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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

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Enfermedad de Marek

Epidemiolog铆a e Impacto Econ贸mico

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EPIDEMIOLOGIA GLOBAL DE MAREK

US$943 million worldwide (Mortality, production losses, vaccination cost) in 1984

1 – 2 Billion dollars lost annually - 2004

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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

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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!

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