. Therefore, the Committee considered that a self-sustaining population of Flu Avert® I.N. vaccine virus would be undesirable.

5. As the Committee considered that a self-sustaining population of Flu Avert® I.N. vaccine virus would be undesirable, the Committee has imposed controls to prevent the formation of a self-sustaining population. To do this, the Committee first identified the pathways by which Flu Avert® I.N. vaccine virus could form a self-sustaining population and then imposed controls to prevent the formation of a self-sustaining population (sections 8.8 - 8.74 of this decision).

6. To form a self-sustaining population, the Committee considered that the attenuated vaccine virus would first need to escape from a vaccinated horse or the vaccine vial and find a compatible host organism and/ or lose its attenuation or cold adaptation. The vaccine virus would then need to replicate in the new host, this animal would need to cough or sneeze and produce an infective dose of viral particles to subsequently infect another animal and so on.

7. The Committee considered the following pathways by which a self-sustaining population could form. The Committee set controls regarding the use, storage and disposal of the organism and included a review requirement which specified the circumstances under which the controls would be reviewed (control 1).

Potential pathways of escape

8. The Committee identified and considered the following pathways of “escape” for Flu Avert® I.N. vaccine virus:

• Escape of Flu Avert® I.N. vaccine virus from the vaccinated horse directly to unvaccinated horses.

• Escape of Flu Avert® I.N. vaccine virus from the vaccinated horses directly to other animals including humans.

• Escape of Flu Avert® I.N. vaccine virus from vaccinated horses indirectly through handlers or equipment to horses or other animals.

• Escape of Flu Avert® I.N. vaccine virus through incorrect use, storage, transport and disposal of the vaccine.

• Escape of the Flu Avert® I.N. vaccine virus by the virus becoming more infectious, virulent or pathogenic by reassorting with an existing virus (through antigenic shift).

• Escape of the Flu Avert® I.N. vaccine virus by the virus becoming more infectious, virulent or pathogenic by mutation (through antigenic drift).

Escape of Flu Avert® I.N vaccine virus from vaccinated horses directly to unvaccinated horses (spontaneous spread)

9. The Committee considered the potential of the Flu Avert® I.N. vaccine virus to be transmitted from vaccinated horses directly to unvaccinated horses through spontaneous spread.

10. The primary mode of transmission for EI is aerosols that are produced from a virus-laden cough (Animal Health Australia, 2007). An infected coughing horse has been observed to spread the EI virus over 35 metres and it is possible that this spread could be even further under favourable weather conditions (Animal Health Australia, 2007).

11. While EI is mainly transmitted via aerosolisation and direct inhalation, transmission can also occur via direct transfer of nasal secretions between horses and by fomites (inanimate objects capable of carrying infectious particles) (Naylor, 2004). Disease transmission by vectors such as insects and rodents is considered not to occur, and the transfer of EI from human nasal secretions to horses has never been reported in field outbreaks (Animal Health Australia, 2007).

12. A field safety trial of Flu Avert® I.N. vaccine involving 435 horses ranging from 3 months to 30 years of age looked at any adverse reactions to the vaccine from within a few hours of vaccination, to up to one week. This study showed that the vaccine applicator (supplied with the vaccine) administered the vaccine directly to the ventral nasal meatus. After vaccine administration, the horses showed a typical phlegmon response (the curling the upper lip and elevating or outstretching the head or neck). It was considered that this phlegmon response helped to retain the vaccine in the nose. In some horses it was found that a small amount of vaccine dripped from the nostril where the vaccine was administered. Over the seven study sites, it was found that a small proportion of the horses showed a nasal discharge (5.1%), an ocular discharge (0.7%) or a cough (0.5%). The nasal discharge was serous (clear watery fluid), scant, transient in nature (within 24-48 hours after administration), and only in the nostril to which the vaccine was administered (Wilson and Robinson, 2000).

13. Another study showed that after the vaccination of 8 horses, no overt signs of disease were detected. Nasopharyngeal swabs were taken daily for 11 days post-vaccination and it was found that virus was detected for at least 7 days and up to 10 days post-vaccination (Youngner et al, 2001). In addition, in nasal secretions isolated from vaccinated animals, virus was found to be present up to 1-7 days post-vaccination (Lunn et al, 2001).

14. Studies which looked at the spontaneous spread of the Flu Avert® I.N. vaccine virus within a group of horses showed that the virus spread to only one of 13 non-vaccinated horses when they were kept in the same field as 39 vaccinated horses and shared a water fixture. As wild type EI spreads easily to horses via aerosol transmission, this reduced ability to spread was attributed to the fact that highly efficient viral replication does not occur after vaccination with Flu Avert® I.N. vaccine and that vaccinated animals do not cough (Chambers et al, 2001).

15. In addition, it was shown that when the vaccine virus was forcibly passaged from horse to horse, it was difficult to spread the vaccine virus over more than one passage. A trend of reduced shedding was observed with each passage and the virus failed to replicate in two out of five horses in the final passage group (Chambers et al, 2001).

16. The Committee considered that, due to the attenuated nature of the vaccine, although vaccinated animals can shed virus (as observed by nasal swabs), only a very limited number of horses had either a transient nasal discharge or cough and this dramatically reduced the chances of the spread of an infectious dose of the vaccine virus.

17. However, the effects of this vaccine on a naïve population of horses have not been investigated (for example will greater nasal discharges or coughing occur after vaccination of naïve horses?), and therefore, to provide assurance that a self-sustaining population of the vaccine virus will not form, the Committee imposed the following controls.

18. The Committee noted that the information used to evaluate this vaccine and impose controls is based on the Flu Avert® I.N. vaccine being used at the specified dose and route of administration. Therefore, to ensure that the vaccine is administered at the correct dose and route of administration, control 6.3 states that Flu Avert® I.N. vaccine is to be administered as per the intranasal dose listed in the Flu Avert® I.N. vaccine product label (Intervet, no date).

19. The Committee noted that the vaccine virus can be shed for up to 10 days post-vaccination (Youngner et al, 2001; Lunn et al, 2001). But the Committee noted that a minimum 14 day quarantine period within a registered transitional facility is required for an imported horse (MAF BNZ, 2007). Therefore, to prevent the vaccine virus being passed to unvaccinated horses, control 6.5 states that that vaccinated horses are to be isolated from unvaccinated horses for the 14 day post-vaccination period. The Committee noted that in the submission from DOC it was suggested that vaccinated horses could be given cough medicine to prevent the potential spread of the vaccine virus. The Committee considered that control 6.5, which requires the isolation of vaccinated horses from unvaccinated horses, will be sufficient to prevent spread by coughing.

20. The Committee considered how compliance of the controls could be achieved. The Committee believed that a register requiring a list of animals that have been vaccinated and proof that the vaccinated horses were isolated from unvaccinated horses for the 14 day post-vaccination period (for example signed statements from the veterinarians or horse owners) (control 7) should be maintained. This register is to be made available for compliance purposes (control 7). The Committee consider that it would be appropriate for MAF BNZ (or an organisation approved by MAF BNZ) to maintain such a register.

21. A concern with the use of a live vaccine is that within immunocompromised animals, the vaccine virus could result in a disease causing infection, with the resulting horse becoming highly infectious therefore allowing the easy spread of the vaccine virus. But research using the Flu Avert® I.N. vaccine has found that there are no significant differences in the clinical responses between vaccinated immunosuppressed and non-suppressed animals suggesting that administration of this vaccine to immunosuppressed animals is safe (Lunn et al, 2001).

22. The Committee considered that with the controls in place, it is highly improbable that a self-sustaining population of the Flu Avert® I.N. vaccine virus will form through the transfer of Flu Avert® I.N. vaccine virus from the vaccinated horses directly to other horses by spontaneous spread.

Escape of Flu Avert® I.N vaccine virus from vaccinated horses directly to other animals including humans (spontaneous spread)

23. The Committee considered the spread of the vaccine virus from recently vaccinated horses to other animals including humans (excluding horses).

24. As previously noted in section 7.4 of this decision, the HA subtype determines the host range of the virus. As a result, IA viruses are typically species-specific. However, very rarely IA can mutate and acquire specificity for another species. For example avian H5N1 has recently expanded its host range to infect humans and domestic cats more readily (Kamps and Reyes-Terán, 2006; Behrens and Stoll, 2006).

25. The Committee noted that EI viruses preferentially bind to the carbohydrate residues (N-glycolylneuraminic acid (NeuGc) α2,3 Gal moieties) found on horse tracheal epithelial cells. In contrast, human influenza A preferentially binds to the carbohydrate residues that are found on human tracheal cells (NeuAc α2,6 Gal moieties) (Suzuki et al, 2000). The Committee noted that specific mutations in avian influenza viruses can significantly alter receptor specificity and allow binding to human cells (Gambaryan et al, 2006).

26. The Committee noted that while the experimental infection of humans with EI produced mild influenza-like symptoms, the natural transmission of EI from infected horses to humans has yet to be reported (Animal Health Australia, 2007). Therefore, changes in the binding specificities of EI would need to occur (either thorough antigenic shift or antigenic drift) to allow EI to cause infections in humans.

27. The Committee considered whether dogs could be potential hosts for the vaccine virus, noting that transmission of influenza from horses to dogs was observed in racing greyhounds in January 2004. Investigations showed that this disease had >96% sequence identity to EI H3N8. It was proposed that a single transmission event occurred to spread EI from horses to dogs and then the adapted virus (which was mutated at specific HA amino acids) spread horizontally between dogs (Crawford et al, 2005). It is now believed that the virus was spread to the dogs through the consumption of contaminated raw horse meat (Animal Health Australia, 2007).

28. The Committee considered whether birds could be potential hosts for the vaccine virus. A virus that was closely related to avian H3N8 was detected in horses during a disease outbreak in China in 1989. This virus was unable to replicate in birds but could replicate and cause disease or death in mice and ferrets. There is no evidence that birds are susceptible to this strain of EI (Guo et al, 1992).

29. Therefore, the Committee considered that the Flu Avert® I.N. vaccine virus would need to mutate (through antigenic drift or shift) for non-horses to become host organisms. As described in section 8.4 of this decision, the Committee considered that the formation of a self-sustaining population of the Flu Avert® I.N. vaccine virus would significantly increase the opportunity for mutations to occur in the vaccine virus.

30. As described in section 8.12, as only a small proportion of the vaccinated horses show a transient nasal discharge, an ocular discharge or a cough (Wilson and Robinson, 2000) this reduces the opportunity for spread of the vaccine virus to other animals.

31. However, to provide assurance that the spread of the vaccine virus to dogs will not occur, the Committee imposed control 6.7 which restricts the access of dogs to recently vaccinated animals (within the 14 day post-vaccination period).

32. The Committee noted the previously documented outbreak of canine influenza may have occurred through the consumption of contaminated raw horse meat (section 8.27 of this decision). Therefore, to provide assurance that such an event would not occur, control 6.8 was imposed which states that for a period of 14 days post-vaccination, horse products such as raw meat and bones (excluding urine and faeces) from a vaccinated horse will not be consumed. The Committee noted that DOC supported such a control.

33. The Committee considered that with the controls in place, it is highly improbable that a self-sustaining population of the Flu Avert® I.N. vaccine virus will form through the transfer of Flu Avert® I.N. vaccine virus from the vaccinated horses directly to other animals.

Escape of Flu Avert® I.N vaccine virus from vaccinated horses indirectly through handlers or equipment to other horses or other animals

34. The Committee noted that contaminated transport vehicles, equipment and people who have close contact with horses (such as grooms and veterinarians) are all potential means of transferring EI between premises (Animal Health Australia, 2007).

35. The Committee considered the indirect spread of the vaccine virus through personnel handling recently vaccinated horses to unvaccinated horses or other animals or from contaminated equipment.

36. The Committee noted that the IA virus can survive for 24-48 hours on hard non-porous surfaces, from ................
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