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.
25/02/2013
1
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
25/02/2013
2
• 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
25/02/2013
3
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
25/02/2013
4
Advantages• It is a good product if used properly
(right season and gestation period):CheapOne injection Strong and long lasting immunity
Live-modified vaccine
25/02/2013
5
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
Diseased animals:250,662
Outbreaks: 432
Diseased animals:3,698
Outbreaks: 3,709
Diseased animals:93,954
BTV4New serotype
Sardinia: 24 cases
Tuscany: no cases
25/02/2013
6
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
25/02/2013
7
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
25/02/2013
8
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
25/02/2013
9
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).
Adverse events observed in the use of MLV
Adverse events observed in the use of MLV
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
25/02/2013
10
Circulation of BTV-16 vaccine strainin Italy2006
2008
2007
2009
25/02/2013
11
BTV-16 in Croatia
…. or if the vaccines are administered in animals with existing infections …….
Adverse events observed in the use of MLV
25/02/2013
12
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.
Adverse events observed in the use of MLV
• 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)
Adverse events observed in the use of MLV
25/02/2013
13
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
25/02/2013
14
Malformation induced by MLVs
25/02/2013
15
• 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%)
Adverse events observed in the use of MLV
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.
Adverse events observed in the use of MLV
25/02/2013
16
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
Adverse events observed in the use of MLV
-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
Days following vaccination
% 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
25/02/2013
17
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
Days following vaccination
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)
25/02/2013
18
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.
Adverse events observed in the use of MLV
25/02/2013
19
• 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
25/02/2013
20
… 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
…
25/02/2013
1
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)
25/02/2013
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!!!!
25/02/2013
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
25/02/2013
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
BLUETONGUE VACCINATION PROGRAMME
• 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
25/02/2013
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
BLUETONGUE VACCINATION PROGRAMME
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
BLUETONGUE VACCINATION PROGRAMME
25/02/2013
7
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
25/02/2013
8
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
25/02/2013
9
CURRENT SITUATION: BT RESTRICTION ZONES
FUTURE: BTV-1 VACCINATION ZONES?
25/02/2013
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
Health andConsumersHealth andConsumers
Outline
Evolution bluetongue in the EU 2001 – 2012 EU reaction: policy and measures Impacts and Costs Lessons learnt Conclusions
2
Health andConsumersHealth andConsumers
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
Health andConsumersHealth andConsumers
Bluetongue in the EU
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
Health andConsumersHealth andConsumers
Bluetongue in the EU
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
Health andConsumersHealth andConsumers
Evolution Bluetongue in the EU
http://ec.europa.eu/food/animal/diseases/controlmeasures/bt_outbreaks_en.htm
4
Health andConsumersHealth andConsumers
Evolution Bluetongue in the EUNumber of outbreaks notified by year
Normal scaleLogaritmic scale
Health andConsumersHealth andConsumers
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
Health andConsumersHealth andConsumers
EU response: Measures in the EU
Sustainable control
Movement restrictions
SurveillanceVaccination
Health andConsumersHealth andConsumers
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
Health andConsumersHealth andConsumers
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:
Health andConsumersHealth andConsumers
EU response: EU funds
7
Health andConsumersHealth andConsumers
Lessons learnt
- EU rules not easy to understand- Impact of bluetongue- Economics: Costs (vaccination) vs Benefits (disease control)
Health andConsumersHealth andConsumers
EU rules not easy to understand
Modified live vaccine
8
Health andConsumersHealth andConsumers
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
Health andConsumersHealth andConsumers
Impact – calves born 2005-2012
Source: FAVV, Belgium
Belgium
9
Health andConsumersHealth andConsumers Source: UECBV, 2012
France
Impact – births 2002-2012
Health andConsumersHealth andConsumers
Impact – dead cattle 2007-2011
Source: FAVV, Belgium
Belgium
10
Health andConsumersHealth andConsumers
Impact – milk production 2007-2012
Source: FAVV, Belgium
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
Health andConsumersHealth andConsumers
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
Health andConsumersHealth andConsumers
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
Health andConsumersHealth andConsumers
Costs of disease control measures: EU contribution
Health andConsumersHealth andConsumers
Costs of vaccination: Unitary costs per vaccine dose claimed by MSs for EU co-funding
13
Health andConsumersHealth andConsumers
Costs of vaccination: Unitary costs per vaccine dose claimed by MSs for EU co-funding
Health andConsumersHealth andConsumers
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
Health andConsumersHealth andConsumers
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…
Health andConsumersHealth andConsumers
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
Health andConsumersHealth andConsumers
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
Titre du diaporama
3
• 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)
Titre du diaporama
4
• 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
Titre du diaporama
5
multi-strain concept
NOT compulsory !
standard dossier
or
multi-strain dossier
BACKGROUND (4)
Titre du diaporama
6
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
7
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
8
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
9
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
10
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
11
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 !
Titre du diaporama
12
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
13
MULTI-STRAIN DOSSIERPRINCIPLES (4) - SAFETY
MSV 1 MSV 2 MSV 3
FINISHED PRODUCT A FINISHED PRODUCT B
Max. Ag amount
MSV 4
SAFETY A
=Pre-requisites !
Titre du diaporama
14
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
15
MULTI-STRAIN DOSSIERPRINCIPLES (6) - STABILITY
MSV 1 MSV 3
FINISHED PRODUCT A FINISHED PRODUCT B
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
16
Requirements of PhEur. (5)