Protecting our way of life | EPA



FORM NO1Q

Application for approval to

RELEASE A QUALIFYING ORGANISM(S)

BY RAPID ASSESSMENT

under section 38I of the

Hazardous Substances and New Organisms Act 1996

Application Title: FluAvert® I.N. (Intranasal) live modified equine influenza vaccine

Applicant Organisation: Ministry of Agriculture and Forestry Biosecurity New Zealand

|ERMA Office use only |

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|Application Code: [pic] Formally received:____/____/____ |

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|ERMA NZ Contact: Initial Fee Paid: $ |

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|Application Status: |

IMPORTANT

1. An associated User Guide is available for this form on the ERMA website. If you need further guidance in completing this form please contact ERMA New Zealand.

2. This application form only covers applications for approval by rapid assessment to import for release or to release from containment qualifying organisms. A qualifying organism is a new organism (including a genetically modified organism) that is contained in a medicine or veterinary medicine.

3. This form replaces all previous versions of Form NO1Q. Older versions will not be accepted. You should check with ERMA New Zealand or the ERMA New Zealand website for the most up-to-date version of this form.

4. You can talk to either an Applications Advisor at ERMA New Zealand who can help you scope and prepare your application. We need all relevant information early on in the application process. Quality information up front will speed up the process and help reduce costs.

5. This application form may be used to seek approvals for more than one new organism where the organisms are of a similar nature.

6. Any extra material that does not fit in the application form must be clearly labelled, cross-referenced, and included as appendices to the application form.

7. Commercially sensitive information must be collated in a separate appendix. You need to justify why you consider the material commercially sensitive, and make sure it is clearly labelled as such.

8. Applicants must sign the form and enclose the correct application fee (plus GST). The initial application fee can be found in our published Schedule of Fees and Charges. Please check with ERMA New Zealand staff or the ERMA New Zealand website for the latest schedule of fees. We are unable to process applications that do not contain the correct initial application fee.

9. Unless otherwise indicated, all sections of this form must be completed for the application to be progressed.

10. Please provide an electronic version of the completed application form, as well as sending a signed hard copy. We cannot begin processing your application until we have received payment of the application fee and a signed hard copy of the application form.

11. You can get more information by contacting ERMA New Zealand, the Ministry of Health or MAF Agricultural Compounds and Veterinary Medicines Group (ACVM). One of our staff members will be able to help you.

This application form was approved by the Chief Executive of ERMA New Zealand on 2 June 2004.

If you need further information, one of our Application Advisors will be able to help you. Please contact:

|ERMA New Zealand |

|20 Customhouse Quay |

|PO Box 131 |

|Wellington |

|New Zealand |

|Telephone: 64-4-916-2426 |

|Facsimile: 64-4-914-0433 |

|E-mail: info@t.nz, t.nz |

Section One – Applicant Details

1.1 Name and postal address in New Zealand of the organisation or private individual making the application:

Name > MAF Biosecurity New Zealand

Postal Address > PO Box 2526, Wellington

Physical Address > Pastoral House, 25 The Terrace, Wellington

Phone > 04 894 0299

Fax > 04 894 0735

E-mail >

1.2 If application is made by an organisation, provide name and contact details of a key contact person at that organisation

This person should have sufficient knowledge to respond to queries and have the authority to make decisions that relate to processing of the application.

Name > Dr Brendan Pollard

Position > Senior Adviser

Address > Pastoral House, 25 The Terrace, Wellington

Phone > 04 894 0299

Fax > 04 894 0735

E-mail > brendan.pollard@t.nz

1.3 If the applicant is an organisation or individual situated overseas, provide the name and contact details of the agent authorised to transact the applicant’s affairs in relation to the application

This person should have sufficient knowledge to respond to queries and have the authority to make decisions that relate to processing of the application.

Name > Not applicable

Position >

Address >

Phone >

Fax >

E-mail >

Section Two – Purpose of the Application

This form is to be used for an application to import for release or release from containment qualifying organisms under section 38I of the HSNO Act. If a qualifying organism is not approved by rapid assessment under section 38I of the Act, then it must be fully assessed under section 38.

2.1 Give a short summary statement of the purpose of this application to be used on ERMA New Zealand’s public register (Maximum of 255 characters including spaces and punctuation marks). What medical or veterinary purpose will these organisms be used for?

> To release FluAvert® I.N., an intranasal vaccine to be used to prevent or combat an outbreak or in vaccination programmes against equine influenza

2.2 Provide a short description of the background and aims of the medicine or veterinary medicine suitable for lay readers.

Describe the rationale for the overall purpose and use of these organisms so that people not directly connected with the prescription or use of the qualifying organism can understand why they are required. This explanation is particularly important if the qualifying organisms have been genetically modified, and especially if DNA from native flora and fauna, or human genes have been inserted into the organism.

> Equine influenza (EI) is a disease of the respiratory system of horses caused by an Influenza A virus. This disease is highly contagious and can be debilitating to horses.

Until August 2007, New Zealand and Australia were the only countries in the world with a significant number of breeding and working horses as free of equine influenza. This allowed for the free movement of horses between New Zealand and Australia as well as to other destinations.

The presence of the disease in Australia has resulted in the prevention of all horse movements in the affected areas of Australia as well as all movement of horses from Australia to New Zealand. This has resulted in a significant effect on people working for the horse industry as well as cancellation of race meetings, shows, club meetings and breeding programmes in Australia. There has also been a direct effect on the associated gambling industries. All of these have had significant financial and economic implications, many of which are already affecting New Zealand. If an outbreak was to occur in New Zealand these effects would become far worse. A strategy for the prevention of infection or the containment and eradication of the disease should it occur would thus be of great benefit to the economic and social wellbeing of New Zealand.

The current equine influenza vaccines available in New Zealand are killed vaccines Equilis Prequenza and Equip F. Both of these vaccines are currently registered only for use in an emergency. Another dead vaccine, Fluvac Innovator 4, is registered for use only in export horses in a containment facility. However, horses vaccinated overseas, with vaccines registered into the country of origin, are regularly imported into New Zealand. There is evidence that the existing inactivated vaccines may not induce the appropriate spectrum of immune responses as rapidly and provide shorter duration of immunity, therefore requiring multiple doses of the vaccine.

Therefore we propose to import FluAvert® I.N. vaccine for release. This vaccine is registered in the United States in 1999 and Canada in 2001and has been used extensively there.

The FluAvert® I.N. vaccine is a cold adapted attenuated live strain of equine influenza A virus which means that it is only able to multiply in the cooler environment of the nose and the sinuses and is unable to multiply in the lungs or rest of the body where the temperature is higher. This vaccine stimulates the immune system but causes either no symptoms or only very mild symptoms of the disease. A single dose of FluAvert® I.N. vaccine can produce a rapid onset of immunity which can last 6 months.

This vaccine has a good safety record and to date there have been no field reports of suspected reversion to virulence, severe side effects or any mortality. Five stage backpassage trials also showed no evidence of reversion.

This vaccine may be used as part of a programme to combat an outbreak of equine influenza or to prevent or reduce the risk of the disease becoming established in New Zealand.

Initially vaccination would not be used as a control mechanism until the presence of equine influenza had been confirmed (ie a large scale pre-emptive vaccination before the disease is confirmed is not currently being considered as an option for this vaccine).

Vaccination of a large percentage of the New Zealand horse population may need to be considered if called for the New Zealand equine owning stakeholders but is beyond the scope of this application.

Section Three – Information on the Organism(s) to be used

If more than one type of qualifying organism is to be imported or released, this section must be completed separately for each organism. If there are commercial reasons for not providing full information here alternative approaches must be discussed with and agreed by ERMA New Zealand.

3.1 Provide unique name(s) for the new organism(s) that can be used on the public register.

(Maximum 100 characters). For example, “Live attenuated SARS coronavirus vaccine 575-G” or “Vibrio cholerae CVD 103-HgR”.

> FluAvert® I.N. live, attenuated, cold adapted equine influenza (H3N8) vaccine

3.2 Is the new organism genetically modified? No

For non-genetically modified organisms, complete sections 3.2 and 3.4 (do not fill out section 3.3). For genetically modified organisms complete sections 3.2, 3.3 and 3.4.

3.3 Give the unequivocal identification of the new organism or host organism (if the organism is genetically modified)

Please include details on the following:

Latin binomial, including full taxonomic authority and taxonomic class, order and family:

> Influenza A/Equine/2/Kentucky/1/91/ H3N8 (Lamb & Krug, 2001)

Viruses; ssRNA viruses; ssRNA negative-strand viruses; Orthomyxoviridae; InfluenzavirusA

Common name(s), if any:

> Influenza A virus

Type of organism (eg bacterium, virus, fungus, plant, animal, animal cell):

>Virus

Strain(s) if relevant:

> Strain H3N8 Influenza A/Equine/2/Kentucky/1/91/ (Lamb & Krug, 2001)

Other information, including presence of any inseparable or associated organisms, and whether a prohibited organism is involved:

>EI is an Unwanted and Notifiable organism Not applicable

3.4 Details of the genetic modification if the qualifying organism is genetically modified

How was the organism developed? Please attach any experimental data and information relating to how the genetically modified organism was developed to the application. Also provide details of the following:

Identify the category or categories of experiment(s) as described in the HSNO (Low-Risk Genetic Modification) Regulations 2003.

Identify the specific class of experiment(s) (eg Category A genetic modification of a Category 1 host organism) and explain your characterisation.

> Not applicable as the vaccine is not genetically modified.

Vector system(s):

> Not applicable as the vaccine is not genetically modified.

Type and source of additional genetic material:

> Not applicable as the vaccine is not genetically modified.

Use of special genetic material: please complete this table by marking the correct box

Not applicable as the vaccine is not genetically modified

| |Yes |No |

|Does this application use native flora or fauna as host organism(s)? If Yes, provide additional | | |

|details below. | | |

|Does this application use genetic material from native flora and fauna? If Yes, provide additional | | |

|details below. | | |

|If native flora and fauna are involved, are the species concerned endemic to New Zealand? | | |

|Does this application involve human cell lines? Answer Yes if human cell lines in any form are used,| | |

|ie obtained directly from humans (either Māori or non-Māori) or from a commercial supplier etc. | | |

|Please provide additional details below. | | |

|Does this application use cell lines obtained directly from human beings? | | |

|Does this application involve human genetic material? Answer Yes if human genetic material in any | | |

|form is used, ie obtained directly from humans (either Māori or non-Māori), from a gene bank, | | |

|synthesised, copied and so on. Please provide additional details below. | | |

|Does this application use genetic material obtained directly from human beings? | | |

If native flora and fauna are involved, from where in New Zealand or elsewhere was this material obtained? Be as specific as possible as this information will be needed to decide whether Māori have been appropriately involved.

> Not applicable as the vaccine is not genetically modified.

If genetic material or cells are derived from humans provide details of where the material was obtained from, and whether approval was obtained from an Ethics Committee, and/or consultation with Māori has taken place.

>Not applicable as the vaccine is not genetically modified.

Other relevant details of the development of the organism (such as what techniques or experimental procedures were used, if any unusual manipulations were carried out, and if the foreign genetic material is expressed):

>Not applicable as the vaccine is not genetically modified.

3.5 Characteristics of the qualifying organism(s).

Provide information on the main features or essential characteristics of the new organism(s). For genetically modified organisms you should note characteristics of the host organism as well as any new characteristics introduced by the genetic modifications. For example, note pathogenicity, production of spores/cysts, conditions for growth and reproduction. This information should be relevant to the identification of the risks of the organism (sections 4.1 and 4.2).

Background on Influenza

Influenza viruses are enveloped, single-stranded RNA viruses. Two of the RNA segments encode the envelope glycoproteins, hemagglutinin (HA) and neuraminidase (NA). HA and NA are important for pathogenicity and are the main antigenic determinants of influenza.

Influenza viruses are highly infectious and can evade the immune system through antigenic drift and antigenic shift. Antigenic drift occurs due to point mutations that result in changes in the amino acid sequence in the HA and NA glycoproteins. Rapid evolution can occur through antigenic shift when one cell is infected with more than one influenza virus. The viruses can exchange RNA segments and form new reassortments viruses containing a combination of gene segments derived from the parental virus strains (Centre for Disease Control, No Date).

While influenza viruses can infect a wide variety of species, host cellular receptor specificity determines host species restriction. For example, avian and equine influenza strains preferentially bind to sialic acid residues linked to galactose by an α-2,3 linkage, as found in specific avian (Werner and Harder, 2006) and equine cells (Suzuki et al, 2000).

Transmission of influenza virus can occur either by direct contact, or indirectly via contaminated aerosols, water, feed and other materials. Aerosols do not remain suspended in the air and therefore close contact (up to 1-2 metres) is required for transmission of human viruses to other individuals (Kamps and Reyes-Terán, 2006).

Influenza viruses can cause a spectrum of disease ranging from asymptomatic infection, or mild respiratory illness, through to severe and rapidly fatal systemic failure.

Background on Equine influenza

Equine influenza (EI) is not known to infect humans or other non-equid mammals. EI has two main subtypes H7N7 (Equine-1) and H3N8 (Equine-2). The currently circulating EI strain is H3N8; H7N7 has not been isolated from horses since prior to 1980 (Naylor, 2004; Daly et al, 2004).

EI is highly contagious, with an incubation period of 1-3 days. Clinical signs include a high fever, a deep dry cough (sometimes severe), serous to mucopurulent nasal discharge fever, cough and nasal discharge lasting for about 10 days (Naylor, 2004). Other symptoms include depression, myalgia (muscle soreness), anorexia (weight loss), photophobia (light sensitivity), corneal opacity (clouding of the eyes) and enlarged regional lymph nodes (swelling of glands). Spasmodic impaction colic causing abdominal pain and oedema (swelling due to fluid accumulation) of the legs and scrotum have also been observed.

FluAvert ® I.N. vaccine ()

FluAvert® I.N. vaccine has been approved by the USDA since 1999 (Heska Corporation, 1999) and approved by the Canadian Food Inspection Agency since September 2001 (Heska Corporation, 2001).

Production of cold adapted attenuated vaccines

FluAvert® I.N. vaccine is a live attenuated cold adapted virus with replication restricted to the upper respiratory tract. After immunisation, the vaccine replicates in the horses nasal mucosa stimulating a rapid local immune response. Unlike clinical EI, this vaccine has very low pathogenicity and causes no or very mild upper respiratory symptoms. This cold adapted vaccine was developed through serial passage at progressively cooler temperatures from 34oC to 26oC. The resultant virus, unlike the EI disease-causing virus, is not able to replicate at 39.5oC (Younger, 2001).

We note that cold adapted vaccines (for humans) have been available in the US since 2003 (Korsman, 2006).

Safety of FluAvert® I.N. vaccine

FluAvert ® I.N. vaccine has been subjected to a rapid risk assessment by MAF BNZ. A number of biosecurity risks have been identified including reversion to virulence, potential for vaccine to be contaminated with adventitious agents and potential for reassortment with other influenza A viruses. We note that:

• Reversion to virulence of the FluAvert ® I.N. vaccine was not demonstrated in a five backpassage study and satisfied the safety requirements for registration in the USA and Canada (Chambers et al, 2001).

• There is no specific information about the possible generation of vaccine strain/ fieldstrain recombinants in horses vaccinated with FluAvert® I.N. vaccine. Since reassortment is known to occur with influenza viruses this is a theoretical possibility but would be hard to detect under field conditions and the relevance of the recombinants developed in a population of horses already infected with a field strain is questionable.

Results of various safety trials of FluAvert® I.N. vaccine

Information about the safety trials for the FluAvert® I.N. vaccine is listed on the Intervet website . This information is also found in the peer-reviewed papers (Chambers et al, 2001, Lunn et al, 2001, Holland et al, 1999).

A field safety trial of FluAvert® I.N. involving 435 horses ranging from 3 months to 30 years of age (including pregnant animals) was performed (Wilson and Robinson, 2000). This study showed that only a small proportion of the horses showed nasal discharge (5.1%), ocular discharge (0.7%) or coughing (0.5%). The nasal discharge was transient in nature and only occurred within 24-48 hours after administration.

Also in separate studies:

• Nasal secretions were isolated from animals vaccinated with FluAvert ® I.N. vaccine and it was found that virus was present from 1-7 days post vaccination (Lunn et al, 2001).

• No overt signs of disease were detected in vaccinated animals. The vaccine virus was shown to be shed for up to 10 days post-vaccination (Youngner et al, 2001).

Chambers et al (2001) showed that vaccine spread to only one of 13 unvaccinated horses when they were maintained in a field with vaccinated horses and proposed that the lack of efficient viral replication and clinical signs of disease such as coughing reduces the efficiency of spread to non-vaccinated horses.

No safety issues have been identified regarding exposure of humans or other non-equid mammals to the vaccine virus.

Efficacy of FluAvert® I.N. vaccine

Six months after a single dose of FluAvert® I.N. vaccine, significant clinical protection and decreased concentration and duration of virus shed were observed among animals that were challenged with wild type EI virus. Even 12 months post vaccination, decreased amounts of virus was isolated and shorter duration of viral shedding was also observed after a challenge with wild type EI virus (Townsend et al, 2001). As the post-vaccination trials were performed using a very severe challenge, protection against a natural EI infection could be expected to be better still.

Evidence that FluAvert® I.N. vaccine does not revert from a cold adapted vaccine to a more virulent one

There is evidence that FluAvert® I.N. vaccine will not revert from a cold adapted attenuated state to a more virulent form for the following reasons:

• This cold-adapted vaccine has been serially passaged through 5 groups of horses to determine the stability of this vaccine strain and in this study no reversion was detected (Chambers et al, 2001).

• A concern is that the administration of a live vaccine to an immunosuppressed animal may result in a major infection which could result in a horse which is more infectious or more likely to produce a mutated virus that is more virulent. In a study that looked at the safety, efficacy and immunogenicity of FluAvert ® I.N. vaccine in horses that were immunosuppressed, it was found that there were no significant differences in the clinical responses between immunosuppressed and non-suppressed animals suggesting that administration of this vaccine to immunosuppressed animals is safe (Lunn et al, 2001).

This vaccine has been approved since 1999 and we can find no evidence of reversion of this vaccine to a more pathogenic or virulent form.

The chemical composition of FluAvert® I.N. vaccine

FluAvert® I.N. vaccine does not fall under the criteria of a hazardous substance under the HSNO Act.

3.5 Provide details of the doses and routes of administration of the qualifying organisms

FluAvert® I.N. vaccine is supplied as individual doses containing a minimum of 107.2 TCID50 to be mixed with 1 mL of sterile diluent supplied and introduced into the nasal cavity using the supplied nasal applicator.

The dose and administration of FluAvert® I.N. vaccine is described in the FluAvert® I.N. vaccine product insert (Appendix1)

The directions for use according to the product insert are as follows:

• The vaccine is supplied lyophilized in vials containing individual doses.

• Each dose of vaccine is mixed with 1 mL of the supplied sterile diluent.

• The vaccine is administered into the back of the horse’s nose using a special applicator supplied with the vaccine (entire contents of vial are used).

• One applicator is used for each horse.

• Containers are to be burned after use.

• Horses to be vaccinated are to be 11 months or older.

• Pregnant horses are not to be vaccinated.

• For veterinary use only.

• It is recommended that the vaccine is administered by a veterinarian or trained technician.

• For intranasal use only.

The FluAvert® I.N. vaccine Material Safety and Data Sheet (Appendix 2) lists identified hazards, handling, storage, exposure control and accidental release measures.

These include:

• Storage: Keep refrigerated, protect containers from damage.

• Accidental release measures: spray spill with a mild disinfectant such as bleach and wipe up spill with absorbent material. Place in secure container for disposal.

• Exposure protection/Personal protection: Wear splash protective eyewear, chemical resistant drugs, impervious long-sleeves and trousers.

• Always wash hands after handling live virus (if pregnant, do not work with live viruses).

We propose that the following HSNO Act controls are imposed to ensure that the vaccine is administered, used and disposed of correctly.

1. The vaccine must be used according to the FluAvert® I.N. vaccine insert (Appendix 1) and Material Data Safety Sheet (Appendix 2) (see section 5.2 controls 5 and 6).

2. The vaccine will be administered by veterinarians or veterinary assistants who have been trained in the correct handling, use and disposal of the vaccine (see section 5.2 controls 3 and 5).

A single administration of FluAvert ® I.N. vaccine will give immunity for EI for up to 6 months. Revaccination every 3 months is recommended if the horses are at high risk for exposure.

Section Four – Identification and Assessment of Adverse Effects

This section should include information on the adverse effects of the type referred to in the HSNO Act, particularly in section 38I(3). The Authority will take into account (i) whether the dose and routes of administration of the medicine or veterinary medicine would have significant adverse effects on public health or any valued species; and (ii) whether the qualifying organism could form an undesirable self-sustaining population that would have significant adverse effects on:

• The health and safety of the public

• Any valued species

• Natural habitats

• The environment

It is expected that the qualifying organism meeting the criteria for low risk in section 38I(3) will not normally have any significant biological risks associated with them, so that an assessment of adverse effects will not normally be required. However, there may still be some adverse effects that need to be identified and assessed.

4.1 Ability of the qualifying organism(s) to establish a self-sustaining population:

Describe the ability of the organism to establish a self-sustaining population and whether such a population would be considered undesirable.

> Live virus vaccines such as FluAvert® I.N. vaccine can multiply in the host and therefore have the potential to be shed from vaccinated animals, contaminate the environment and spread to other animals and people. However, influenza A viruses cannot multiply outside of a living host and survive poorly outside of a host. It has been demonstrated that influenza viruses will survive on hard non-porous surfaces for 24-48 hours while they survive for less than one day on cloth, paper and tissue (Bean et al, 1982).

After immunisation with FluAvert ® I.N. vaccine, the vaccine replicates in the horse’s nasal mucosa and virus can be shed for up to 10 days post-vaccination. In a study of the ability of the vaccine virus to spread to unimmunised horses, vaccine virus spread to one of 13 unvaccinated horses when they were maintained in a field of vaccinated horses (Chambers et al, 2001). This lack of spread may be due to the lack of clinical signs of disease, such as coughing, following vaccination.

Influenza viruses evade the immune system through antigenic drift and antigenic shift (section 3.4), therefore, with a live attenuated virus, reversion to virulence and increased pathogenicity in horses is a potential concern.

The spread of the vaccine to other non-equid animals is a possibility. Cases of dogs (greyhounds) infected with an EI strain have been described (Crawford et al, 2005). This is an example of interspecies transfer of an entire virus. This is generally regarded as a very rare occurrence given the host cell receptor specificity of influenza viruses (section 3.4). In addition the strain of influenza A (canine/FL/43/2004) involved is related but phylogenetically distinct to the strain used in FluAvert® I.N. vaccine (Crawford et al, 2005).

For interspecific transmission to occur, the influenza A strain in the vaccine would need to mutate for infection of dogs or other animals to occur. It is considered highly improbable that the supplied vaccine could mutate as the vaccine would be produced and tested by the manufacturer under strict conditions. Another scenario for interspecific transmission to occur would require the virus to uncontrollably spread within in an equid population, mutate and then spread to other animals.

It has been shown previously that when FluAvert® I.N. vaccine was subjected to a repetitive back passage safety trial, no reversion of the vaccine to a more virulent form was seen (Chambers et al, 2001). In addition, in a study that looked at the safety, efficacy and immunogenicity of FluAvert® I.N. vaccine in horses that were immunosuppressed, it was found that there were no significant differences in the clinical responses between immunosuppressed and non-suppressed animals (Lunn et al, 2001).

We note that while FluAvert® I.N. vaccine virus has been shown to be shed for up to 10 days post vaccination, if nasal secretions are seen these are only transient in nature and coughing is rarely seen (coughing is the primary method of viral spread).

We consider that the uncontrolled spread of the vaccine to equids or other animals and the subsequent loss of attenuated phenotype is a remote possibility. Therefore while it is possible that the vaccine could be transferred from equid to equid (or from horse to other animals), we believe that we can prevent this occurring by imposing the following controls:

1. So that the vaccine is correctly administered and handled, control 5 states that the vaccine must be administered as per the listed dose and route (ie intranasally) described in the FluAvert® I.N. vaccine insert by MAF BNZ- trained veterinarians or under veterinary supervision by trained veterinary assistants (control 5). MAF will oversee the training of veterinarians and veterinary assistants in the correct use and handling of the vaccine (control 3).

2. To prevent inadvertent spread of vaccine through incorrect use and disposal, control 6 states that the hygiene and handling procedures for biohazardous material shall be used as described in the FluAvert® I.N. vaccine MSDS sheet to prevent to spread of vaccine from humans to other horses.

3. To prevent the uncontrolled spread of vaccine between horses, control 7 states that all the horses on a property are to be vaccinated. Vaccinated horses will remain isolated from other horses for 10 days (control 8).

We believe with these controls, it will be highly improbable that a self sustaining population of the vaccine could form.

In the unlikely event that a self-sustaining population were to establish, it is unlikely that such a population would be undesirable. The only effect of a self-sustaining population would be that additional horses became vaccinated and therefore immune to EI.

4.2 Identify and assess any potential adverse effects which relate to whether or not the organism is a qualifying organism under section 38I(3) of the HSNO Act:

Consider effects under the following headings. Indicate whether or not it is highly improbable that significant adverse effects should occur. Consider both the doses and routes of administration of the medicine or veterinary medicine, and whether the qualifying organism could form an undesirable self-sustaining population.

A. Potential significant adverse effects on the health and safety of the public (This does not include effects on people being treated with the medicine):

> Equine influenza virus infection of people with accompanying mild clinical signs and seroconversion has been demonstrated experimentally. However, transmission under natural conditions of exposure during an outbreak of equine influenza in horses has not been demonstrated (Ausvetplan, 2007)

Based on the biological characteristics of the equine influenza virus and the FluAvert® I.N. vaccine (see section 3.4) and the extremely remote chance of this vaccine forming a self-sustaining population and therefore mutating (section 4.1), the risk of infection with an attenuated cold adapted vaccine strain and the likelihood of risk to human health and safety resulting from an infection would be highly improbable and the magnitude minimal.

B. Potential significant adverse effects on any valued species (This does not include effects on animals being treated by the veterinary medicine):

> Influenza viruses evade the immune system through antigenic drift and antigenic shift (section 3.4), therefore, with a live attenuated virus, reversion to virulence and increased pathogenicity in horses is a potential concern.

We consider that any potential effects on valued species would only occur after the uncontrolled spread of the vaccine and the subsequent loss of attenuated phenotype and other mutations that change host specificity. We have suggested controls that will make it highly improbable that a self sustaining population could form (section 4.1).

As it is highly improbable that this vaccine virus could form a self sustaining population, the likelihood of reversion to a more pathogenic strain is highly improbable, therefore, it is highly improbable that this vaccine virus would have any adverse effect of a valued species and the magnitude of any adverse effect to valued animals would be minimal.

C. Potential significant adverse effects on natural habitats:

> No potentially significant adverse effects on natural habitats have been identified.

D. Potential significant adverse effects on the environment:

> No potentially significant adverse effects on natural habitats have been identified.

4.3 Identify and assess any other potential adverse effects:

Consider any other adverse effect, especially adverse effects which are not covered under section 4.2 above but which are relevant to matters set out in Part II of the HSNO Act. Consider effects under the following headings:

A. Potential effects relating to the relationships of Māori and their culture and traditions with their ancestral lands, water, sites, waahi tapu, valued flora and fauna and other taonga

(taking into account the principles of the Treaty of Waitangi). This section is best completed after consultation with Māori. Please provide details of consultation undertaken and the outcome.

> No adverse effects in this category have been identified. We have discussed with staff at ERMA New Zealand the need for Māori consultation and have been advised that we do not need to undertake Māori consultation for this application.

B. Potential adverse economic and related effects derived from the use of the qualifying organism:

> No adverse effects in this category are expected.

C. Potential adverse effects related to New Zealand’s international obligations:

> No adverse effects in this category are expected.

D. Potential adverse social, cultural, ethical or spiritual effects:

> No adverse effects in this category are expected.

Section Five – Application of controls

5.1 Potential controls imposed under the ACVM Act or Medicines Act:

Qualifying organisms will have controls imposed under other legislation as well as the HSNO Act. List controls which are expected to be imposed under the ACVM Act (for veterinary medicines) or the Medicines Act (for human medicines).

> Qualifying organisms will have controls imposed under other legislation as well as the HSNO Act. List controls which are expected to be imposed under the ACVM Act (for veterinary medicines) or the Medicines Act (for human medicines).

Possible controls that could be considered under the ACVM Act:

• Controls requiring that the vaccine is manufactured in accordance with ACVM standards.

• Registration of FluAvert ® I.N. vaccine as a prescription only medicine.

• Controls requiring that FluAvert ® I.N. vaccine is distributed and used only by veterinarians, under veterinary supervision or trained veterinary staff.

• Controls limiting the use of FluAvert ® I.N. vaccine for use as part of an official eradication or containment programme.

• Controls requiring that FluAvert ® I.N. vaccine is only administered as per the instructions on the label, eg route and dose.

The following ACVM controls have been previously applied to vaccines that contain live organisms such as:

• Equine arteritis virus (#A008026) Conditions 2, 11, 14, 31, 37, 58

• Canine distemper virus, canine adenovirus type 2, canine parainfluenza virus, canine parvovirus (# A007374) Conditions 2, 11, 12, 15, 37 (ACVM database of currently registered Veterinary Medicines, Plant Compounds and Vertebrate Toxic Agents )

Condition 2: The product must be manufactured in accordance with the ACVM Standard for Good Manufacturing Practice and to the chemistry and manufacturing specifications provided by the registrant and approved as part of the registration.

Condition 11: Veterinary Medicine: In addition to any labelling, advertising or promotion requirements specified in the current registration, labelling, advertising or promotion of the product must comply with the current ACVM New Zealand Labelling and Advertising Guide for Veterinary Medicines Requiring Registration

Condition 12: The product may be used at the discretion of a registered veterinarian, when acting in accordance with any applicable code of practice approved under section 28 of the ACVM Act; and on animals under the direct care of that veterinarian, unless that use is specifically prohibited in the current registration.

Condition 14 Class II Prescription Animal Remedy. The product must be sold only by an approved trader. The product must be sold only to an approved trader, or to any person with a veterinary prescription or authorisation. The product must be administered to an animal only by, in the presence of or under the control of a veterinarian, unless specified otherwise in the current approval.

Condition 15: Class I Prescription Animal Remedy. The product must be sold only by an approved trader. The product must be sold only to an approved trader, or to any person with a veterinary prescription or authorisation. The product must be administered to an animal only by a veterinarian, or under and in accordance with the authority or prescription of a veterinarian.

Condition 31: This product must only be used as specified in the label content.

Condition 37: Ongoing obligations: The registrant must provide an annual summary of adverse events to the ACVM Group. Adverse events which have serious implications for the continued use of the product must be notified immediately.

The registrant must also advise the ACVM Group of any new studies or data that contradict information previously supplied.

Condition 38: Every person must comply with the requirements specified in the Product Specific Approval part of the current registration.

Condition 58: Advertising and promotion must only be directed to registered veterinarians or persons with an ACVM approval to trade in this product.

Therefore we expect that similar types of ACVM controls will be imposed for FluAvert ® I.N. vaccine.

In addition, additional controls can be imposed in “Product Specific Approval” documentation which can list further conditions. For example, the distribution and use of the vaccine, the requirement for an inventory and requirements for identification of vaccinated animals.

5.2 Potential controls proposed under the HSNO Act:

The Authority has discretion under section 38I(1) as to whether to approve the release of a qualifying organism with or without controls. The assessment of whether a new organism meets the criteria set out in section 38I(3) to be considered as a qualifying medicine or qualifying veterinary medicine must also take into account all the controls that will be imposed (if any) on the release of that medicine. Therefore, if your medicine does not meet these criteria to be considered as a qualifying organism in the absence of controls, you must clearly state the potential controls that may be imposed in order for the organism to meet these criteria.

If you consider that imposing a particular type of control will not reduce risks to people and the environment, you should say so, and justify your position. If you consider that some risks may be reduced by imposing controls in this section, you should suggest a control, and explain why you think this proposed control will reduce risks. When proposing controls you must consider the practical implications and application of the controls.

> We note that the controls that ERMA may wish to impose would be similar to the controls that it is expected that registration under the ACVM Act will require.

We note that the risks related to the release of this vaccine differ depending upon whether (a) EI has not arrived in the country (and this vaccine is to be used for pre-emptive vaccination), (b) has just arrived in the country (and horses are vaccinated in response to an outbreak), or (c) if EI becomes endemic.

At this stage (as EI is not in the country), MAF BNZ asks for the tighter set of controls as described below (including that MAF BNZ control the importation and use of the vaccine, oversee the training of veterinarians and veterinary assistants and oversee the maintenance of a register of vaccinated horses (control 1)) but if these circumstances were to change (ie EI becomes endemic), we may seek a review of the controls.

We propose that the following controls be imposed:

Control 1: MAF BNZ will have overall responsibility for the use of this vaccine.

Control 2: The vaccine will be stored and delivered to approved veterinarians by the manufacturer on the instructions and with the oversight of MAF BNZ.

Control 3: MAF BNZ will oversee training of veterinarians and veterinary assistants in the correct handling and disposal of the vaccine.

Control 4: MAF BNZ (or organization approved by MAF BNZ) will maintain a register that will list the quantity of vaccine imported, the distribution of the vaccine to approved veterinarians and the identification of which horses are vaccinated. This register is to be accessible for confirmation of compliance of this approval.

Control 5: Vaccine is to be administered as per listed dose and route (ie intranasally) as described in the FluAvert® I.N. vaccine insert by trained veterinarians or veterinary assistants under supervision.

Control 6: The following hygiene and handling procedures for biohazardous material will be used when handling and using this vaccine as described in the FluAvert® I.N. vaccine MSDS sheet:

• Safety glasses and gloves must be worn when administering vaccine.

• Hands must be washed after vaccination or when handling horses that have been vaccinated.

• The applicator and vaccine vials, gloves and any other material potential infected with the vaccine must be disposed of as a biohazard waste (ie incineration, autoclaving or chemical treatment).

Control 7: All the horses on a property will be vaccinated.

Control 8: Vaccinated horses will remain isolated from other horses for 10 days.

Section Six – Additional Information

6.1 Do any of the organism(s) need approvals under any other New Zealand legislation (apart from the ACVM or Medicines Acts)?

For example, the development may involve modification of whole animals, which also requires an approval under the Animal Welfare Act 1999; or if genetic material from species listed by CITES is used, then approval is required from both the importing and exporting countries.

> Compliance with the MAF BNZ Import Health Standard for biologicals and a rapid risk analysis would be required for importation and use of this vaccine.

6.2 Have any of the new organism(s) in this application previously been considered in New Zealand or elsewhere?

For example, has the organism(s) already been approved under HSNO for import or development in containment or has the organism been approved under another country’s regulatory system? If the answer is yes, please provide details of any relevant approvals (including approval codes) and any risk assessments that were performed.

> FluAvert® I.N. has been registered in:

• USA, U.S. Vet. Lic. No. 286

• Canada, CFIA VBS No 830VV/E11.0/D5

6.3 Is there any additional information that you consider relevant to this application that has not already been included?

>

6.4 Provide a glossary of scientific and technical terms used in the application.

>

6.5 List of appendices

Give the names of any appendices included with this application.

>

Appendix 1: FluAvert® I.N. vaccine product label ()

Appendix 2: FluAvert® I.N. vaccine Material Safety Data Sheet ()

6.6 List of references

Please include a list of the references cited in and supplied with this application. Originals of the references must be supplied in full.

ACVM database of currently registered Veterinary Medicines, Plant Compounds and Vertebrate Toxic Agents no date. (accessed November 2007).

Ausvetplan Disease Strategy Equine Influenza 9-10 (accessed Nov 2007)

Bean B, Moore BM, Sterner B, Peterson LR, Gergling DN and Balfour HH Jr 1982. Survival of Influenza viruses on environmental surfaces. The Journal of Infectious Diseases 146: 47-51.

Centre for Disease Control –Avian influenza (flu), no date. (accessed November 2007).

Chambers TM, Holland RE, Tudor LR, Townsend HGG, Cook A, Bogdan J, Lunn, DP, Hussey S, Whitaker-Dowling P, Younger JS, Sebring RW, Penner SJ, Steigler GL 2001. A new modified live equine virus vaccine: phenotypic stability, restricted spread and efficacy against heterologous virus challenge. Equine Veterinary Journal 33(7): 630-636.

Crawford PC, Dubovi EJ, Castleman WL, Stephenson I, Gibbs EPJ, Chen L, Smith C, Hill RC, Ferro P, Pompey J, Bright RA, Medina M-J, Influenza Genomics Group, Johnson CM, Olsen CW, Cox NJ, Klimov AI, Katz JM, Donis RO 2005. Transmission of Equine Influenza Virus to Dogs. Science 310: 482-485.

Daly JM, Newton JR, Mumford, JA 2004. Current perspectives on control of equine influenza. Veterinary Research 35: 411-423.

Heska Corporation 2001. Heska Corporation’s Equine Influenza Vaccine now available in Canada September 24 2001. 'S accessed November 2007.

Heska Corporation 1999. Heska Corporation announces USDA approval for new equine flu vaccine November 18 1999. accessed November 2007.

Intervet (no date) (accessed November 2007).

Holland, Robert E. et al. 1999New Modified-Live Equine Influenza Virus Vaccine: Safety and Efficacy Studies in Young Equids AAEP PROCEEDINGS 38-39.

Kamps BS, Reyes-Terán G 2006. Chapter 1: Influenza 2006. In: Kamps BS,Hoffman C, Preiser W(eds) Influenza Report 2006. Flying Publisher, Paris pp. 17-47.

Korsman S 2006. Chapter 6: Vaccines. In: Kamps BS,Hoffman C, Preiser W(eds) Influenza Report 2006. Flying Publisher, Paris pp. 127-149.

Lunn P, Hussey S, Sebring R. Rushlow K, Radecki SV, Whitaker-Dowling P, Younger JS, Chambers TM, Holland RE, Horohov DW 2001. Safety, efficacy and immunogenicity of a modified-live equine influenza virus vaccine in ponies after induction of exercise-induced immunosuppression. Journal of American veterinary medicine association. 218(6): 900-906.

Naylor JM 2004. Influenza in horses, birds, and humans. Large Animal Veterinary Rounds Volume 4 Issue 6 June/July 2004.

Townsend HGG, Penner, SJ, Watts, TC, Cook A, Bogdan J, Haines DM, Griffin S, Chambers T, Holland RE, Whitaker-Dowling P, Younger JS 2001. Efficacy of a cold-adapted, intranasal, equine influenza vaccine: challenge trials. Equine Veterinary Journal 33 (7): 637-643.

Suzuki Y, Ito T, Suzuki T, Holland RE Jnr, Chambers TM, Kiso M, Ishida H, Kawaoka Y 2000. Sialic acid species as a determinant of the host range of Influenza A viruses. Journal of Virology 74: 11825-11831.

Wilson WD, Robinson D 2000. Field safety of a modified-live, cold-adapted intranasal Equine Influenza Vaccine (HESKATM Flu AvertTM I.N. vaccine) in Horses. Journal of Equine Veterinary Science 20: 8-10

Younger JS, Whitaker-Dowling P, Chambers TM, Rushlow, KE, Sebring R 2001. Derivation and characterisation of a live attenuated influenza vaccine virus. American Journal of Verterinary Research 62 (8): 1290-1294.

Section Seven – Application Summary

Summarise the application in clear, simple language that is able to be understood by the general public. Include a description of the new organism(s), the purpose for which they will be developed, how they will be developed, the proposed containment system, and any risks and benefits associated with their development or use. This summary will be used to provide information for those people and agencies who will be notified of the application (e.g. Ministry of Agriculture and Forestry, Ministry for the Environment, Department of Conservation, Local Authorities etc) and for members of the public who request information. Note: Do not include any commercially sensitive information in this summary. Confidential information should be attached as a separate appendix and clearly marked as “confidential”.

> FluAvert® I.N. is an intranasal vaccine used for the control of equine influenza. Equine influenza is a disease of the respiratory system of horses caused by an influenza A virus. The vaccine is a cold adapted live strain of influenza A virus, which means that it is only able to multiply in the cooler environment of the nose and the sinuses and is unable to multiply in the lungs or rest of the body where the temperature is higher. This stimulates the immune system but causes either no symptoms or only very mild symptoms of the disease. The vaccine is supplied as individual doses and is administered by mixing the vaccine with a sterile diluent and using an applicator to place the liquid vaccine into the nose. The vaccines will be administered by veterinarians or trained veterinary assistants and may be used as part of vaccination programmes.

Checklist

Please check the following before submitting your application:

|All sections completed |Yes |

|Appendices enclosed |Yes/ NA* |

|Confidential information identified and enclosed separately |Yes/NA |

|Copies of additional references attached |Yes/NA |

|Application signed and dated |Yes |

| | |

|If application submitted to ERMA New Zealand: | |

|Initial fee enclosed (incl. GST) |Yes |

|Electronic copy of application e-mailed to ERMA New Zealand |Yes |

*NA – not applicable

Signed: Date:

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