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CEVA’S APPROACH FOR CONTROLLING GUMBORO DISEASE By Dr. Vilmos PALYA Director of Viral Development, CEVA-PHYLAXIA BUDAPEST 19 October 2005.

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Presentation on theme: "CEVA’S APPROACH FOR CONTROLLING GUMBORO DISEASE By Dr. Vilmos PALYA Director of Viral Development, CEVA-PHYLAXIA BUDAPEST 19 October 2005."— Presentation transcript:

1 CEVA’S APPROACH FOR CONTROLLING GUMBORO DISEASE By Dr. Vilmos PALYA Director of Viral Development, CEVA-PHYLAXIA BUDAPEST 19 October 2005

2 KANATLI BAĞIŞIKLIK SİSTEMİ

3 BAĞIŞIKLIK SİSTEMİNİN YAPISI VE İŞLEVİ Lymphoid organlar Primer: Thymus (T lymphocytes) Bursa fabricius (B lymphocytes) Sekonder: Dalak Harderian bezi Kemik iliği Konjuctival lymphoid doku (CALT) Bağırsak lymphoid dokusu (GALT) Başta lymfoid dokular (HALT) Bronşiyal lymphoid organlar (BALT)

4 Immune cells Lymphocytes: T cells B cells Mononuclear phagocytes Tissue macrophages Follicular dendritic cells lymphocyte thrombocyte eosinophyl heterophyl monocyte

5 Bursal B hücre morfogenesisi

6  Civcivlerde inkübasyon periyodu: 21 days  Bursa’da B hücrelerinin gelişimi: Follikule formasyonu (cortex, medulla) B hücrelerinde gen değişimi B hücrelerinin periferal bölgelere göçü  Thymus’ta T hücrelerinin gelişimi Embryonasyonun 9.gününde T hücreleri gelişir T hücreleri çıkımdan sonra perifere göç eder Tavuk embriyoları spesifik immun cevabı başlatma yeteneğine sahiptirler In ovo aşılama Bağışıklık hücrelerinin gelişimi

7 Natural or innate immunity Adaptive or acquired immunity CellsPhagocytes, dendritic cells, NK cellsT- and B-lymphocytes Humoral factors Complement system Cytokines Antibodies Interleukines Chemical property of identified structure Carbohydrate, lipidProtein MemoryNoYes ProtectionNon-transferableTransferable Rapidity of the immune response PromptFew days or week bağışıklık

8 Innate and adaptive immunity

9  Active immunity specific immune response against antigens Primary response (first contact with antigen) –IgMIgY –Immune memory (B-ly) Secondary response (second contact with antigen) –Rapid and longer immune response –IgY  Passive immunity Maternal antibody (transmitted from hen to chick via egg yolk) Transfusion of antibodies by sera Adaptive or acquired immunity

10  Maternally derived antibodies in offsprings The level of the maternal antibodies can be increased by purposive immunisation of breeder flock Protect the chicks against diseases at early stage of life Antibodies decay 2-6 weeks after hatching The maternally derived antibodies neutralise the live vaccine viruses → inhibition of active immune response Passive immunity

11 FcRY transports IgY from yolk sac into embrionic blood (West et al., Immunity, 2004) -pH dependent IgY binding to the yolk sac membrane - the first IgY binding Fc receptor in birds Maternal immune transport in the chicken

12  Three Ig classes: IgM, IgY, IgA IgM: pentamer, expressed on the surface of B cells IgY: functionally homologous to mammalian IgG IgA: dimeric or tetrameric forms in mucosal secretion monomeric molecule in serum critical role in local immunity Specific immune response Antigen → IgM class switching mediated by T cells and cytokines IgY or IgA Strong immune memory Methods for determination of antibody response: ELISA, SN, IF, agglutination, hemagglutination Humoral immune response I.

13 Humoral immun cevap

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15 T lympocytes are the principal cells in the cell mediated immunity Two subsets CD4+ cells: helper function – central role in humoral and cellular immunity CD8+ cells: cytotoxic function Important role in antiviral and antitumor immunity Cell mediated immunity

16 Activity of different factors of immune system after viral infection

17 Role of the bursa in immune response Gene conversion in B cells → humoral immunity Intact Bursa Fabricius Chronic Bursitis after vvIBDV infection

18 GUMBORO HASTALIĞI NEDİR

19 Infectious Bursal Disease Virus (IBDV) Virus properties: Virion not enveloped, 60nm diameter, icosahedral symmetry Two genome segments, Double stranded RNA genome Segment B VP 1 VP2 VP4 VP3 VP5 Segment A Taxonomy: Family: Birnaviridae Genus: Avibirnavirus Prof. Steward McNulty, Queen’s University of Belfast

20  Serotipeleri Serotype 1 and 2 Variant suşlar (serotip 1)  Virulans bazlı grublanırsa Classical virulent IBDV Very virulent (vvIBDV) Moderately attenuated „intermedier plus”, „hot” Medium attenuated „intermedier” Heavily attenuated „mild” Infectious bursal disease (IBD, Gumboro disease) ] vaccine strains

21  Enfeksiyon ilk 3 hafta içerisinde immünosüpresyon nedenidir  3-6 haftalar içerisinde hastalığın klınik formu oluşur: Klınik bulgular enfeksiyondan 2-3 gün sonra Mortalite enfeksiyondan 5-8 gün sonra

22  IBDV infects cells of the cloacal bursa - primarily immature B- cells.  Immature B-cells mature into antibody producing cells.  If B-cells are destroyed early in life the bird may become immunosuppressed for life.

23 Picture: Y. Gardin, 2003

24 Klınik görünümler

25 Picture: Y. Gardin, 2003

26 Bursa histopatolojisi Sağlıklı

27 Bursa büyüklüğü Gün From U. Lohren, 2005

28 IBD İMMÜNODEPRESSİF ETKİSİ Enfeksiyon yaşı (Gün) Immunodepresyon (ND antikor cevaplarına göre) 1ÖNEMLİ 7 ORTA DERECEDE 14 YOK 21 YOK (after Faragher et al, 1974)

29 Characterisation of the vvIBDV strains  Pathotyping  Up to 100% mortality in SPF chickens  50-60% mortality in layers, 25-30% in broilers  Break through higher levels of MDA  not possible anymore to protect passively broilers  Antigenicity  Panel of neutralizing Mabs  no (major) antigenic drift  High cross-neutralization indices measured in SPF embryonnated eggs  Classical serotype 1 vaccines still satisfactory on SPF birds  Molecular characterisation  Sequencing of the variable domain of the VP2 gene  Amino acid residues substitutions at positions 222Ala, 256Iso, 294Iso and 299Ser = Genetic fingerprints of vvIBDV  RT-PCR of vVP2 followed by sequencing and/or RE Analysis

30 Mortality rates  Challenge of 5-week-old Lohmann SPF chickens (n=25-30) with 10 5 EID 50 of IBDV strains of varying virulence in isolated conditions by the oculonasal route.  vvIBDV induce higher mortality rates than classical virulent IBDVs  Confusion in nomenclature  Need for standardized challenge model

31 HİPERVIRULENT IBDV : MORTALİTENİN YAŞLA İLİŞKİSİ (after Meulemans et al, 1990) Mortalite (%) Bulaşma yaşı (gün)

32 Dose effect in IBDV challenge Comparison of a classical virulent IBDV (Cu1wt) and a vvIBDV (HK46): Inoculation of increasing doses 10 3  10 7 EID 50 Classical IBDV: maximum 60% mortality vvIBDV: up to 100% mortality Existence of a dose effect in IBDV challenge

33 Multiplication rates Titration of virus in BF of birds dying (or sacrificed) 3-4 days after challenge Higher multiplication rates for more virulent IBDVs 1 attenuated IBDV particle  10 particles 1 classical virulent IBDV particle  10 2 to 10 3 particles 1 vvIBDV particle  10 4 to 10 5 particles

34 VIRUS ETKİMESİ YAŞ (GÜN) PATOGENEZ LEZYON + MORTALITE LEZYON ENFEKSİYON YOK GÜÇLÜ VIRUS ZAYIF VIRUS

35 WHAT FORM OF GUMBORO DISEASE AT FIELD LEVEL ? WHICH CONTROL STRATEGY ?

36 Laboratory tools From Di Fabio et al, 2000

37 OIE I.B.D.V. Classification N. Eterradossi - AFSSA Lab - Ploufragan France R.N.A. : Characterisation by sequencing: Sequence of Nucleotids and deduced a.a. CAPSIDE ANTIGENS Characterisation by Monoclonal Antibodies (Mab) 8 Mab put in contact with the virus = bind or not.

38 Specific Antigen-Capture ELISA Mab specific  Polyclonal anti -IBDV Capture of the virus Fixation or not Revelation OIE I.B.D.V. Classification N. Eterradossi - AFSSA Lab - Ploufragan France

39 VP2 Protein Ag3 Ag4 Ag1 Ag5Ag6 Ag7 Ag8 Ag9 Classical IBD virus : All Mabs bindings positive OIE I.B.D.V. Classification N. Eterradossi - AFSSA Lab - Ploufragan France

40 VP2 Protein Ag1 Ag5Ag6 Ag7 Ag8 Ag9 vv IBD virus : Bindings to Mab 3 and 4 are negative - - OIE I.B.D.V. Classification N. Eterradossi - AFSSA Lab - Ploufragan France

41 CEVA’S APPROACH OF GUMBORO CONTROL

42 Results of the IBDV survey done by CEVA in with AFSSA OriginMab 1Mab 3Mab4Mab5Mab6Mab7Mab8Mab9 F52/70 (Classic)66%91%78%75%110%114%96%77% 1% (vvIBD)61%1%5%68%118%113%80%53% 4%24% Algeria94%4%24%90%143%153%131%49% 3%10% Bulgaria89%3%10%77%167%172%115%78% 1%14% Hungary81%1%14%72%166%174%135%74% 1%10% India65%1%10%70%121%126%81%73% 1%10% Iraq74%1%10%70%121%126%81%73% 1%11% Jordan106%1%11%69%206%220%167%74% 0%11% Kenya104%0%11%63%192%177%144%86% Malaysia83%123%94%61%89%106%132%38% 1%5% Morocco86%1%5%83%205%189%141%62% 1%7% Pakistan94%1%7%60%181%175%137%76% 2%3% Romania60%2%3%37%112%105%48%78% 1%20% Tanzania79%1%20%91%131%140%118%42% 0%12% Tunisia93%0%12%73%155%162%120%91% 1%6% Turkey69%1%6%54%151%152%78%102%

43 OriginMab 1Mab 3Mab4Mab5Mab6Mab7Mab8Mab9 91%78% F52/70 (Classic) 66%91%78%75%110%114%96%77% 1% (vvIBD) 61%1%5%68%118%113%80%53% Cevac IBD L64%89%74%23%94%93%91%91% CEVAC IBD L derived from classical IBDV strain and NOT from vvIBDV AFSSA 2001 CEVAC IBD L Antigenic typing CEVA’S APPROACH OF GUMBORO CONTROL

44 Molecular typing of IBDV strains Segment B VP 1 VP2 VP4 VP3 VP5 Segment A 709 Hypervariable region PCR reaction P1 P PCR reaction P2.3 P Nucleotide numbering according to IBDV-STC strain (Kibenge et al, J. Gen. Virol (71) ). PCR and sequencing

45 Differentiation of IBDV strains (VP2 gene 414bp BseD I RFLP) Gp82LIBDV 2512 P3 OKYM 52/70 STC FS D69 IBD B.WSV D142 FS D69 AEG1 50 bp DNA ladder VarE vaccine classical var very virulent subc CEVA vv 2512 Jakabszállás CEVA’S APPROACH OF GUMBORO CONTROL

46 MOH94/94H" MOH97/97H" Csengele/97H" PECS/97H" OKYMT/95J DV86/86N OKYM/91J KABA/97H" UK661/86GB CS89/89GB FS/97H" AEG1/97H" Toszeg/97H" Diosjeno/97H" 849VB/87B PBG98/76GB GP82/75H" D78" TAD" Cu1/76D LIBDV/75H" P2/73D VarE/85US U28/88US VarA/85US 3212/88US GLS/87US 52/70GB P1/75H" P1II/75H" STC/67US IBDL(2512)/80US" P3/77H" P6/78H" P7/78H" P9/81H" P10/81H" P11/81H" 00273/73Aus OH/82US Phylogenetic study of IBDV strains vv classical vacc US var subc serotype I serotype II vacc (based on the hypervariable region of the VP2 gene, 414bp) CEVA’S APPROACH OF GUMBORO CONTROL

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48 Aşı türleri  Canlı attenue Mild Intermedier Intermedier plus („hot”) İlk ve devamı aşılamalar için  Inaktive Sadece canlı aşılama devamına Yüksek titre ve uzun süreli korunma

49 Conventional IBD Vaccines  Mild IBD Vaccine - Easily eliminated by low levels of maternal antibody.  Intermediate Vaccine - relatively safe to use in ovo or at hatch. Eliminated by low to moderate levels of maternal immunity.  Intermediate Plus Vaccine - not safe to give in ovo unless modified in some manner. Eliminated by high level maternal immunity.

50 IBDV aşılarının filogenetik grupları (Palya, 2003) MB group STC group 2512 group 228E group P2 group D78 group Lukert group V877 group

51 Aşı ve enfeksiyon sonu lezyon gelişimi (4 hft.SBF) IDBV strains Days post infection mild intermedier ---- ●●● R intermedier plus - ●●●●●● R classical - ●●*●* ●*●* ●*●* ●●● very virulent ●●●*●* ●*●* ●*●* ●●● vaccine strain [ * clinical signs, death ** 4-week old SPF birds R: regeneration

52 Immunity induced by strains of different virulence ** 4-week old SPF birds

53 Immunity induced by strains of different virulence - CONCLUSIONS - Strains of higher virulence cause earlier bursa damage and earlier serological reponse Only strains that casue bursal damage induce immune response The tissue-culture adopted „mild” vaccine strain does not induced immune response in 4-week old SPF chicks (probably due to lack of receptors)

54 positive bursa negative bursa Infection at 11 days age The influence of maternal antibody level on the replication of classical IBDV strain

55 Infection at 11 days of age The influence of maternal antibody level on the replication of vv IBDV strain positive bursa negative bursa

56 Vaccination at 15 days of age positive bursa negative bursa The influence of maternal antibody level on the replication of intermedier plus IBDV

57 Vaccination at 18 days of age The influence of maternal antibody level on the replication of intermedier IBDV strain positive bursa negative bursa

58 Antibody titre D1 Age Passive immunity Age at vaccination Protection level Subclinical IBDV Vaccine take level Intermediate V. AGE AT VACCINATION VARIES ACCORDING TO VACCINE TYPE and EPIDEMIOLOGICAL SITUATION IBD: The concept of constant protection Protection level v.v. IBDV Vaccine take level Intermediate + V.

59 Farm No IBDscl. IBDvv IBD Neighborhood No IBDMildIntermediate Intermediate plus scl. IBDIntermediate Intermediate plus vv IBD Intermediate plus Vaccination programme versus epidemiology

60 Farm No IBDscl. IBDvv IBD Neighborhood No IBDCevac Bursa LCevac Gumbo LCevac IBD L scl. IBDCevac Gumbo L Cevac IBD L vv IBDCevac IBD L

61 CEVA’S APPROACH OF GUMBORO CONTROL Farm No IBDscl. IBDvv IBD Neighborhood No IBD Cevac Transmune IBD scl. IBD vv IBD

62 CEVAC IBD L field use: Is it immunosuppressive ? CEVA’S APPROACH OF GUMBORO CONTROL

63 round 1round 2 round 4 round 3 Intermediate plus vaccination Net income (FF/m 2 ) O Benefit level (After Y. Gardin, 1992) Economical Interest of Using an Intermediate Plus Vaccine in a Farm Contaminated with vvIBDV CEVA’S APPROACH OF GUMBORO CONTROL

64 CEVAC IBD L field use TURKEY IMMUNOSUPPRESSION IN CHICKENS

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67 PI = livability x average slaughter BW / FCR  > 240: very good  : good  : medium  : poor

68 IMMUNOSUPPRESSION IN CHICKENS Intermediate Plus IBD live vaccines use in Europe: CEESA figures.  CEESA means European Centre for Animal Health (Centre Europeen de la Sante Animale, in French).

69 IMMUNOSUPPRESSION IN CHICKENS Intermediate Plus IBD live vaccines use in Europe: CEESA figures.  It includes 12 countries: Austria, Belgium, Denmark, France, Germany, Italy, the Netherlands, Portugal, the Republic of Ireland, Spain, Switzerland, the United Kingdom.

70 IMMUNOSUPPRESSION IN CHICKENS

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72 CEVAC IBD L field use BRAZIL IMMUNOSUPPRESSION IN CHICKENS

73 90,000 broiler chickens Vaccination with CEVAC IBD L IMMUNOSUPPRESSION IN CHICKENS

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78  Increased performances thanks to the optimum control of vvIBD in Brazil by Cevac IBD L. COMMENTS Other countries constantly report the same benefit.

79 IMMUNOSUPPRESSION IN CHICKENS COMMENTS Rate of usage of Cevac IBD L in the top 4 Brazilian broiler integrations in SADIA100% 2PERDIGAO100% 3FRANGOSUL0%* 4SEARA100% * Use intermediate vaccine only.

80 IMMUNOSUPPRESSION IN CHICKENS 2005: Sadia (2nd largest Brazilian integration): Cevac IBD L is used in 100% of its capacity, i.e. 45 million broilers per month. Four Brazilian broiler chickens produced out of 10 are vaccinated using Cevac IBD L. From its introduction (2000) in Brazil, Cevac IBD L is now used at a rate of 140 million doses per month:

81 CEVAC IBD L Immunodepression study IMMUNOSUPPRESSION IN CHICKENS

82 Immunosuppression study according to the European Pharmacopoeia requirements Ceva-Phylaxia study 11-day old SPF birds. Vaccination by eye drop (Day 0) with Cevac IBD L Control 50 birds per group. Four days later (D4, ie at maximum IBD vaccine replication in the bursa), ND vaccination by eye drop with Hitchner B1 strain (Cevac Uni L). ND challenge (Herts 33 strain, 10 6 EID50 per bird, by im route): day 18 (14 days after ND vaccination). ND challenge assessment: day 32. IMMUNOSUPPRESSION IN CHICKENS

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84 CONCLUSIONS Cevac IBD L is safe upon the immunological functions. Cevac IBD L is the right tool to prevent vvIBD. Cevac IBD L is the right way to come back to performances and profits.

85 CEVA’S APPROACH OF GUMBORO CONTROL  And tomorrow… CEVAC TRANSMUNE IBD

86 IBD: INNOVATIVE VACCINATION STRATEGY Main issues around the protection against IBD:  Differences in level of MDA  Variability in quality of vaccine application Drinking water administrationDrinking water administration  To adapt to the epidemiological context

87 Maternal antikor dağılımı Heterojen titreler: C.V. = 114% Homojen titreler C.V. = 29% Kötü dağılımlı titreler C.V. = 67%

88 IBD: INNOVATIVE VACCINATION STRATEGY CEVA’s answer to address these issues: Cevac Transmune IBD  Winterfield 2512 strain of IBDV  Specific Antibodies  Live, immune-complex vaccine  Injected In-ovo, orIn-ovo, or Sub-cutaneous route at day-oldSub-cutaneous route at day-old

89 Ability of the chick / the embryo to develop an immune response. IBD: INNOVATIVE VACCINATION STRATEGY Background 1985, Sharma: First in ovo Gumboro vaccination but MDA or safety problems: Intermediate and intermediate + vaccines: Efficacious in front of MDA but unsafe for SPF Embryos. Mild vaccines: safe for Embryos but susceptible to MDA

90 SAFETY EFFICACY ???? IBD: INNOVATIVE VACCINATION STRATEGY

91 The IMMUNE-COMPLEX concept ( ) It will CONTROL and PROTECT the vaccine virus: Virus + Antiserum IBD: INNOVATIVE VACCINATION STRATEGY

92 The IMMUNE-COMPLEX concept ( ) MECHANISM ?? IBD: INNOVATIVE VACCINATION STRATEGY

93 1 / Antiserum neutralises the vaccine virus  embryo and vaccine are protected 2 / Progressively, the MDA are metabolised, as well as antiserum  Release of vaccine virus is synchronised with decrease of MDA 3 / When vaccine virus is stronger than antiserum + MDA action, it starts to replicate  and to Vaccinate !!! IBD: INNOVATIVE VACCINATION STRATEGY

94 Antibody titre VACCINATION 0 Age (days) Not protected chicken Protected chicken - 3 Maternally Derived Antibodies Protection on individual basis. Bird by bird !!! Active Immunity IBD: INNOVATIVE VACCINATION STRATEGY

95 CEVAC TRANSMUNE IBD 100% protection

96 CEVAC TRANSMUNE IBD Protection of the Bursa of Fabricius after vvIBD challenge at 3,4,5 weeks of age (histology) Age at challenge 345 Cevac Transmune IBD SQ YES Competitor vaccine dw 12 days NO YES

97 CEVAC TRANSMUNE IBD

98 IBD: INNOVATIVE VACCINATION STRATEGY  Vaccination as soon as possible  Mass vaccination – quick and correct  Single vaccination – no follow-ups  No need for date determination  No effect of variable MDA levels  Winterfield 2512 safety and efficacy  Compatible with Marek vaccines, … Advantages of Cevac Transmune IBD

99 IBD: INNOVATIVE VACCINATION STRATEGY THANK YOU FOR YOUR ATTENTION !


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