THE NATIONAL FOOT & MOUTH GROUP

&

VETS FOR VACCINATION

 

 

 

 

 

 

 

DRAFT PROGRAMME FOR THE CONTAINMENT,

CONTROL & ERADICATION OF FMD

 

INCORPORATING THE USE OF EMERGENCY,

PROTECTIVE VACCINATION

 

 

 

 

 

 

 

April 2002
January 2003

 

 

 

 

 

 

 

 

THE NATIONAL FOOT & MOUTH GROUP

& VETS FOR VACCINATION

An affiliation of organisations affected by 2001 UK epidemic

 

Co-ordinating Office:  3 The Common, Siddington, Cirencester, Glos  GL7 6EY

Tel: 01285 644319 / 01285 656812

 

 

 

 

 

PREFACE

 

 

The National Foot & Mouth Group and Vets for Vaccination were invited to present  evidence to the Royal Society of London Inquiry into Infectious Diseases in Livestock with regard to Foot and Mouth Disease (FMD).   During the course of our meeting we were asked by Sir Brian Follett, Chair of the Inquiry, how we would use vaccination to control a future outbreak of FMD.   This document, which addresses the use of Emergency, Protective Vaccination to control FMD,  was prepared in response to that request.

 

The Programme was submitted to both the Royal Societies of London and Edinburgh Inquiries in April 2002, and also to the Lessons Learned Inquiry, the European FMD Inquiry and the Cumbria Inquiry.

 

Subsequently, the Royal Societies of London and Edinburgh and the EU FMD Inquiry all advocated the use of Emergency, Protective Vaccination to control future outbreaks of FMD.  Also, both Royal Society Inquiries concurred with the views on vaccination, carriers and science based risk assessment to determine disease free status, which are raised and considered in the Programme.

 

The Programme was developed with extensive advice and assistance from Dr Keith Sumption, while in post at the Centre for Tropical Veterinary Medicine, University of Edinburgh and prior to his appointment as Secretary to the EU FMD Commission at the UN FAO in Rome, and also with the guidance of Dr Paul Sutmoller and Dr Simon Barteling of the Netherlands, both of whom have been involved internationally in the control of FMD and the use of vaccination.   In addition, Dr Paul van Aarle of Intervet provided technical advice regarding the use of FMD ABC marker tests.

 

The Programme demonstrates a feasible and practical procedure for the use of Emergency, Protective Vaccination and sets out a surveillance and testing regime to determine extent and spread of infection, freedom from disease and a protocol to enable a return to Disease Free Status post vaccination.

 

With regard to the return to Disease Free Status using Emergency, Protective Vaccination and FMD Marker tests for non-structural protein, this approach has now been adopted and endorsed by the international regulatory body for FMD and animal diseases; the Office International des Epizooties.   The required time scale has now been incorporated into the International Animal Health Code, relating to FMD, at Article 2.1.1.7.    This allows for a return to Disease Free Status after 6 months if this control method and procedure are applied.

 

The Programme is submitted for consideration and discussion by all interested parties; to enable the adoption of vaccination as the primary means of FMD control in the event of a future outbreak

 

NATIONAL FOOT & MOUTH GROUP

& VETS FOR VACCINATION

 

January 2003

 

 

 

 

 

 

 

 

 

 

CONTENTS

 

 

 

1          INTRODUCTION

 

 

2          THE PRINCIPLE OF VACCINATION USING NSP FREE VACCINES & DIFFERENTIAL TESTS

 

 

3          BENEFITS CONFERED BY EMERGENCY PROTECTIVE VACCINATION

 

 

4          DRAFT PROGRAMME FOR THE CONTAINMENT, CONTROL AND ERADICATION OF FMD INCORPORATING EMERGENCY PROTECTIVE VACCINATION

 

 

5          CONTROL IN THE FUTURE & THE ROLE OF VACCINATION

 

 

 

5.1       Modern Vaccines and Tests

            The issues of efficacy, potency and availability

 

 

 

5.2       The Role of the OIE,  Sale of Meat and Animal Products Post Vaccination, Carriers, Disease Free Status and Export Markets

 

 

 

6          RECOMMENDATIONS

 

 

 

 

 

 

 

 

 

 

 

 

THE NATIONAL FOOT & MOUTH GROUP

& VETS FOR VACCINATION

An affiliation of organisations affected by 2001 UK epidemic

 

Co-ordinating Office:  3 The Common, Siddington, Cirencester, Glos  GL7 6EY

Tel: 01285 644319 / 01285 656812

 

 

 

DRAFT PROGRAMME FOR THE CONTAINMENT, CONTROL & ERADICATION OF FMD INCORPORATING THE USE OF EMERGENCY, PROTECTIVE VACCINATION

 

 

 

1          INTRODUCTION

 

1.1       The UK 2001 FMD epidemic caused widespread damage and loss to many people, their businesses and their communities.   The impact of the control of the disease on animal welfare, farming, tourism, the wider rural economy, individuals and the social fabric of rural Britain was massive and far reaching. 

 

1.2       In financial terms, the control of the epidemic created a fiscal cost of circa #3billion, a loss to the tourism sector of between #4-5 billion and an overall cost to the general economy of circa #20 billion*.   The control measures also resulted in the slaughter of over 10 million animals, the vast majority of which were healthy.   The measures also created unacceptable welfare problems for animals that could not be moved and faced starvation, adverse weather conditions and totally inappropriate circumstances for lambing and calving.  In many instances the provisions for humane slaughter were totally ignored and animals were subject to unacceptable suffering and cruelty.

 

1.3       The impact on communities and individuals faced with the vast extent of slaughter and culling, the loss of livelihoods and often their life’s work generated distress and despair.  The despoilment of the countryside due to the construction of the funeral pyres and burial pits needed for the disposal of such huge numbers of animals was untenable.   The psychological impact to many involved is still manifest and will take many years to recover from – some may never do so.

 

1.4       Both NFMG and Vets for Vaccination witnessed at first hand the effects and impacts of the adopted control policies on individuals, communities, animal welfare and on the economy and social infrastructure of rural UK.  The inter-dependent and inter-related nature of this economy and its society directs that control measures must minimise the effects of FMD control and seek to restore normality in the swiftest time scale.

 

1.5       We have therefore sought to prepare a programme for the containment and control of  FMD which does not create such major and widespread impact to all concerned and enables a modern, scientific and socially responsible approach to FMD control. 

 

*           Source of data: HM Govt, English & Welsh Tourism Council and IOD

 

 

2          THE PRINCIPLE OF VACCINATION USING NSP FREE VACCINES &  DIFFERENTIAL TESTS

 

 

2.1       The ability to differentiate between animals which have responded to vaccination and those that have responded to infection is key to the utilisation of an emergency, protective vaccination policy.

 

This differential ability enables the presence or circulation of virus to be monitored, and thus can in turn lead to the eradication of potential carrier animals.  It can also be used to determine freedom from infection and subsequently a rapid return to disease free status.

 

2.2       In recent years vaccines for FMD have become greatly refined.   Modern, state of the art vaccines can be produced with highly purified antigens, which are free from Non-Structural Proteins (NSP) of the FMD virus.

 

2.3       Animals, vaccinated with highly purified, NSP-free vaccines, produce antibodies against the Structural Proteins (SP) but not against NSP.

 

However, FMD virus infection induces antibodies against both Structural Proteins as well as Non Structural Proteins.

 

2.4       Marker tests have now been developed which can differentiate between antibodies due to vaccination as opposed to antibodies due to infection.

 

2.5       NSP-free vaccines used in combination with an NSP-test enables differentiation between animals that have responded to infection (antibodies for both NSP and SP present) and those that have solely responded to vaccination (only antibodies for SP present).

 

            NSP free vaccination stimulates an antibody response only to structural (capsid) proteins, whereas infection also stimulates an antibody response to non structural proteins.

 

2.6       The conventional tests – Virus neutralisation (VN), VP1-ELISA, demonstrate antibodies against FMD without differentiation between infection and vaccination.  The VN test has to be carried out in high containment, because it is carried out with FMD virus.  The test will only give a positive result if the field strain is of the same serotype as the test strain.

 

2.7       The marker test principle which we are advocating – for example – the Intervet Chekit-FMD-3ABC - demonstrates antibodies only after infection and not after vaccination.

 

            Furthermore, the Chekit-FMD-3ABC is not serotype specific and will be positive for all FMD viruses, irrespective of the serotype.

 

            We understand that both Merial and United Bio-Medical are in the process of  developing similar vaccines and tests.  However we base our programme on the Intervet Checkit FMD 3ABC system as this system has been advanced in the technical papers presented to the 22nd  Conference of the Office International Epizooties (OIE) Regional Commission.

 

 

            Any commercial NSP free vaccine could be used with the appropriate test, subject to validation by the OIE and the Veterinary Laboratories Agency based at Weybridge.

 

 

  2.8     As the NSP free vaccine and marker test enables animals to be screened to determine which animals have responded solely to vaccination, as opposed to those that have responded to viral challenge, this process overcomes two of the key objections to the use of vaccination, namely:

 

1          that vaccination can mask carrier animals resulting from viral  challenge, pre or post vaccination – and thus pose a risk to the rest of the national population

 

2          that vaccination would hinder or compromise a national eradication programme.

 

 

 

2.9       Our proposal is to screen herds and flocks with the 3ABC marker test, post vaccination with NSP free vaccines,  and to cull those herds and flocks where tests detect any animals with antibodies against the 3ABC protein – thus indicating a response to viral challenge by field infection. 

 

We have followed the precautionary principle, since the sensitivity of the anti-NSP tests is not 100% and therefore does not allow unambiguous classification of each tested animal.   By applying the test on a herd or flock basis greatly reduces the probability of non-detection of previously exposed animals which might harbour virus.

 

In culling these herds and flocks this then eliminates any possible carriers among the positive animals, and among false negative animals which might also be present in the same herd.

 

            Herds and flocks in which no animals test positive to 3ABC protein are found can be allowed to live out the rest of their economic life and continue into the food chain as this demonstrates that these herds/flocks have not been exposed to the virus.

 

Although the  sensitivity of the test is reported to be more than 99% (ie less than a 1 in 100 chance of failing to detect a previously exposed animal -see attached paper from Intervet), until quantitative assessment of the risk of non-detection of individual animals which have been exposed to virus is available, we propose that the test should be applied on a herd/flock  basis to reduce any risk that individual animals may be missed.

 

This can be considered, therefore, to be a highly precautionary measure which may in future be able to be modified; following experience in countries where post-vaccination surveillance is conducted.

 

 

 

 

3          BENEFITS CONFERED BY EMERGENCY PROTECTIVE VACCINATION

 

 

3.1       The implementation of an emergency, protective vaccination programme enables herds and flocks to gain immunity from FMD infection and thus prevent further spread and dissemination of the virus.  FMD cases rapidly cease in well-vaccinated populations.

 

3.2       If animals are protected from viral challenge by vaccination and thus cannot contract the infection, then these animals cannot then pass on the disease.

 

3.3       Furthermore, vaccination not only prevents further hosts of infection being created, but also means that such animals do not have to be culled, nor do they then need any provision for disposal processes.

 

3.4       Also the need for compensation for the slaughtered animals does not arise.

 

3.5       During the UK 2001 FMD epidemic the disease was only brought under control with a ‘stamping out’ policy after seven months.   The first case was confirmed on the 20 February and the last case on the 30 September 2001.

 

3.6       Under an emergency vaccination regime, cases would not be expected to occur in the vaccination zone more than 30 days after the start of a vaccination campaign that takes no longer than 10 days to complete. Experience in other countries indicates the last case often occurs well before this if stamping-out of infected premises also occurs

 

3.7       In our proposals, the use of emergency protective vaccination, applied in conjunction with other measures, seeks to ensure that the disease is brought under control in a far shorter time period.  In addition, and of great benefit to the wider rural economy and its communities, the need for the countryside to remain ‘closed’ for an indeterminate time period would not be necessary. 

 

            The paramount need for a swift return to normality and the minimisation of impact of FMD is therefore greatly enhanced by the use of a vaccination protocol.

 

3.8       In essence the draft programme proposes a containment of the virus by isolating the outbreak and surrounding the infected area with vaccinated animals that will have developed herd and flock immunity.  This prevents the virus from spreading and replicating and thus enables the disease to be brought under control.

 

            In the 2001 outbreak in the Netherlands the disease was brought under control and further outbreaks ceased 8 days after the completion of the vaccination programme.

 

We submit the following programme for consideration by interested parties and

stakeholders in the FMD debate.  Its purpose is to prepare a deliverable, practical

programme that can be proposed in due course to UK Government, the EU and the

OIE.

 

4          DRAFT PROGRAMME FOR THE CONTAINMENT, CONTROL AND ERADICATION OF FMD INCORPORATING EMERGENCY PROTECTIVE VACCINATION

 

 

1          Although we acknowledge that there are statutory procedures that must be followed, once clinical symptoms have been identified and the presence of the disease is suspected,  there is also a need for the subsequent process to be clear and easily understood by all those involved.

 

2          Given the implications of the extensive animal movements now occurring daily in the UK and Europe, the length of time taken to confirm the suspect case is critical.   An explicit Contingency Plan must set out and determine precisely how, when and where the laboratory confirmation of the first suspect case is to be undertaken.  Most importantly it must define the time scale for these actions.

 

3          An agreed course of action, also specified and detailed in an adopted Contingency Plan, must then be followed. 

 

 

4          Such actions, which are crucially time dependent, must involve:

 

a          Rapid and accurate laboratory diagnostic tests, if possible in regional facilities (or when developed – cow side/ farm gate) using PCR viral assay. – to ascertain definite confirmation, or otherwise,  of the infection in the shortest possible time.

 

A pen-side test for virus antigen has been recently described with excellent sensitivity and detection of virus in 10 minutes. RT-PCR  will detect virus during the latter part of the incubation period and sub-clinical infection, in addition to clinical cases.

 

b          Immediate isolation of suspect premise(s), imposition of movement restrictions and effective farm quarantine, involving full bio-security, bio-sanitary arrangements to the premise(s).

 

c          Notification of potential outbreak and temporary ‘holding’ position to neighbouring farms and small holdings.

           

d          A placing on alert of the relevant authorities and agencies

 

 

5          If laboratory confirmation is negative then it may be sensible to consider compensation for any losses to the farmer incurred through the imposition of restrictions and bio-security arrangements.  The purpose being to inculcate a culture of responsibility and incentive for farmers to swiftly report suspect cases without loss of earnings, even if the case subsequently proves to be a false alarm.

 

6          In the event of positive confirmation then the following procedures should be implemented: 

 

Again a pre-agreed, adopted contingency plan must detail operations and involve:

                       

                        a          Immediate imposition of nation wide movement restrictions

 

                        b          Immediate slaughter of index premise

                       

                        c          Immediate effective farm quarantine

 

                        d          Tracing of dangerous contacts

 

                        e          Surveillance and laboratory testing of contiguous premises,

 

 

7          Should it be found that the disease has not been contained, but that it has already been dispersed and seeded before movement restrictions have been imposed, as happened in the 2001 outbreak, then an emergency, protective, vaccination to live policy should be applied.  

 

8          The vaccination to live procedures should be effected without the need for a pre-determined and pre-agreed threshold of confirmed cases, but should be introduced as the primary method for control for the high risk area surrounding the location of confirmed IPs.

 

 

9          This vaccination procedure should be introduced in conjunction with the following provisions:

 

a          Immediate, enforced, effective farm quarantine – with a pre agreed protocol, including safe animal separation distances from neighbouring farms

 

b          Immediate, enforced bio-security - with pre agreed protocol, measures etc –these plans should cover all animal, vehicle, personnel, feed and milk tanker movements – (milk should not be collected from Form D farms without strict adherence to air filter maintenance.)

 

10        Monitoring and surveillance - Any clinically identified infected stock – preferably supported by PCR viral assay confirmation, would be slaughtered.

 

11        Immediate implementation of ring, or zonal, or defined administrative area for application of protective, emergency, vaccination programme - around IP(s), dependent on geographical dispersal, local conditions - extent and scale of vaccination zone to be determined via  pre-detailed criteria, and current assessment of on the ground situation and circumstances.

 

Vaccination should be applied from edge of zone or area towards centre of outbreak(s), and simultaneously with different teams on contiguous premises at the highest risk of receiving and amplifying infection at the heart of the zone, and to all susceptible livestock.

 

            (Responses to initial consultations with Intervet have suggested that  surveillance zone radii of 10 km may be applied by the EU.  However, for administrative purposes and depending on the scale of the outbreak, we consider that the extent of the vaccination zone will need to be determined as above – but with regard for the need to establish a sufficient area of immunity to enable infection to be contained.)

 

            The principle consideration is to rapidly achieve a protected zone around the area with high herd immunity 5 days or more ahead of anticipated first virus challenge, together with vaccination at the “heart” of the area to reduce potential virus amplification at the centre, and protect farms at highest risk.

 

The vaccination programme should aim for completion in less than10 days, so that response to vaccination is seen from about 5 -7 days post-commencement and cases should cease by day 24 post-commencement.

 

12        All tracings back from index premise should be traced, and animals inspected, and dependant on the period elapsed since the contact, tested for evidence of exposure on a probability basis.

 

If within the vaccination zones, these farms should be vaccinated if no evidence of infection is clinically detected.  If outside an existing vaccination zone, the decision to keep under surveillance, to vaccinate or to slaughter will depend on a number of factors.  A thorough risk assessment to determine the probability or likelihood of exposure to infection should form part of this process.

 

13        Standstill period to allow response to vaccine, or response to viral challenge pre or post vaccination.  (this time scale should be a minimum of 14 days, preferably 21 days)

 

14        Regular Monitoring and surveillance for clinical signs

 

15        30 days post vaccination commence screening with 3ABC marker test to differentiate and determine which animals have responded to vaccine and those who have responded to viral challenge, either pre or post vaccination – if not previously identified by clinical means during monitoring.  

 

These animals which have responded to viral challenge will then be slaughtered.  We propose that herds and flocks with 3ABC positive animals be culled.  Those with herds and flocks with 3ABC negative animals do not need to be culled and can be allowed to live. 

 

The prevalence of animals with antibodies to viral challenge may be highest close to the index IP, but the majority of herds and flocks would not be infected.

 

16        Those animals which have not shown any response to viral challenge and are 3 ABC negative should be subject to the provisions detailed in the Strategy for Emergency Vaccination against FMD – which was adopted by the EU in March 1999.

 

            Section 7 of the Strategy for Emergency Vaccination sets out “Guidelines for the movement of animals and animal products within and out of an area which has been subject to emergency vaccination”.

 

            When the Emergency Strategy was adopted – March 1999,  the OIE  rules did not take into account  the new serological tests for FMDV-NSP, able to discriminate between vaccinated and infected herds, and this is acknowledged in the Strategy  - see page 17.  However this situation has now changed with the new OIE Ruling 2.1.1.7 adopted May 2002.

 

            The authors of the report, the Scientific Committee on Animal Health and Welfare, recommend that not less than 30 days from the completion of vaccination, an adequate surveillance system must be established.

 

            Restrictions can be lifted when the surveillance has been completed with negative results.  (This surveillance is detailed in paras 7.2.1 to 7.2.3 of the Strategy.)   Copy attached

 

17        We submit that the provisions contained within Paras 7.2.1 to 7.2.3 must be followed to determine FMD free herds and flocks.  However, given that the process we proscribe should not result in any carriers or false negative cases of FMD, we submit that the requirement for separation and treatment of vaccinated meat and meat products must now be re-assessed.

 

18        In the following sections we contend that the programme we are advocating, using NSP free vaccines and marker tests, directs:

 

1          that the separation and treatment processes for vaccinated meat, meat and milk products do not need to be applied.

 

2          that the surveillance regime can be utilised to demonstrate freedom from FMD infection.

 

As a consequence there should be no distinction between;

 

1          the end use of meat, and meat and milk products of vaccinated animals, and

 

2          the length of time to return to disease free status,

 

regardless of whether vaccination or stamping out is applied to control

the disease.

 

* PCR – polymerase chain reaction

 

* 3ABC Marker test – papers available on request

 

 

 

 

 

5          CONTROL IN THE FUTURE & THE ROLE OF VACCINATION

 

5.1       Modern Vaccines and Tests

 

5.1.1    The issues of efficacy, potency and availability of vaccines and tests are key to the acceptance of the incorporation of vaccination as part of a control programme.

 

We have considered the published documents of Merial, Intervet and United BioMedical*, consulted with vets and virologists and raised this issue with the Chief Veterinary Officer regarding vaccination of the hefted flocks (Aug 2001).

 

*All these papers are available and we can forward them if required.

 

 

5.1.2    Modern vaccines can be produced in a highly purified and inactivated form.  If administered in the appropriate form and in the right conditions they can provide effective immunity when used as part of a programme to control the disease with subsequent surveillance and testing.  Ref Drs Sutmoller, Barteling, Watkins, Merial publication, etc

 

 

5.1.3    The main opposition that we have encountered to the use of vaccination is that the non structural protein test, used to distinguish between response to vaccine as opposed to response to infection, has not yet been fully validated to the guidelines of the OIE.

 

Intervet have now introduced a 3ABC marker test which is capable of differentiating between response to vaccination and response to viral challenge.  This has been extensively tested and trialled and provides a definitive tool to differentiate between those animals that have responded to vaccination or viral challenge, for use at herd level.  We understand that this test is now ready for submission to the OIE for validation.

 

Merial have also produced a similar test and had the test independently assessed although the test is a ‘described’ test, but it is not yet ‘proscribed’, as it has not yet been validated.

 

United Bio-Medical (UBI) have also developed a range of similar tests and state:  “The complete UBI NS test system has a specificity approaching 100% on vaccinated livestock.  We believe that our system has sufficient sensitivity and specificity to detect evidence of infection in vaccinated herds (eg, potentially infectious carrier animals if they truly exist) while distinguishing the antibody response to infection from the response to vaccination.”

 

UBI is currently going through a licensure process with the US Dept of Agriculture for the UBI FMDV NS EIA.

 

5.1.4    The benefits of such tests is that they provide the key tool to screen herds to determine the presence, or otherwise, of animals which have met FMDV infection.  Herds with a low proportion of reactors on a primary screen could then be re-tested by serology in a complete herd test,  with possible addition of a second test to determine if virus or viral RNA, or anti-FMDV IgA was present in a pharyngeal sample of positive animals. 

 

Such a system was used in Korea in 2000 following emergency vaccination with results presented to OIE as part of the process of regaining FMD freedom.  This means that rapid surveillance methods can be used as a means of demonstrating freedom from infection, which is paramount in regaining disease free status. 

 

We refer to the attached paper from Dr Sutmoller and Dr Barteling presented to the Royal Society Inquiry.

 

In our discussions regarding the vaccination of the hefted flocks in Wales, the subsequent surveillance and testing, using the NSP test to differentiate between response to vaccination as opposed to challenge pre or post vaccination, was to have provided an effective method of establishing the extent of disease spread, response to vaccination and in determining disease free status.

 

 

5.1.5    Availability of Vaccines

 

We raised the following questions with Intervet and enclose below their response:

 

1   Are NSP free, highly purified, inactivated, oil-adjuvanted vaccines

available in sufficient quantity to enable them to be used as part of           

the Programme?

 

and following from this, do Intervet produce them, or any other commercial company?

 

The product, which is produced in the Netherlands, is being sold in the

Middle East and the Far East.  This product is free from NSP.  We deliver

millions of doses to the market.  Availability depends on the quantities,

which are required.  Antigen-banks ensure availability of sufficient

quantities of vaccine within days in case of emergency.

 

 

2    Also, is it known what rate of production could be achieved and in   

      what time scale?

 

From an antigen-bank we can deliver 500,000 doses within 4 days and

subsequent quantities, depending on availability of antigen within days. The

critical factor really is the availability of antigen and that can be ( and in

the UK is) arranged by contract.  Normally the first quantity would be

produced even before the definite decision to vaccinate is taken.  

 

 

 

5.2       The Role of the OIE,  Sale of Meat and Animal Products Post Vaccination, Carriers, Disease Free Status and Export Markets

 

5.2.1    The Office International Epizooties (OIE) based in Paris is the international body responsible for conferring disease free status (DFS).   As of May 2002, the return to DFS post vaccination, with NSP free vaccines and the requisite sero-surveillance, now stands at 6 months, while only 3 months is required following a ‘stamping out’ method of control.

 

5.2.2    However “These trade regulations are not based on risk assessments, but rather:

* on the notion that vaccination might perpetuate carriers in the population and that those carriers may pose a risk for FMD free countries that do not practice vaccination.

* that there are no methods available for the detection of carriers in vaccinated populations”

 

“Normal export should be resumed, when after any outbreak, the veterinary services would show the absence of FMD.

*This should be independent of whether stamping-out plus ring vaccination or vaccination only was used to control the outbreak.

*There should not be a set time limit.

*The sooner the country or region shows the absence of viral activity the earlier normal trade can be resumed.”

 

See attached paper of Dr Sutmoller’s presentation to the Royal Society.

 

5.2.3    Because the tests now exist to determine between antibody response to infection and antibody response to vaccination those animals which have responded to infection can now be identified and slaughtered.  Such infection may have arisen as a result of pre or post vaccination viral challenge before the vaccinated animal has responded to the vaccine.

 

Those animals which have responded only to vaccination can thus be identified.

 

5.2.4    Animals which have been vaccinated and not responded with anti-NSP antibodies to infection might not be detected if tests of low sensitivity are used.  Therefore tests should be used on herd basis where the probability of non-detection can be estimated and would be extremely low with a well designed screening program.  Further, there has been no scientific evidence to show that such animals have ever infected other animals, so non-detection carries exceptionally low risk.

 

            Carriers or persistently infected animals

            *The fear that vaccination causes FMD carriers and interferes with the eradication effort is completely hypothetical and scientifically unfounded.

            *There is much more chance of getting FMD carriers among cattle and sheep with clinical or sub-clinical FMD.”

 

            See attached paper from Dr Sutmoller’s presentation to the Royal Society.

 

 

5.2.5    It is therefore necessary to move to a science based risk assessment to determine absence of disease, rather than rely on an arbitrary time scale.

 

5.2.6    Post vaccination surveillance and serology, with the use of the 3ABC marker tests, provide the definitive tools to determine disease free status and can thus be used to restore DFS possibly sooner than with stamping out.   There is certainly no justification to apply a penalty of a longer time period with vaccination.

 

5.2.7    Our programme proposes only to utilise NSP free vaccine in conjunction with the 3 ABC marker test to enable a swifter return to Disease Free Status, by  demonstrating freedom from FMD.

 

5.2.8    In May 2002 the OIE agreed a further Article determining Disease Free Status in relation to vaccination – Article 2.1.1.7.  This allows the return to the status of ‘FMD-free without vaccination’  at 6 months after the last vaccination, provided that absence of infection has been demonstrated with a NSP test. This proposal includes the condition that a NSP-free vaccine is used.

 

5.2.9    Similarly the restraints placed upon the use of vaccinated meat, meat products and milk are not required as it can be clearly demonstrated that the animals have not been exposed to infection, and herds proven to be clear of past exposure present no risk.

 

5.2.10  It is therefore fundamentally important that the criteria governing return to DFS and export markets are based on science based risk assessment.   If this basis is established then the current penalties incurred with the use of vaccination are no longer applicable.  Vaccination as a modern, humane approach to FMD control can be used without the need for any pre-determined or pre-agreed thresholds, but as the preferred and primary means of control for at-risk farms, together with immediate slaughter of animals where acute infection is confirmed.

 

 

 

 

6          RECOMMENDATIONS

 

6.1       The Adoption of Process and Procedures to deal with future outbreaks      

 

6.1.1    May we respectfully ask the Royal Society Committee to consider:

 

1          Agreeing a process and procedure with farmers, livestock owners, local veterinary practitioners and the State Veterinary Service to establish surveillance regimes.

 

2          The drawing up of national, regional and local contingency plans which are in the public domain and produced in consultation with local communities representing all sectors and stakeholders.

 

3          That the Contingency Plans should include clear protocols detailing diagnostic facilities, effective farm quarantine, safe animal separation details, and bio-security arrangements for farms, personnel, vehicles and animals.

 

4          The Contingency Plan should make provision for vaccine banks and determine how, and who should deliver the vaccine and how this is to be regulated, recorded and monitored.

 

5          The Contingency Plan should make proper provision for humane slaughter and disposal of infected stock.

 

6          The Contingency Plan should also define a regime and protocol for post vaccination surveillance, monitoring and testing programmes.

 

7          Discussions should be undertaken now with the OIE and EU to agree such protocols and define all procedures.  Particular regard should be had to the process to be adopted to demonstrate freedom from FMD.

 

 

 

NFMG & VETS FOR VACCINATION

April 2002

 

 

Acknowledgements:

The National Foot & Mouth Group and Vets for Vaccination are very grateful for the assistance and advice from various vets and scientists in the preparation of this paper. 

 

In particular we would like to thank Dr Keith Sumption, of Edinburgh University, for his extensive assistance and guidance throughout the preparation of the Programme. 

 

Also we thank Dr Paul Sutmoller and Dr Simon Barteling of the Netherlands for their various papers, presentations and advice on vaccination, its applications in various control protocols and on carriers and science based risk assessment.

 

We are also grateful to Dr Sheila Crispin and Dr Sarah Binns of Bristol University for their constructive comments and advice on the proposal.

 

Finally we thank Dr Paul van Aarle of Intervet for providing further information on the availability,  uses and application of vaccines and tests.

 

 

REFERENCES

 

1          Strategy for Emergency Vaccination Against FMD – Report of the Scientific Committee on Animal Health & Animal Welfare

Adopted by the EU 10 March 1999

 

                       

            2          Intervet Technical Paper – The use of a 3ABC marker-test for FMD

Presented to the 22nd Conference of the OIE Regional Commission for Asia, the Far East and Oceania

 

3          Dr Paul Sutmoller’s power point presentation to the Royal Society of London – January 2002

 

4          Dr Paul Sutmoller & Dr Simon Barteling paper to the Brussels Conference on FMD of December 2001

 

5          OIE – International Animal Health Code 2001 – Chapter 2.1.1 Foot and Mouth Disease

 

From the Powerpoint presentation of Dr Paul Sutmoller at the Government's Royal Society Inquiry "Vaccination" meeting on January 15th 2002

What makes sense for prevention, control and eradication of FMD?


How to get rid of the disease soonest?
How can we minimize impact on animal production and welfare?
How can we limit the damage to the rural society as a whole?

Long-term ban on free international trade of vaccinated animals
Arguments:

* Convalescent or sub-clinical infected animals, become FMD virus carriers.
* Vaccinated animals have antibodies against FMD and that this obscures the tracing of the disease.
* (One cannot eat meat from vaccinated animal)

Risk of vaccinated animals
* Just how large is that risk of creating vaccinated carriers and what would be the risk posed by such animals?
* Does that risk justify the assumed zero-risk approach of "stamping-out" or, when vaccination is used, the killing of the healthy vaccinated livestock?
* Could the risk of infected animals in vaccinated populations be managed effectively by the use of modern diagnostic methodologies?
* Is stamping-out to the bitter end really assuring zero risk?

Questions to be answered
* Once the disease is brought under control what should be required to get a FMD-free status back?
* What did we learn from the recent experiences?
* Are the current international rules still adequate?
* What are the risks of (re-) introduction of FMD?
* What are the risks of international trade, tourism, swill feeding, FMD-laboratories and vaccine plants, and terrorist actions?
* How can these risks be mitigated and managed?

Eradication strategies
* stamping-out of infected farms and direct potential contagious contacts;
* stamping-out of infected farms plus ring (circle) culling;
* stamping-out of infected farms plus ring or area vaccination followed by slaughter of all vaccinated animals ("suppressive" vaccination);
* stamping-out of infected farms plus ring or area vaccination ("protective" vaccination);
* ring vaccination only without stamping-out of infected farms and slaughter of vaccinated animals
* strategic or general vaccination.

Some risks of stamping-out
* Heavy equipment used in these operations is difficult to decontaminate and might be a source of infection or contamination of roads when being driven to another job or back home.
* Disposal of cadavers presents a risk since virus in lesions, excrements and excretions is not rapidly destroyed after death and is disseminated by transport of cadavers, by pyres, at burial sites or digester plants.
* Transport systems for carcasses are not bio-secure, neither is the handling of the carcasses at the rendering plants.
* Large numbers of contractors not trained in disease containment become heavily contaminated.
* Intensive, active surveillance represents a risk.

Ring- (circle) culling
* "circle culling" and culling of contiguous farms were applied in the UK and in the Netherlands as an extension of usual stamping-out procedures.
* The circle represents a "fire break" around the outbreak.
* The diameter of the circle was based on the analysis of spread of FMD during the outbreak using computer models.
* The calculated distance of spread probably is due largely to the culling process itself as an additional risk of spreading the disease.
* Circle culling reduces the need for surveillance, but it creates potentially much higher numbers of cadavers, some of which might be infected.

Disadvantages of Ring- (circle) culling
* Most culled farms within the circle are not infected and, therefore, are culled without necessity.
* The operation itself has a high risk of disseminating FMD virus over short and long distances.
* A long drawn-out campaign is very disruptive for the rural society as a whole.
* The consequent application of circle culling (and of contiguous culls) is a threat to zoological collections and valuable (rare) breeding stock.
* Massive killing and destruction of livestock usually is not done with adequate respect for animal welfare.
* The small risk represented by hobby farms and small-holdings is not taken into account.
* Many culls represent a human tragedy and traumatic experience Ring- (circle) culling must be based on the evaluation of how virus spreads, and not be determined by mathematical circles.


The principal routes of virus spread to be considered are:
* animal movements from the farm, during the pre-clinical phase;
* wind, usually for a limited distance;
* vehicles (e.g. animal transport, machinery) contaminating roads that are used by the farmer's family and associates;
* contaminated vehicle from companies serving the farm;
* people (veterinarians, inseminators, visiting farmers, cleaning and disinfecting crews, etc.)

 

Ring vaccination
should be included in any contingency plan:
* to avoid all disadvantages of the massive killing and destruction of infected and healthy animals;
* to stop the disease from spreading;
* to prevent to the maximum extent possible the suffering of animals;
* to ascertain that a few week after vaccination life in the affected area can resume its normal course, with minimal socio-economic consequences

Ring vaccination
The logistics of a vaccination campaign are rather simple.
* It can be carried out on a large scale by a limited number of (trained) staff under full bio-safety conditions
* by farmers and trained farm hands as is common practice in South America (no risk of cross-contamination between farms because of people movements).

If FMD occurs in a previously FMD free country or zone without vaccination:
* If no vaccination is used to control an outbreak and stamping-out and serological surveillance are applied, the FMD free status can be regained and normal trade resumed 3 months after the last case;
* If stamping-out and emergency ("suppressive") vaccination are applied the waiting period is 3 months after the last vaccinated animal is slaughtered. A serological surveillance in the zone around the vaccination zone must demonstrate freedom from FMD.

If FMD occurs in a FMD free country or zone where vaccination is practised:
* If vaccination is used and stamping-out is applied, it takes 12 month after the last case to obtain the FMD free status;
* If vaccination is used, without stamping-out, it takes 24 month after the last case to obtain the FMD free status.


These trade regulations are not based on risk assessments, but rather:
* on the notion that vaccination might perpetuate carriers in the population that those carriers may pose a risk for FMD free countries that do not practise vaccination.
* that there are no methods available for the detection of carriers in vaccinated populations.

Normal export should be resumed, when after any outbreak, the veterinary services would show the absence of FMD
* This should be independent of whether stamping-out, stamping-out plus ring vaccination or vaccination only was used to control the outbreak.
* There should not be a set time limit.
* The sooner the country or region shows the absence of viral activity the earlier normal trade can be resumed.

Trade in live animals
* The current export of live animals practised from countries that do not practise vaccination has proven to be not risk-free.
* The international movement of vaccinated animals is restricted due to perceived risk of persistently infected animals.
* Under an adequate protocol the risk posed by the import of vaccinated animals is negligible.

 

True or false?
* "FMD free without vaccination" is risk free.
* "FMD free without vaccination" is not risk free.
* "FMD free with vaccination" is risk free.
* "FMD free with vaccination" is not risk free.

Meat and meat products from vaccinated cattle
* Negligible risk when slaughtered and processed under GMP and according to OIE regulations.
* Disease surveillance, control of the source cattle and slaughterhouse inspections are the main risk reduction measures.
* The risk reduction by maturation and deboning is probably over-emphasized.
* The fear of mechanical contamination of cattle carcasses with 'carrier virus' from the pharyngeal area during slaughter and processing is unfounded.

Milk and milk products from vaccinated cows
Risk assessments show that:
* Importation from countries with a high level of herd immunity, pose a close to zero or negligible risk.

Genetic material
Bovine embryos:
* The importation of bovine embryos from vaccinated cows poses a negligible risk.
Semen:
* The risk of the importation of semen from vaccinated bulls is negligible, with an adequate test protocol and when collected at collection centers, approved for semen export.

Vaccination and carriers
* Vaccination by itself cannot cause the carrier status (FMD vaccine is prepared with an inactivated antigen). A vaccinated animal must be exposed to active FMD virus to become a carrier.
* Vaccination suppresses or eliminates the amount of FMD virus (released or discharged) in the environment (low morbidity!) which makes it unlikely that carriers will be induced in vaccinated herds.
* Carriers among vaccinated cattle have not caused FMD outbreaks among susceptible non-vaccinated livestock populations like young cattle, sheep and pigs, nor have they hampered FMD eradication efforts.

Carriers or persistently infected animals
* Researchers have been unable to show that carriers cattle transmit FMD to susceptible contacts
* All experimental evidence of FMD virus transmission by carrier sheep is negative
* Pigs do not become carriers
* Vaccinated cattle or sheep exposed to FMD virus have a much smaller chance of becoming a carrier than susceptibles exposed to FMD virus
* "Vaccinated" carriers were no problem during the FMD eradication by vaccination in South America

 

Carriers or persistently infected animals
* The fear that vaccination causes FMD carriers and interferes with the eradication effort is completely hypothetical and scientifically unfounded
* There is much more chance of getting FMD carriers among cattle and sheep with clinical or subclinical FMD

Back

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

EXTRACTS FROM:

 

EU STRATEGY FOR EMERGENCY VACCINATION AGAINST FOOT AND MOUTH DISEASE (FMD)  - adopted by the Scientific Committee – March 1999

 

Page 16

 

7.      Guidelines for the movement of animals and animal

products within and out of an area which has been subjected to emergency vaccination.

 

7.1       Regionalisation

 

The concept of regionalisation in these circumstances has already been incorporated in Community law e.g. Council Directive 90/423/EEC (art. 2.3) amending Council

Directive 64/432/EEC.

 

The Committee considers that there is no scientific reason to refuse a regionalisation

policy for Member States which have used emergency vaccination under the following conditions:

 

*          the disease control measures laid down in Council Directive 85/511/EEC are

fully implemented;

 

*          a detailed report giving up to date epidemiological information and full details of measures taken must be available;

 

*          the region is submitted to rigorous controls;

 

*          the control of movement of animals and animal products is effective.

 

Similar provisions should apply to third countries, according to OIE rules. In the context of emergency vaccination, international acceptance of regionalisation is essential.

 

 

7.2       Movement of vaccinated live animals within and out of the

vaccination zone

 

The Committee notes that when a foot and mouth disease outbreak occurs in a free zone where prophylactic vaccination is not practised, there are two possible scenarios, in relation to the policy adopted:

 

*          Policy 1:         stamping out and surveillance.

 

Taking into consideration Council Directive 85/511/EEC, free movement of live animals (ruminants and pigs ) out of the restricted area (i.e. protection and surveillance zones) is permitted 30 days after the completion of stamping out in the last outbreak, provided

 

Page 17

 

that adequate surveillance of the protection zone and cleaning and disinfection of the

contaminated holdings have been carried out.

 

*          Policy 2:         stamping out, surveillance and emergency vaccination

 

The OIE International Zoo-Sanitary Code (1997), Chapter 2.1.1., states that a

vaccinated area can be considered free

 

*          1 year after cessation of the vaccination (Article 2.1.1.2; page 87),with

documented evidence that an effective system of surveillance is in operation and that the regulatory measures for the prevention and control of FMD have been implemented,

 

or

 

*          3 months after slaughtering of the last vaccinated animal (Article 2.1.1.2; page

91), where stamping-out, serological surveillance and emergency vaccination are applied.

 

The OIE code does not state that free movement of vaccinated animals from free areas is permitted but this would be a logical conclusion.

 

In addition, the OIE rules do not take into account the new serological tests for FMDV-NSP, able to discriminate between vaccinated and infected herds. In spite of the uncertainties with regard to vaccinated herds, the Committee is of the opinion that the application of NSP-tests allows for an earlier lifting of the restrictions on the movement of vaccinated animals.

 

NFMG Note – As of May 2002 the OIE have now recognised this approach and applied a time period of 6 months from the end of emergency vaccination to the return to Disease Free Status – Article 2.1.1.7 of the OIE Animal Health Code, Chapter 2.

 

The Committee recommends that not less than 30 days 11 from the time of completion of vaccination, an adequate surveillance system (see 7.2.1 and 7.2.2 below) including

serological tests for NSP in ruminants must be established in the vaccination area.

Restrictions could be lifted when the surveillance described below (paragraphs 7.2.1 to 7.2.3) for ruminants and swine has been completed with negative results. In the period from vaccination until lifting of restrictions, animals shall only be moved to a

 

 

 

11 The 30 day period allows for 14 days needed for the development of complete protection plus a

further14 days as the maximum incubation period reported in the literature. (Roeher and Olechnowitz,

1980).

 

 

 

 

 

Page 18

 

slaughterhouse preferably within the 'protective' vaccination zone, under the conditions detailed in section 7.3 of this report.

 

 

7.2.1   Surveillance to allow movement of ruminants

 

Free movement of vaccinated ruminants can only take place out of the vaccination zone when:

 

1.         clinical inspection in all herds of the vaccination zone have provided no

indication of FMD virus infection and;

 

2.         the NSP-ELISA performed in all vaccinated animals has given a negative result and;

 

3.         all the restrictions applied to protection and surveillance zones have been lifted in accordance with the Council Directive 85/511/EEC.

 

Cattle herds and sheep and goat flocks positive to NSP-test (i.e. herds with more than a singleton 12 reactor)13 shall be treated under the conditions detailed in the paragraph 7.2.3 of this report.

 

 

7.2.2   Surveillance to allow movement of swine

 

It is recognised that the NSP-tests are not yet validated for use in pigs. Until this is done, it is recommended to use tests for virus isolation in this species.

 

Free movement of vaccinated swine can only take place out of the vaccination

zone when:

 

1-         clinical inspection in all herds of the vaccination zone has provided no

indication of FMD virus infection and;

 

2-         the laboratory tests for virus isolation or genome or antigen detection, based

on a statistically valid number of samples, have given negative results and;

 

3-         all the restrictions applied to protection and surveillance zones have been lifted in accordance with the Council Directive 85/511/EEC.

 

Swine herds are considered 'infected' when FMD virus has been isolated or when

genome or antigen has been detected in biological samples.

 

 

12 The precise definition of a singleton reactor needs to be addressed in the context of an accurate

estimation of the specificity of the test in cases where high potency vaccines have been used.

 

 

 

THE NATIONAL FOOT & MOUTH GROUP

VETS FOR VACCINATION

An affiliation of organisations affected by 2001 UK epidemic

 

Co-ordinating Office:  3 The Common, Siddington, Cirencester, Glos  GL7 6EY

Tel: 01285 644319 / 01285 656812

 

 

 

22 April  2002

 

 

For the attention of  Dr Geoffrey Findlay

Inquiry Secretariat

IDL INQUIRY

Royal Society

6 Carlton House Terrace

London SW1Y  5 AG

 

 

Dear Dr Findlay

 

 

FMD CONTROL & ERADICATION – INCORPORATING EMERGENCY, PROTECTIVE VACCINATION

 

Please find attached our Draft Programme for the Containment, Control and Eradication of FMD incorporating Emergency, Protective Vaccination, which we submit for consideration by the Royal Society Inquiry.

 

After our discussions with the Royal Society, when we were asked by Sir Brian Follett how we would use vaccination in a future outbreak, we felt it appropriate to respond by preparing such a proposal.   We have, therefore, developed the attached programme in consultation with several vets and scientists.  In particular we are very grateful for the assistance and guidance of Dr Keith Sumption of Edinburgh University, and also Dr Paul Sutmoller and Dr Simon Barteling of the Netherlands, for their papers, presentations and advice on vaccination, carriers and science based risk assessment. 

 

The programme draws on the principle of Non Structural Protein free vaccines and the associated marker tests now available. 

 

As you may recall, we tabled the technical paper from Intervet on the use of 3 ABC marker test for FMD, when we attended the Royal Society.  We have subsequently liased with Dr Paul van Aarle of Intervet, for further technical and scientific data.

 

We now understand that a proposal is currently before the OIE regarding the return to disease free status post vaccination – and that a period of 6 months, as opposed to 12 months, for return to DFS post vaccination, is now under consideration.

 

"Additional proposal:

6 months after the last case or the last vaccination (according to the event that occurs the latest), where stamping out, emergency vaccination not followed by slaughtering of all vaccinated animals, and serological surveillance are applied, provided that a serological survey based on the detection of antibodies to non-structural proteins of FMDV demonstrates the absence of infection in the remaining vaccinated population."

Although we are aware that the Royal Society is not due to report its Inquiry findings before the OIE consideration of the proposal at the end of May, we feel it would be extremely helpful if the Royal Society could give an interim indication to Government regarding the proposal.

 

We hope that it may be possible for the Royal Society to express its initial thoughts on vaccination and, in particular, the scientific rationale behind the use of marker tests and vaccines, in order for the Government to form a view on the OIE proposal and inform its stance in considering this significant change of policy.

 

Clearly, the ability to achieve a return to DFS in 6 months, as opposed to 12 months, post vaccination, has fundamental consequences to the acceptability of the use of vaccination to control the disease.

 

We attach the technical paper from Intervet as presented to the 22nd Conference of the OIE Regional Commission.

 

We assume that the Royal Society already has copies of the EU Strategy for Emergency Vaccination (March 1999) and the other papers referred to, however, if not, please let me know and I will forward them directly.

 

If you have any further queries regarding our vaccination programme, or require further information, please do not hesitate to contact us.

 

Yours sincerely

 

 

 

 

Janet Bayley    NFMG

 

Peter Wood     Vets for Vaccination

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

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International Animal
Health Code - 2001

PART 2
..+ ;..

SECTION 2.1.
;..

CHAPTER 2.1.1.
;;



Contents
? - Index

 

 

CHAPTER  2.1.1.

FOOT AND MOUTH DISEASE

Article 2.1.1.1.

For the purposes of this Code, the incubation period for foot and mouth disease (FMD) shall be 14 days.

For the purposes of this Chapter, ruminants include animals of the family of Camelidae.

For the purpose of international trade, this chapter deals not only with the occurrence of clinical signs caused by FMD virus (FMDV), but also with the presence of infection with FMDV in the absence of clinical signs.

The following defines the occurrence of FMDV infection:

1)    FMDV has been isolated and identified as such from an animal or a product derived from that animal, or

2)    viral antigen or viral RNA specific to one or more of the serotypes of FMDV has been identified in samples from one or more animals showing clinical signs consistent with FMD, or epidemiologically linked to a confirmed or suspected outbreak of FMD, or giving cause for suspicion of previous association or contact with FMDV, or

3)    antibodies to structural or nonstructural proteins of FMDV that are not a consequence of vaccination, have been identified in one or more animals with either epidemiological links to a confirmed or suspected outbreak of FMD, or showing clinical signs consistent with recent infection with FMDV.

Standards for diagnostic tests and vaccines are described in the Manual.

 

Article 2.1.1.7.

Recovery of free status

1)    When an FMD outbreak or FMDV infection occurs in an FMD free country or zone where vaccination is not practised, one of the following waiting periods is required to regain the status of FMD free country or zone where vaccination is not practised:

a)     3 months after the last case where a stamping-out policy and serological surveillance are applied, or

b)    3 months after the slaughter of the last vaccinated animal where a stamping-out policy, emergency vaccination and serological surveillance are applied, or

c)     6 months after the last case or the last vaccination (according to the event that occurs the latest), where a stamping-out policy, emergency vaccination not followed by the slaughtering of all vaccinated animals, and serological surveillance are applied, provided that a serological survey based on the detection of antibodies to nonstructural proteins of FMDV demonstrates the absence of infection in the remaining vaccinated population.

2)    When an FMD outbreak or FMDV infection occurs in an FMD free country or zone where vaccination is practised, one of the following waiting periods is required to regain the status of FMD free country or zone where vaccination is practised:

a)     6 months after the last case where a stamping-out policy, serological surveillance and emergency vaccination are applied, provided that a serological survey based on the detection of antibodies to nonstructural proteins of FMDV demonstrates the absence of infection, or

b)    12 months after the last case where a stamping-out policy  is applied,

provided that effective surveillance has been carried out.

The application to regain the free status according to one of the procedures described above should be submitted to the OIE by the country in question within 2 years of the occurrence of the first FMD outbreak or the first detection of FMDV infection, otherwise the provisions of either Article 2.1.1.2., or Article 2.1.1.3., or Article 2.1.1.4., or Article 2.1.1.5., as relevant, are applicable to the country.