Consideraciones en el Control de la Enfermedad de Marek Fernando Lozano DVM, Ph.D. Global Veterinary Services
11ยบ Seminario Internacional de Ciencias Avicolas C.A.P.I.A. - Buenos aires, May 10, 2016
CONTENIDO Epidemiología e Impacto Económico
Características y Biología del Herpesvirus Estudios de Eficacia
Nuevas areas de investigación
2
Enfermedad de Marek
Epidemiolog铆a e Impacto Econ贸mico
3
EPIDEMIOLOGIA GLOBAL DE MAREK
US$943 million worldwide (Mortality, production losses, vaccination cost) in 1984
1 – 2 Billion dollars lost annually - 2004
4
EPIDEMIOLOGIA en E.E.U.U.
5 Dunn J.R. & Gimeno I. M. Curent Status of Marek’s Disease in the United States and Globally Based on a Questionnaire Survey. Avian Diseases 2013. 57:483-490.
INCREMENTO EN EL USO DE RISPENS
Fig. 4. Countries reporting increased use of CVI988/Rispens vaccine during the last 10 yr. Colored countries indicate at least one questionnaire response reporting increased use of CVI988/Rispens for that country.
Dunn J.R. & Gimeno I. M. Curent Status of Marek’s Disease in the United States and Globally Based on a Questionnaire Survey. 6 Avian Diseases 2013. 57:483-490.
DOBLE VACUNACION o REVACUNACION
Dunn J.R. & Gimeno I. M. Curent Status of Marek’s Disease in the United States and Globally Based on a Questionnaire Survey. 7 Avian Diseases 2013. 57:483-490.
Uso Hist贸rico de Vacunas de Marek E.E.U.U. Otros Paises
Source: Gimeno I. La enfermedad de Marek. Primera parte. 2015.
Actualmente
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Evoluci贸n de Virulencia ??
% Decomisos en E.E.U.U.
% DECOMISOS ESTACIONALES 0.8 0.7 0.6 0.5 0.4 0.3 0.2 0.1
0
2005 2006
Enfermedad de Marek
Características y Biología De Marek’s Herpesvirus
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Herpesvirus en Humanos y Animales
Bovinos
Humanos
Alphaherpesvirus (4 Géneros)
Pollos y Pavos
Bovine Herpesvirus 2 (BoHV-2)
Herpes Simplex Virus 1 (HSV-1)
Gallid Herpesvirus 1 (GaHV-1 = ILTV)
Bovine Herpesvirus 5 (BoHV-5)
Varicella-zooster virus (HHV-3)
Gallid Herpesvirus 3 (GaHV-3 = MDV-2)
Bovine Herpesvirus 1 (BoHV-1)
Bovine Herpesvirus 3 (BoHV-3 - CMV)
Herpes Simplex Virus 2 (HSV-2)
Betaherpesvirus (3 Géneros)
Human herpesvirus 5 (HHV-5 - CMV)
Human herpesvirus 6 (HHV-6 - Roseola) Human herpesvirus 7 (HHV-7 - Roseola)
Bovine herpesvirus 4 (BoHV-4)
Gammaherpesvirus (2 Géneros)
Human herpesvirus 4 (HHV-4 - EBV) Human herpesvirus 8 (HHV-8 - KS)
Gallid Herpesvirus 2 (GaHV-2 = MDV-1) Meleagrid Herpesvirus 1 (GaHV-1 = HVT)
Virus de la Enfermedad de Marek Gallid Herpes virus 2
Family: Herpesviridae
Sub-Family: Alpha herpesvirinae Genus: Mar di virus
dsDNA Virus – 175 kb Genome Linear
74 Genes (UL:62; US: 12) Meq&pp38
10 glicoproteinas de superficie 15 proteins tegument
Genome of MDV
Capside contiene ADN
Clasificación del Virus de Marek Serotipo:
Serotipo 1 (MDV-1) Rispens Serotipo 2 (MDV-2) SB1 / 301 B1 Serotipo 3 ( MDV-3) HVT
Patotipo:
Atenuado – Rispens Virulencia leve Virulento Muy Virulento Muy Virulento + 15
Vacunas y Serotipos de Marek Serotype
1
Origin Chicken
Pathogenicity
Strain
VV+ MDV
Oncogenic
T King, 648A
Yes
V MDV
Oncogenic
JM, GA
Yes
VV MDV
attenuated
Oncogenic Non oncogenic
RB1B
HPRS-16 (Churchill et al, 1969) CVI 988 /(Rispens et al, 1972) CVI 988/Clone C (de Boer,
1986)
R2/R3
2 3
Chicken
Turkey (HVT)
Spread
Apathogenic
Apathogenic
Non oncogenic
Non oncogenic
SB-1 (Schat, 1978) 301/B1
FC-126 (Witter 1973 and Burnmester 1968)
PB THV1 (Churchill 1973)
Vaccine Efficacy/Safety
Yes No Yes
Safety issues Rhode island red breed
Yes
Equivalent to HVT+SB1
Yes slowly
Yes slowly Yes- slowly No No
Similar to HVT
High does enhance Avian Lymphoid Leukosis?
Ciclo de Infección con el Virus de Marek de Campo (3-4 Wks)
PHASE 1: Infección Citolítica Temprana & inmuno-supresión
Virus infectiousness in litter up to 1 year
~ 1 Week old (24 – 36 Hours PI Respiratory System
Aerosol Infected poultry house environment
X
(intra-tracheal)
X
IFN-ɣ vIL-8
X
Lymphocyte infection & Cells death (T & B)
PHASE 2: Latently infected T cells PHASE 3: T cells transformation – Tumors/Lesions (3-4 Wk PI) PHASE 4: Active virus replication, environmental shedding & transmission through FFE (Follicular Feather Epithelium)
?
Infection Cycle with field MDV (3-4 Wks) Virus infectiousness 4 – 7 Months
Latency FFE
Virus replication Environmental contamination Disease transmission
Tumors
Immuno-
suppression Infected poultry house environment
Infectious Viruses Feather shaft
Dust Skin dander Feathers
Follicular Feather Epithelium (FFE)
Nuclei of FFE containing VP5 MDV Capside protein (By IHC) 7 – 14 DPI
Source: Couteaudier M. & Denesvre C. Marek’s disease virus and skin interactions. Veterinary Research. 2014. 45:36
Infection Cycle with field MDV (3-4 Wks)
PHASE 1: Early Cytolytic Infection & immune-suppression
Virus infectiousness:
Litter 4 Months – Env. RTºC 7 Months
Aerosol Infected poultry house environment
~ 1 Week old (24 – 36 Hours PI Respiratory System
X
(intra-tracheal)
X
IFN-ɣ vIL-8
X
Lymphocyte infection & Cells death (T & B)
PHASE 4: Active virus replication, environmental shedding & transmission through FFE (Follicular Feather Epithelium) Follicular Feather Epithelium (FFE)
Virus replication Environmental contamination Disease transmission
Source: Couteaudier M. & Denesvre C. Marek’s disease virus and skin interactions. Veterinary Research. 2014. 45:36
Detección de la Replicación del Virus de Marek Proteinas virales en plumas Tempranas (pp38) & Tardias (UL47)
Expresión del Virus de Marek desde los 8 días post-infección
Proteinas tempranas de Marek (pp38) En plumas
Source: Jarosinski K. Marek’s disease virus late protein expression in feather follicle epithelial cells as early as 8 days pi. Avian Diseases 2012. 56:725-731.
Enfermedad de Marek Presentación de la Enfermedad • • • • •
Linfomas (Tumores Viscerales) Dermal Neural Ocular Inmunosupresiva
Enfermedad de Marek Lesiones Causadas por Marek
Stunting
Depression Paleness in comb and wattles
Neurological signs
Lesiones Tumorales en Nervios Vagus & Brachial
Sciatic
A
Vagus
N A
Sciatic Loss of cross striations
N
Enfermedad de Marek Enfermedad de Marek Clasica o Cronica
Enfermedad de Marek LESIONES CUTANEAS
© J. Rosenb erger
© J. Rosenb erger
TUMORES EN VISCERAS
© J. Rosenb erger
Sindrome de Linfomatosis Degenerativa
B.W.Calnek
Enfermedad de Marek
Estudios de Eficacia
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Eficacia Comparativa Protección de diferentes vacunas de Rispens contra la mortalidad después de un desafío con un virus de Marek muy virulento 100 90 80 70 60 50 40 30 20 10
0
Control (- Vaccine A Vaccine B Vaccine C Vaccine D )
Control (+)
SOURCE: Beltran G., Hofacre C., Cheng S., Baxter V. and Zavala G. PDRC. 2014. AAAP Annual Meeting, Denver, CO. Efficacy of Four Different CVI-988 Vaccines Against a vv+ Marek’s Disease Virus in Commercial Hy-Line W-36 Layers 30
COMPARATIVE EFFICACY OF CVI 988 FROM 3 ORIGINS
3 Different RISPENS Vaccines DNA detection in feather pulp Monitoring Vaccination CVI 988 DNA 7 Days
Early diagnosis of tumoral DNA 648A vv+ MDV DNA 21 Days 31
EVALUACION DE PROGRAMAS DE VCUNACION EN POLLOS % Chickens with MD Lesions 56 DPC
Diferentes esquemas de Vacunaci贸n Detecci贸n de ADN viral en Plumas
21 DPC
AND Viral Detectable CVI 988 DNA HVT DNA
44%
55%
7DPV
SB1 DNA 648A vv+ MDV DNA
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Enfermedad de Marek
Tendencias Futuras
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Enfermedad de Marek NUEVAS TECNOLOGIAS EN EL CONTROL DE LA ENFERMEDAD DE MAREK
Eliminación de Genes Oncogénicos en Virus Virulentos de Marek como vacunas Vacunas con Inmuno-Moduladores (IFN; IL) Orientacion Molecular:
Interferencia de RNA: Transcriptome; Proteome Micro-RNA’s New Generation Sequence 34
SITUACION ACTUAL vs. TENDENCIAS FUTURAS Resistencia Genetica en Aves
Vacunas Dise帽adas Molecular bases Tendencias Futuras
??
Evoluci贸n del Virus de Marek MAYOR VIRULENCIA
Biolog铆a y Patogenicidad
NUEVOS PATOTIPOS Situaci贸n Actual
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GRACIAS POR SU ATENCION!