EDQM Workshop Bluetongue Vaccines · 1 EDQM Workshop Bluetongue Vaccines 19 February 2013 Strasbourg, France 19/02/13 ©2013 EDQM, Council of Europe. ... Efficacy of vaccination campaign

1

EDQM Workshop

Bluetongue Vaccines

19 February 2013Strasbourg, France

19/02/13 ©2013 EDQM, Council of Europe. All rights reserved.

Session 1

Current Situation

19/02/13 ©2013 EDQM, Council of Europe. All rights reserved.

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Vaccination against bluetongue in Southern Europe: a challenging

experienceGiovanni Savini

OIE Reference Laboratory for BT

Istituto Zooprofilattico Sperimentale dell’Abruzzo e Molise – Teramo

Italy

BTV-4BTV-16

BTV-9

BTV-1EBTV-4

BTV incursions in the Mediterranean Basin from 1998 to 2006

BTV-2&BTV-4

BTV-1W BTV-15 1998

2001

19991978

1999

2006

2003

2002

2004

20062000

2002

2006

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• After the incursion of BTV into SouthernEurope:

- Spanish, French, Italian and Portugueseauthorities have all carried out compulsoryvaccination campaigns to reduce directlosses due to disease and indirect losses dueto trade embargoes caused by the presenceof BTV

European reaction

• After the incursion of BTV into SouthernEurope:

- At that time, the MLVs produced byOnderstepoort Biological Products were usedas they were the only commerciallyavailable BTV vaccines. Based on theserotype(s) present in a given country/area,various MLV monovalent serotypeformulations have been used.

European reaction

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Live-modified vaccine

• Attenuation by egg passages and plaque purification

• Used for decades in South Africa but only in sheep

• MLV used in USA (BTV-10; 11; 13 and 17)• MLV (produced by OBP) have been used

in Israel, Bulgaria, France (Corsica), Spain, Portugal and Italy,

Bluetongue vaccination campaigns in European countries up to 2006

France (Corsica)

Bulgaria

Sheep Sheep Cattle Sheep Cattle Sheep Cattle SheepBTV3,8,9,10,11 1999-2000

BTV2 2000-2002** 2002-2006 2002-20062000-2001**

(Balearic island)BTV4 2004-2006 2005-2006

BTV2&4 2003-2004 2004-2006 2004-20062003 (Balearic

Island) BTV2&9 2002-2006 2002-2006BTV16 2004***

BTV2, 4, 16 2004*** 2004***BTV2,4,9,16 2004*** 2004***

BTV2,4,9 2005-2006 2005-2006BTV9

BTV2 2005

BTV4 2005-2006 2005-2006 2005-2006 2005-2006

BTV2&4 2006 2005-2006

ML

V

Year of vaccination

Inac

tiva

ted

PortugalVaccine

Italy* Spain

* In Italy various monovalent MLV combinations have been used in different regions

** The 2000 vaccination campaigns started on November

*** The use of the BTV-16 MLV was discontinued

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Advantages• It is a good product if used properly

(right season and gestation period):CheapOne injection Strong and long lasting immunity

Live-modified vaccine

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Efficacy of vaccination campaign

The efficacy of MLV vaccinationhas widely been demonstrated inthe field.

Following the 2000-2001 and 2003BT vaccination campaigns in theBalearic Islands, no outbreaks havebeen detected since December2003 in the area.

0 %

< 40 %

40 % - 59,9 %60 % - 79,9 %

80 %

2000 2001 2002 2003

2000 2001 2002 2003

Vaccination coverage

Clinical outbreaks

EFFICACY OF VACCINATION CAMPAIGNS

0 % 0 %

Outbreaks: 6,869

Diseased animals:262,759

Outbreaks: 6,807


Outbreaks: 432


Outbreaks: 3,709


BTV4New serotype

Sardinia: 24 cases

Tuscany: no cases

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2004

0 %< 40 %40 % - 59,9 %60 % - 79,9 % 80 %

2004

Vaccination coverage

Clinical outbreaks

BTV1New serotype

Outbreaks: 127

Diseased animals: 2,481

Outbreaks: 0

Diseased animals: 0

Outbreaks: 238

Diseased animals: 4,861

2005

2005

2006

2006

Outbreaks: 15

Diseased animals: 609

2007

2007

Results of the 2002 BTV vaccination campaign

Not available

0 %

< 40 %

40 % - 59,9 %

60 % - 79,9 %

80 %BTV 2

BTV 2 and 9

BTV 2

BTV 2 and 9

vaccine serotype

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Virus circulation (outbreaks and seroconversions) in the regions where more than 80% of the

livestock animals were vaccinated2001 2002

Not available

0 %

< 40 %

40 % - 59,9 %

60 % - 79,9 %

80 %

Virus circulation (outbreaks and seroconversions) in the regions where less than 80% of the livestock animals were

vaccinated

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Adverse events observed in the use of MLV

• Mild symptoms (5-7 dd post vaccination)

• Possible vaccine virus circulation because of high viraemic titers

Sheep inoculated with BTV-4 vaccine virus

Cyanosis of the whole oral cavity including the tongue (acute oxygen deficiency)

Acute respiratory dysfunction

Swelling and discolouring of the lips and tongue and copious salivation

From IAH, Pirbright

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Most drawbacks are limited if the vaccine isolates are well attenuated (BTV-2 and 4) however they could be considerable if the strains are not well attenuated (BTV-16).



0

20000

40000

60000

80000

100000

120000

140000

160000

180000

200000

220000

0 3 6 10 13 17 20 24 27 31 34

Days following vaccination

Vir

aem

ic t

iter

s (T

CID

50/m

l)

BTV-9 BTV-2

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Circulation of BTV-16 vaccine strainin Italy2006

2008

2007

2009

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BTV-16 in Croatia

…. or if the vaccines are administered in animals with existing infections …….


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According to the results of a field trial, flocks positive to Maedi-Visna have a 2.5 fold increased risk of suffering from side effects compared to flocks with no Maedi Visna infection.


• Possibility that the vaccine virus crosses the placental barrier causing abortion, stillbirth or neonatal mortality

• Preliminary studies were carried out prior and during the BT mass vaccination- No adverse effects on reproduction were

observed in CATTLE (BTV2 and BTV2-BTV9)


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Italian vaccination campaigns 2002-2003

During 2002-2003 BTV Italian outbreaks:1264 ovine, bovine, goat and buffalo

foetuses were tested for the presence of BTV by VIFoetal spleens and/or brains of663 ovines, 429 bovines, 155 goats17 buffaloes

BTV strains were isolated from 31 foetuses (2.4%; IC95%: 1.7-3.4%):24 (3.6%; IC95%: 2.4-5.3%) from ovine

foetal tissues;6 (1.4%; IC95%: 0.6-3.0%) from bovine

foetal tissues;1 (0.6%; IC95%: 0.2-3.5%) from the

spleen of a goat foetus.

Italian vaccination campaigns 2002-2003

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Malformation induced by MLVs

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• Field data (first vaccination campaign): adverse effects were notified in 312 of 87,245 holdings (0.16 % of cattle herds and 0.5% of small ruminant flocks). The presence of vaccine virus was confirmed by the laboratory

• As a purely indicative quantitative assessment of the adverse event observed, one can examine data collected between 1991 and 2001 in the US by the Vaccine Adverse Event Reporting System (VAERS). During the study, 1.9 billion doses of 27 different types of human vaccine were administered and the prevalence of adverse events was 11.4 per 100 000 (equivalent to 0.01%)


Effect on semen: • A decrease in semen quality was also observed

after the second vaccination (BTV-2) in 23 rams; however, at day 69, the semen quality of the vaccinated animals was not significantly different from those of the 23 controls.


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Effect on milk production: • transient decrease of 30% a week after

vaccination with bivalent BTV2 and BTV9 vaccine to sheep. However it was not accompanied by significant changes in milk quality (cell count, pH, fat, protein and lactose) A study involving more than 18,000 dairy cows in

220 herds vaccinated with BTV-2 MLV did not demonstrate any negative effects either on the quality or quantity of milk produced


-50

-45

-40

-35

-30

-25

-20

-15

-10

-5

0

5

10

15

20

0 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 22 23 24


% m

ilk p

roduction p

er head

0

20000

40000

60000

80000

100000

120000

140000

160000

180000

200000

220000

Virae

mic

titers

(TC

ID50/

ml)

Vaccinated group

Unvaccinated group

Total milk production

BTV-9

BTV-2

Effect of BTV-2 and BTV-9 MLV on milk production in sheep

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Effect of BTV-2 and BTV-9 MLV on milk production in cattle

0

2

4

6

8

10

12

14

-4dd

-2dd

1 dd

7 dd

10 d

d

15 d

d

20 d

d

24 d

d

29 d

d

34 d

d


Mea

n p

rod

uct

ion

per

hea

d

(lit

er)

05000100001500020000250003000035000400004500050000

Vir

aem

ic t

iter

(T

CID

50/m

l)

Vaccinated group

Control group

BTV 2

BTV 9

Adverse events in the use of MLV

Possible reversion to virulence of the vaccine viruses and reassortment between vaccine and field strains of the virus

• The reassortment of BTV strains has been monitored in Italy over the last eight years.

• No reassortment between vaccine and field strains has been observed, while it has been witnessed between vaccine virus strains present in the same vaccine- Between BTV2 and BTV4- Between BTV2 and BTV16 (in Israel)

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Segment 2 Segment 5 Segment 6 Segment 10 Segment 7 NTPs AA NTPs AA NTPs AA NTPs AA NTPs AA

BTV2 field 96 98 83 95 88 98 84 98 93 100 BTV2 vaccine 100 100 82 95 100 100 84 95 100 100 BTV4 field 50 41 83 95 70 77 85 98 79 97 BTV4 vaccine 50 41 83 95 69 78 83 93 81 98 BTV9 field 54 41 97 99 69 78 93 99 BTV9 vaccine 51 40 82 95 77 91 84 95 BTV16 field 49 46 82 95 70 78 98 99 BTV16 vaccine 49 46 100 100 70 78 100 100

Segment 2 Segment 5 Segment 6 Segment 10 Segment 7

NTPs AA NTPs AA NTPs AA NTPs AA NTPs AA BTV2 field 96 93 98 88 98 83 94 81 98 BTV2 vaccine 100 95 99 99 99 98 100 81 97 BTV4 field 50 94 98 70 77 83 94 92 99 BTV4 vaccine 49 100 100 69 77 99 99 99 100 BTV9 field 50 83 95 69 97 83 94 BTV9 vaccine 49 96 98 77 90 93 100 BTV16 field 56 95 99 69 78 83 94 BTV16 vaccine 56 83 95 69 78 83 95

Similarity (%) between 88510/04 BTV-2 field isolate and the circulating Italian strains.

Similarity (%) between 87126/04 BTV-2 field isolate and the circulating Italian strains.

• Despite the reassortment hypothesis, the number of existing serotypes is constant and remains 24 (now 26)

• Claims of the factual dangers of the use of MLV vaccine against BT due to either reversion to virulence of the vaccine viruses and reassortment between vaccine and field strains of the virus remain hypothetical for the time being and are not supported by factual scientific data.


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• Both experimental and field experiences proved that MLVs are immunogenic and capable of protecting and preventing viraemia in vaccinated animals after challenge or infection.

• Following several years of vaccination campaigns, several Member States concluded that MLV vaccines, when used correctly, were relatively safe and successful.

Conclusions

• In the absence of effective inactivated vaccines and in an emergency, MLVs a valid option for vaccination, provided that the quality, safety and efficacy of the MLV strains match the International standards.

• These vaccines can be an alternative also in a non-emergency situation when local conditions (e.g. in case a large amount of animal must be immunized in a very short period of time) indicate their use.

Conclusions

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… last year BTV outbreak in Sardinia ….

Thank you

1

Stéphan ZientaraJRU Virology ANSES/INRA/ENVA

Maisons-Alfort, France

Stéphan ZientaraJRU Virology ANSES/INRA/ENVA

Maisons-Alfort, France

VACCINATION AGAINST BLUETONGUE IN NORTHERN EUROPE: ANOTHER CHALLENGING EXPERIENCE

EDQM, 2013, Strasbourg

Vectors : Culicoides(imicola,…)

> 1,500 species

Orbivirus

26 serotypes BTV9 serotypes AHSV7 serotypes EHDV

2

Epidemiological situation in Europe

2006 to 2013

Control

Modified live vaccinesInactivated vaccines

199820081998: Free of BTV

3

5

Situation in the Mediterranean basin (1998-2006)

2, 4, 9, 16, 1

9

22004

12

2

4,16

62, 4, 9, 16, 1

9

22004

12

2

4,16

Summer 2006

8

Emergence in 2006New serotypeNew areaNew clinical pattern

4

2006

Unbelievable year !!

The Netherlands, 2006

beginning mid-August, 20062 sick/90 sheep

5

Clinical bluetongue in cattle

ARSIA,E Thiry, ULG

End 2006695 outbreaks in Belgium914 in Germany7 in France

6

« Overwintering ? »

2007

The invasion

7

End 2007

8

2008

The depression !!!

December 31, 2008

Number and location of BTV cases in France in 2008

31 848 cases of BTV- 26 925 cases of BTV8.- 4 829 cases of BTV1.

- 99 cases BTV 1 and 8 in the same farms

BTV-8 BTV-1

9

17

2006 : 7 cas

2007: 14 000

2008 : 38 000

2009 : 832010 : 1

2011: 0

2012 : 0

2013 : free status

2010

New introductions 2008-2009

BTV-4&

BTV-16

BTV-9

BTV-1

BTV-4BTV-2

&BTV-4

BTV-1

BTV-8?

BTV-11

BTV-1

BTV-6

BTV-8?

BTV-1

BTV-15

BTV-16

BTV-9

10

BTV-6BTV-8BTV-11

BTV-1

BTV-1

2012 in Europe : BTV-14

BTV-14

http://www.defra.gov.uk/animal-diseases/files/poa-btv14-20121130.pdf

11

Modified live vaccines

• Bottle A includes BTV serotypes 1, 4, 6, 12, 14

• Bottle B includes serotypes 3, 8, 9, 10, 11

• Bottle C includes the serotypes 2, 5, 7, 13, 19

OBP, South Africa

Giovanni Savini

12

THE PREVENTION : VACCINATIONEpidemiological situation in Europe

2006 to 2013

Control

Modified live vaccinesInactivated vaccines

18

8

14

23

10

20 1716 3

13 4 11

5

21

6

129

2

221

715 19

24

Serological relationships between BTV serotypes

Strong

weak

very weak

13

VaccinationSerotype 2

49 outbreaks

BTV 2

2000

Bluetongue in Corsica (2000-2006) : co-circulation of vaccine and wild strains

335 outbreaks

0

VaccinationSerotype 2

17 outbreaks

2001 2002

2003

BTV 2 wtVaccine BTV 2

BTV 2 Vaccine wBTV 2 ?

BTV 4Vaccine BTV 4Vaccine BTV 2BTV 2 ?

39outbreaks

2004

BTV 4BTV 16Vaccine BTV 16 (not attenuated enough !!!)Vaccine BTV 4Vaccine BTV 2 (inactivated)wt BTV 2 ?

BTV-16 in Corsica (2004)

. no BTV 16 vaccination performed in Corsica

. first cases in sheep in September 2004

. Virus isolated and typed (16)

November : vaccination with live BTV-16 vaccine

• 19 herds vaccinated in December 2004 (serotype 16)

+ vaccination 2 and 4

• 11/19 herds with BT-like clinical signs

14

Nucleotide Substitutions (x100)0

13.6

24681012

BT 4 Spain 2003BT 4 Morocco 2004BT 4 Corsica 2003BT 2 Tunisia 1999BT 2 Corsica 2000

BT X Réunion 2003BT 4 Greece 1979BT 4 Greece 1999BT 4Greece 2000

BT 1 SABT 2 SA

BT 11 SABT 11 SA

BT 8 SABT 8 SABT 4 Dom Rep

BT 17 ChinaBT 16 Corsica 2004BT 16 Vaccine

BT 9 Greece 1998BT 21 Aus AsiaBT 20 Aus Asia

BT 12 Jam

BT 2 USA

BT 2 Vaccine

BT 11 chinaBT 2 SA

ABT 3 SABT 4 SA

BTV 4 SABT 18 SA

BT 8 SABT 3 Reunion

BT 10 USABT 11 USA

BT 4 Vaccine

Phylogenetic relationships Nucleotide sequences (segment 10, NS3, GenBank)

MODIFIED LIVE

VACCINE

STRAIN DATE AND PLACE OF

ISOLATION

HISTORY

BTV-2 VRYHEID/5036 1958, REPUBLIC OF SOUTH AFRICA

Virus passaged 50 times in embryonated chicken eggs and plaque selected three times and passaged twice in BHK21 cells

BTV-4 THEILER/79043 1900, REPUBLIC OF SOUTH AFRICA

Virus passaged 60 times in embryonated chicken eggs, followed by 3 small plaque selections and 9 passages in BHK21 cells.

BTV-9 1900, REPUBLIC OF SOUTH AFRICA

Virus passaged 70 times in embryonated chicken eggs, followed by 3 small plaque selections and 6 further passages in BHK21 cells.

BTV-16 PAKISTAN/7766 PAKISTAN Virus passaged 37 times in eggs, followed by 3 large plaque selections, 2 passages in BHK21 cells and 1 in VERO cells.

Characteristics of the Bluetongue virus vaccine strains (OBP)

15

Current global position of bluetongue live attenuated vaccinesCountry/Origin Serotype Details of the strain Passage history

RSA, 1958RSA, 1958Cyprus 1944RSA~1900RSA, 1953RSA, 1958RSA, 1955RSA, 1937RSA, 1942Portugal, 1956RSA, 1944RSA,1941RSA, 1959RSA, 1959PakistanRSA, 1976

Colorado serum Co.,Denver, Colorado, USA

Central Veterinary Control& Research Institute,Ankara, Turkey

Biopharma, Morocco

California, USA

BTV-1BTV-2BTV-3BTV-4BTV-5BTV-6BTV-7BTV-8BTV-9BTV-10BTV-11BTV-12BTV-13BTV-14BTV-16BTV-19

BTV-10

BTV-4

BTV-4

BTV-10BTV-11BTV-17

Biggarsberg/8012Vryheid/5036Cyprus/8231Theiler/79043Mossop/4868Strathene/5011Utrecht/1504Camp/8438University Farm/2766Portugal/2627Nelspoort/4575Estantia/75005Westlands/7238Kolwani/89/59Pakistan/7766143/76

Modified live virus of serotype 10

Freeze-dried modified, sheep

Live attenuated, sheep

Bluevac-10Bluevac-11Bluevac-17

50E 3P 4BHK50E 3P 4BHK

45E 2BHK 3P 5BHK60E3Pa 9BHK

50E 2BHK 3Pa 6BHK60E 3Pa 7BHK60E 3Pa 7BHK

50E 3BHK 10Pa 7BHK70e 2BHK pp 3BHK 7P 6BHK

E8135E 3P 5BHK55E 3P 4BK

45E 2BHK 3Pa 4BHK60E 3Pa 4BHK

37E 3P 2BHK 1Vero29E 3Pa 3BHK

-

-

-

-

Onderstepoort Biological Products

(EFSA, AHAW 2007)

Modified live vaccines

-infection and teratogenicity of MLVs for the developing fetus : MLVs have the capacity to cross the ruminant placenta leading to embryonic or fetal death and cerebral malformations (hydroencephaly in calves) after infection of older fetuses that survive congenital infection

- BT related reproductive disorders include early embryonic deaths, abortions, malformed fetal calves or lambs, transient infertility in bulls and rams

- possibility that vaccine viruses will infect vectors and establish in the environment as quasispecies with possible reversion to virulence or creation of new strains of BTV (reassortment)

16

Number of vaccinated animals with the modified live vaccines (adverse effects)

• Balearic Islands (2000-2001) : 320 000 sheep and goats (BTV-2)

• Corsica (2001-2004) : > 130 000 sheep and goats (BTV2) ;

130 000 sheep and goats (BTV4)

• Italy (from 2002) : 4 000 000 sheep and goats (BTV2 and BTV2-4) ; 400 000 cattle (BTV2-4) ; 1 700 000 (BTV2-9) ; 1 000 000sheep, goats and cattle (since 2005)(BTV2-4-9)

• Corsica (2004) : BTV16 : adverse effects

• Sardinia : BTV2, 4 and 16 : adverse effects (sheep and goats)• South of Italy : BTV2-4-9-16 : 600 000 animals : no adverse effets

Inactivated vaccines

17

Current global position of bluetongue inactivated vaccines (EFSA, AHAW 2007)

Country Serotype

Merial SAS, Lyon, France

Intervet (MSD)

Fort Dodge (Pfizer)

India (TANUVAS)

India (CADRAD)

IAH & VB, Bangalore

Italy

BTV-2BTV-4BTV-9BTV-8BTV-1

BTV-8BTV1

BTV-8BTV1

BTV-1BTV-23

BTV-18BTV-1BTV-2

BTV1 & BTV23

BTV11,17

BTV2, 4BTV16

Liquid, mono/multivalent. Commercialized under ATU in France, Italy, Spain and Portugal

(i) Bivalent, BEI-Formaldehyde inactivated & adjuvanted Montanide ISA50. Passed in house and field trials.

(ii)BEI-Formaldehyde inactivated & adjuvanted with a combination of mineral oil, Span 80 and Tween 80 (Aqueous: 40 parts, Oil: 60 parts) Passed in house and field trials

Hydroxylamine inactivated & adjuvanted with saponin, aluminium hydroxide individually & in combination

BEI inactivated BEI inactivated & saponified BTV1BEI inactivated & saponified BTV 2BPL inactivated and adjuvantedBEI inactivated & Al(OH)3 adjuvantedInactivated BT vaccine

Bivalent inactivated BT vaccine Inactivated BT vaccine

2005-2006

Bluetongue vaccination campaigns in European countries (EFSA, AHAW 2007)

France (Corsica)

Bulgaria

Sheep Sheep Cattle Sheep Cattle Sheep Cattle SheepBTV3,8,9,10,11 1999-2000

BTV2 2000-2002** 2002-2006 2002-20062000-2001**

(Balearic island)BTV4 2004-2006 2005-2006

BTV2&4 2003-2004 2004-2006 2004-20062003 (Balearic

Island) BTV2&9 2002-2006 2002-2006BTV16 2004***

BTV2, 4, 16 2004*** 2004***BTV2,4,9,16 2004*** 2004***

BTV2,4,9 2005-2006 2005-2006BTV9

BTV2 2005

BTV4 2005-2006 2005-2006 2005-2006 2005-2006

BTV2&4 2006 2005-2006

ML

V

Year of vaccination

Inac

tiva

ted

PortugalVaccine

Italy* Spain

2008 : vaccination > 120 000 000 inactivated vaccine BTV-8

18

2008 – 2009 :

BTV8 Vaccination on aCOMPULSORY basis

- in Belgium for cattle (younganimals in priority) and sheep

- in Germany

VOLUNTARY basis- in Germany in 2010- in the Netherlands

2006-2007 : Lack of BTV-8 inactivated vaccines

Vaccination Roll‐out plan – UK in 2008

High and early coverage in areas infected with BTV

Around 80-90%

C Oura, IAH

Voluntary vaccination policy

19

The Netherlands

voluntary basis in both years 2008 and 2009In 2008, farmers could receive reimbursement directly.

2009, they had to pay all by their selves. Decrease of the willingness to vaccinate !!!

2008 2009

73% in sheep 42%

71% in cattle 58%

43% in goat farms

19%

DGAl18 339 cases

Situation in France (beginning of 2008)

Initial zone of vaccination

20

Name of the vaccine Name of the lab species Site of vaccination ml/dose boost Minimal Age at vaccination

BTV1

Zulvac 1 cattle FORT DODGE (PFIZER)

Cattle IM 2 12 2.5 months

Zulvac 1 ovine FORT DODGE (PFIZER)

Ovine SC 2 12 1

Bluevac 1 CZ Cattle SC 4 12 2

Bluevac 1 CZ Ovine SC 2 12 2.5

Syvazul 1 SYVA Ovine SC 2 12 3

BTV8

Bovilis INTERVET

(MSD)

Cattle SC 1 12 1

Bovilis INTERVET

(MSD)

Ovine SC 1 12 1

BTV Pur Alsap 8 MERIAL Cattle SC 1 12 1

BTV Pur Alsap 8 MERIAL Ovine SC 12 1

Zulvac 8 Bovis FORT DODGE

(PFIZER)

Cattle IM 2 6 2.5

2009 -2010Vaccination in France

•Vaccination against BTV1 and 8 : compulsory

•Cattle > 2.5 months of age

•Sheep > 3 months age

•Beginning 2 of November 2009 for 12 months

•Budget : 98 millions € (State)

21

PROGRAMA DE VACUNACIÓN FRENTE A

LA LENGUA AZUL EN ESPAÑA

MINISTERIODE MEDIO AMBIENTEY MEDIO RURAL Y MARINO

Luis Jose Romero Gonzalez , MAPA

Vaccination against BT in Spain

COBERTURA VACUNAL MEDIA

0

20

40

60

80

100

120

OVINO-ST1 OVINO-ST8 BOVINO-ST1 BOVINO- ST8

MINISTERIODE MEDIO AMBIENTE

Y MEDIO RURAL Y MARINO

November 2007 to December 2008

96.6% 90% 73.6%76.3%

compulsory vaccination

vaccination of cattle, sheep > 3 months-old in restriction zones

vaccination costs : State, Commission

22

Prevention : summary

BTV-9

1999

2001

2000

MLV3-8-9-10-111999-2000

MLV2-9

2002-20062002

Kris de Clercq

From 2000 to 2006

Modified live vaccine : OBP, South Africa

23

BTV-22000

BTV-22001-2002

MLV-22001-2004

MLV-22000-2001

MLV-22002-2006

Kris de Clercq

From 2000 to 2006

BTV-4 BTV-4

BTV-4BTV-16

BTV-162002

20032004

2003

2004

20052005-6

2002

MLV-4Inact-42005-6

MLV-2-4 2004-06MLV-2-4-16 2004

MLV-2-4-9-16 2004MLV-2-4-9 2005-06Inact-2-4 2005-06

MLV-4 2004-06Inact-4 2005-06

MLV-2-42003

MLV-2-4 2003-04MLV-4 2004

MLV-16 2004Inact-2 2005

Inact-2-4 2006

Kris de Clercq

From 2000 to 2006

24

BTV-6BTV-8BTV-11

BTV-1

BTV-1 Inact-82008

Inact-12008

MLV1-42007-08

From 2006 to 2010

in 2010-2012: Sardinia: vaccination with BTV1, BTV2 and 4 inactivated vaccines

in 2010:Piemonte Region: vaccination

with BTV8 inactivated vaccine

Giovanni Savini

25

Conclusion

-Control by (compulsory) vaccination(live/inactivated vaccines)

-Bivalent 2-4 and 1-8 inactivated vaccines

- Eradication of BTV in the North of Europe

Acknowledgements

Jose-Manuel Sanchez-Vixcaino, UCM, Spain

Kris de Clercq, CERVA-CODA Belgium

Chris Oura, Pirbright Insitute, UK

Martin Beer, FLI, Germany

Bernd Hoffmann, FLI, Germany

Giovanni Savini, IZST Teramo, Italy

Peter Mertens, Pirbright Institute, UK

Piet van Rijn, CVI, The Netherlands

…

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VACCINATION AGAINTS BT VIRUS:SPANISH EXPERIENCE

Luis J. Romero González: [email protected]

Subdirectorate General for animal health, animal hygiene and traceability

Strasbourg, 19th February 2013

25/02/2013

2

BALEARIC ISLANDS 2000: BTV-2

Adopted measures:

• Control of susceptible species movements• Vaccination of ovine population: attenuated vaccine BTV-2 (>322.000 animals, October 2000-May 2001) •Virus circulation not detected during 2001-2002

BALEARIC ISLANDS 2003: BTV-4

Adopted measures:

• Control of susceptible species movements•Vaccination of ovine population: attenuated vaccine BTV-4 (>339.000 animals, October 2003-March 2004) •BTV-2 free since 2002 and BTV-4 free since 2005.

16 OUTBREAKSEpizootic wave 2 months

(27/10/03 a 11/12/03)

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3

SPAINISH MAINLAND 2004-2006: BTV-4

Adopted measures:

• Control of susceptible species movements

• Vaccination of ovine population: attenuated vaccine BTV-4 (2004-2005).

• Problems with the cattle movement: inactivated vaccine?

•No outbreaks of BTV-4 (November 2006-October 2010)

2004: 322 outbreaks

2005: 88 outbreaks

2006: 0 outbreaks

BT SITUATION IN SPAIN 2007: BTV-4 and 1

2007 first BTV-1 incursion: high level of ovine mortality

Vaccination a must!!!!

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4

BT SITUATION IN SPAIN 2008: BTV-4, 1 and 8

First BTV-8 incursion in 2008

BT SITUATION 2010-2013: BTV-4, 1 and 8

Reintroduction of BTV-4 October 2010

BTV-8 free since January 2013

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5

BLUETONGUE VACCINATION PROGRAMME

• OBJECTIVE: vaccination of all the ruminant population(sheep and cattle) within the restricted zone so that:

• the viral circulation diminishes

• neither clinical signs nor deaths in ovine

• allowing movements to free zone

• achieving the eradication of the disease


• 2001-2005 and first semester of 2006; attenuated live vaccine (Onderstepoort – South Africa)

• Meeting with “Veterindustria” January 2005: to develop inactivated vaccine for ovine-bovine.

• Five laboratories attend the request of development of BTV-4 inactivated vaccines: Merial, CZ, Calier, SYVA and FortDodge

• Eficacy trials were performed in different Spanish BSL-3 animal facilities, and the laboratorial tests in LCV of Algete (Spanish NRL for BT)

• Since May 2006: BTV-4 inactivated vaccine

VACCINES USED

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6

INACTIVATED vs LIVE ATTENUATED

It can be used not only in sheep, BUT ALSO in bovine

It can be used along all the year

Useful tool to facilitate animal movements (no viraemia)

More expensive and two doses per animal (at least for cattle)

Safer


Compulsory vaccination programme (until July 2011)

All the ovine and bovine population older than 3 months in the restricted zones

The cost of the vaccine was supported by the Ministry of Agriculture (co-financed by Commission), and the cost of the vaccination by the Autonomous regions

The vaccine could be applied by official veterinary services or by authorised veterinaries, depending on the Autonomous region, but always under official control

Vaccinated animals must be marked by ear tag, microchip or in the bovine identification passport


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VACCINATION DATA

YEAR 2005 2006 2007 2008 2009 2010 2011

TOTAL BOVINE IN RESTRICTED ZONE

1,424,161 7,723,787 2,351,115 6,327,685 5,951,452 5,835,901 6,532,594

BOVINE VACCINATED

BTV-1 51,060 4,660,000 5,600,947 5,302,145 1,457,952

BTV-4 43,497 140,123 1,178,499 1,615,000 293,708 141,986

BTV-8 4,200,000 5,643,323 5,303,344 340,627

TOTAL OVINE IN RESTRICTED ZONE

6,977,990 6,086,632 11,185,980 16,698,938 16,649,010 16,804,479 17,047,105

OVINE VACCINATED

BTV-1 1,170,197 16,000,000 14,592,099 14,544,559 6,925,672

BTV-4 6,287,965 3,409,742 8,014,031 6,460,000 483,697 214,091

BTV-8 14,000,000 14,908,306 14,528,249 749,230

VACCINATION COVERAGE

2008

0.00

20.00

40.00

60.00

80.00

100.00

OVINE BTV-1 OVINE BTV-8 BOVINE BTV-1 BOVINE BTV-8

YEAR OVINE BTV-1 OVINE BTV-8 BOVINE BTV-1 BOVINE BTV-8

2008 96.60 76.30 90.00 73.60

2009 95.00 93.00 91.00 90.00

YEAR

2008

2009

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INMUNISATION CONTROL

Antibody detection by ELISA

Vaccinated bovine-ovine animals 3-12 moths old

15 days after vaccination

95/5: 115 bovine samples and 45 ovine samples per AR

Ovine Bovine

Samples Positive % (IC95%) Samples Positive %

(IC95%)

2008 2.115 2.072 97,97% (97,38:98,36) 2.121 1.954 92,13%

(91,09:93,02)

2009 515 462 89,71% (87,09:92,33) 1.238 970 78,35%

(75,76:80,94)

BLUETONGUE EVOLUTION

6777

0 0

2861

0 29377

0 1 80 10 1 9 3 0 2 0 0

0

2000

4000

6000

8000

S 1 6 7 7 7 2 8 6 1 3 7 7 8 0 9 2

S 4 0 0 0 10 3 0

S 8 0 2 9 1 1 0 0

2 0 0 7 2 0 0 8 2 0 0 9 2 0 10 - 2 0 11 2 0 11- 2 0 12 2 0 12 - 2 0 13

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CURRENT SITUATION: BT RESTRICTION ZONES

FUTURE: BTV-1 VACCINATION ZONES?

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10

CONCLUSIONS

Vaccination prevents clinical signs and mortality

It controls viral circulation and leads to decrease of outbreaks number

It facilitates animal movements

It led to eradication of BTV-2 in 2002, BTV-4 in 2005 (Balearic Islands), BTV-4 in 2009 (Spanish Mainland) and BTV-8 in 2013

Benefit is not only for own country but also for the rest of the region

THANK YOU FOR YOUR ATTENTION!

1

Health andConsumersHealth andConsumers

Vaccination against Bluetongue in the EU

Lessons learnt

Francisco Javier Reviriego GordejoEUROPEAN COMMISSION HEALTH & CONSUMERS DIRECTORATE-GENERAL G2 - Animal Health Head of Sector Disease Control and identification

Edqm – International workshop 19/02/13, Strasbourg


Outline

Evolution bluetongue in the EU 2001 – 2012 EU reaction: policy and measures Impacts and Costs Lessons learnt Conclusions

2


Bluetongue in the EU

2002 -2006: Bluetongue mainly presentin Mediterranean area (serotypes 1, 2, 4, 9, 16)

Autumn 2006: Start of BTV-8 epidemic Netherlands, Luxembourg, Belgium and Germany



2007: BTV-8 spreads southwards towards France

BTV-1 in Spain, Portugal and France

Start of mass vaccination campaign against BTV-1 and BTV-8

3



2009-2012Due to successful vaccination campaigns:

• BTV8 disappeared• BTV1 only sporadically

in Spain and Portugal

Local circulation of BTV 1, 2, 4, 9 and 16 in Italy, Greece and Cyprus


Evolution Bluetongue in the EU

http://ec.europa.eu/food/animal/diseases/controlmeasures/bt_outbreaks_en.htm

4


Evolution Bluetongue in the EUNumber of outbreaks notified by year

Normal scaleLogaritmic scale


8

EU Response: four pillars

EU legislation• Council Directive (2000/75/EC)• Commission Regulation (1266/2007)

EU funds• Council Decision 2009/470/EC

OIE Terrestrial Animal Health Code• Chapter 8.3

European Food Safety Authority (EFSA)http://www.efsa.europa.eu/

5


EU response: Measures in the EU

Sustainable control

Movement restrictions

SurveillanceVaccination


EU response: Changes in legislation

Commission Regulation (EC) No 1266/2007 as amended 12 times Vaccinated animals can always move

Council Directive 2000/75/EC amended by Directive 2012/5/EU of the European Parliament and the Council No restriction for vaccination with inactivated vaccines Still some restrictions for for live attenuated vaccines

6


EU response: Vaccination

Inactivated vaccines approved under exceptional circumstances

Mass emergency vaccination campaign in 2007-2008 against BTV1 and BTV8

Vaccination essential part of eradication programmes EU initial allocation of funds for bluetongue vaccination and

surveillance:


EU response: EU funds

7


Lessons learnt

- EU rules not easy to understand- Impact of bluetongue- Economics: Costs (vaccination) vs Benefits (disease control)


EU rules not easy to understand

Modified live vaccine

8


Impact of Bluetongue depends on: (un-) favourable conditions for virus persistenceweatherdensity of susceptible animals

importance of trade: mainly sending animals or receiving animals

susceptible population:mainly ovine bovine animals

virus serotype


Impact – calves born 2005-2012

Source: FAVV, Belgium

Belgium

9

Health andConsumersHealth andConsumers Source: UECBV, 2012

France

Impact – births 2002-2012


Impact – dead cattle 2007-2011


Belgium

10


Impact – milk production 2007-2012


Belgium

Health andConsumersHealth andConsumers Source: GEB-Animal Breeding Institute as per Eurostat

323

54

20

35

38

17

18

107

22132

20

48

34

424

35

135

28

28

48

24 70

141

50

24

45

44

24

10629

47

2149

77

Turkey

LebanonAlgeria

37

122

Movement of cattle in Europe in 2011 (x 1000 heads)

5 million European cattle cross the borders every year

(7% of the EU livestock)

1121

Impact: Trade movements within the EU

11


Total amount

EXAMPLE: Movement of weanlings within

France for the production of young

cattleFrance

Has 1/3 of the European suckler cows

50% of male calves are exported as weanling (around 1Mln)

17% of the cows are relocated within France to deliver young cattle (200 000)

Impact: Domestic movements


Costs of disease control measures

Swiss study:• "the surveillance and intervention programme

[vaccination] implemented in 2008–2009 was economically beneficial, while its continuation in the same form in 2010–2012 [when free status was regained] would produce net costs"

12


Costs of disease control measures: EU contribution


Costs of vaccination: Unitary costs per vaccine dose claimed by MSs for EU co-funding

13


Costs of vaccination: Unitary costs per vaccine dose claimed by MSs for EU co-funding


Lessons learnt on vaccination (I)

Vaccination is effective as a tool for control and eradicationExample BTV8 and BTV1 in many MSs

But not everywhere…

Preventive vaccination in high risk areas can be worthwhile Legal obstacles to perform vaccination were removed

But currently not so widely implemented…

Mass vaccination is very expensiveSuccessful exercise

But doubts about proportionality…

14


Lessons learnt on vaccination (II)It takes time to develop and produce inactivated vaccines (~ 18 months?)Live vaccines are available…

Pharmaceutical industry expected a big-long lasting vaccines marketHowever this was not the case…

Responsibility on vaccination moved from policy makers to animal keepersAs they know best…


Conclusions• - Bluetongue is an actual disease…• - Bluetongue is a problem with many dimensions:

ProductionVeterinaryScientificEnvironmentalClimaticEconomicTradePolitical…

• - Bluetongue is there and will continue to be there…• - Vaccine is the only control tool

15


Thanks

1

MULTI-STRAIN DOSSIER CONCEPTImpact on drafting potential PhEur

Monographs on Bluetongue vaccines

Dr Jean-Claude ROUBYPhone : 02 99 94 78 82

Mail : [email protected]

Agence Nationale de Sécurité Sanitaire de l’Alimentation, de l’Environnement et du Travail

Agence Nationale du Médicament Vétérinaire

8 rue Claude Bourgelat, Parc d’activités de la Grande Marche - Javené

BP 90203 – 35302 FOUGERES CEDEX, France

Titre du diaporama

2

Directive 2001/82/EC (as amended by Directive 2009/9/EC), Title IV, section 1B – Multi-strain dossier :

• For certain immunological veterinary medicinal products (foot-and-mouth disease, avian influenza and bluetongue) the concept of the use of a multi-strain dossier is introduced.

BACKGROUND (1)

2

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• A multi-strain dossier means a single dossier containing the relevant data for a unique and thorough scientific assessment of the different options of strains/combinations of strains permitting the authorisation of vaccines against antigenically variable viruses.

multi-strain multivalent !

BACKGROUND (2)

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• Scientific guidelines for the submission and evaluation of multi-strain dossiers shall be adopted by the Agency.

Guideline EMA/CVMP/IWP/105506/2007

(in effect since 1 July 2010)

BACKGROUND (3)

3

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multi-strain concept

NOT compulsory !

standard dossier

or

multi-strain dossier

BACKGROUND (4)

Titre du diaporama

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CURRENT SITUATION (1)

MSV 1 MSV 2 MSV 3 MSV 4 MSV 5

FORMULATION A FORMULATION B

FINISHED PRODUCT A FINISHED PRODUCT B

SAFETY A SAFETY BPOTENCY AEFFICACY A

POTENCY BEFFICACY B

ANNEX

I

4

Titre du diaporama

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CURRENT SITUATION (2)

BT = 24 serotypes

3 MSV CHOSEN 2 024 POSSIBILITIES

5 MSV CHOSEN 42 504 POSSIBILITIES

multi-strain concept = pragmatic approach

Titre du diaporama

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MULTI-STRAIN DOSSIERPRE-REQUISITES (1)

• Diseases:

Avian Influenza, Foot-and-Mouth Disease, Bluetongue

• Inactivated vaccines only

• Not to be built in emergency situation!

multi-strain dossier emergency dossier

5

Titre du diaporama

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MULTI-STRAIN DOSSIERPRE-REQUISITES (2)

• Maximum number of strains/subtypes/Ag/AI fixed by the Applicant

• Same method of preparation of each Active Ingredient

• Standardized blending volume, excipients, adjuvants, target content for each

Active Ingredient

• Control of Finished product : specific of each Active Ingredient (cross-reactions to be limited)

Titre du diaporama

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MULTI-STRAIN DOSSIERPRINCIPLES (1) - POTENCY AND EFFICACY

MSV 1 MSV 2 MSV 3

Finished Product 1 Finished Product 2 Finished Product 3

ANNEX

I

POTENCY 1EFFICACY 1

POTENCY 2EFFICACY 2

POTENCY 3EFFICACY 3

Target Ag amount

CLAIM 1 CLAIM 2 CLAIM 3

Limited

cross-reactions

between potency

tests 1, 2 and 3

6

Titre du diaporama

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MULTI-STRAIN DOSSIERPRINCIPLES (2) - POTENCY AND EFFICACY

MSV 1 MSV 2 MSV 3

Finished Product A

POTENCY A = POTENCY 1 and POTENCY 2 and POTENCY 3

INDICATION A = INDICATION 1 + INDICATION 2 + INDICATION 3

Target Ag amount

Pre-requisites !

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MULTI-STRAIN DOSSIERPRINCIPLES (3) - SAFETY

MSV 1 MSV 2 MSV 3

FINISHED PRODUCT A

Max. Ag amount

MSV 4

SAFETY A

7

Titre du diaporama

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MULTI-STRAIN DOSSIERPRINCIPLES (4) - SAFETY

MSV 1 MSV 2 MSV 3


Max. Ag amount

MSV 4

SAFETY A

=Pre-requisites !

Titre du diaporama

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MULTI-STRAIN DOSSIERPRINCIPLES (5) - STABILITY

MSV 1 MSV 2

FINISHED PRODUCT 1 FINISHED PRODUCT 2

1st Option

STABILITY 1 STABILITY 2FINISHED PRODUCT

MSV 1 MSV 2

THE SHORTEST SHELF-LIFE

Pre-requisites !

8

Titre du diaporama

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MULTI-STRAIN DOSSIERPRINCIPLES (6) - STABILITY

MSV 1 MSV 3


2nd Option

STABILITY on 3 batches

of FINISHED PRODUCT A

STABILITY on 3 batches,

related to active ingredient 3

MSV 2

Shelf-life of FINISHED PRODUCT A

Pre-requisites !

Titre du diaporama

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Requirements of PhEur. (5)

Documents

EDQM Workshop Bluetongue Vaccines · 1 EDQM Workshop Bluetongue Vaccines 19 February 2013 Strasbourg, France 19/02/13 ©2013 EDQM, Council of Europe. ... Efficacy of vaccination campaign