no hay conflicto de interes relacionado con esta presentación · 2016-04-30 · rotavirus...
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Disclosure
ROTAvolutionProf. Dr. F. Martinón-Torres (FMT)
No hay conflicto de interesrelacionado con esta
presentación
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Prof. Dr. F. Martinón-TorresHead of Translational Pediatrics and Infectious Diseases
Hospital Clínico Universitario de Santiago (Spain)
GENVIP – www.genvip.org / @fedemartinon
Jornadas vacunas AEP
Toledo 2016
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DogmasclásicosenIDs
@fedemartinon, GENVIP 2016
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@fedemartinon, GENVIP 2016 From https://www.gov.uk (accessed 7-april 2016)
Efectividad espectaculardelavacunaciónfrentearotavirusallídondeseutiliza
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ImpactodelavacunaciónfrentearotavirusenGalicia
Martinón-Torres F, et al. Human Vaccine & Immuno, vol 8, issue 7, July 2012, epub ahead of print@fedemartinon, GENVIP 2016
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Figure 1a: Hospitalizations rates RV-AGE
0
200
400
600
800
1.000
1.200
Jul2003-Jun2004
Jul2004-Jun2005
Jul2005-Jun2006
Jul2006-Jun2007
Jul2007-Jun2008
Jul2008-Jun2009
Jul2009-Jun2010
Hosp
italiz
atio
n ra
te (p
er 1
00,0
00) <12 months
12-23 months24-35 months36-59 months
Rotavirus vaccines introduction
Rotavirusvaccine impact with moderatevaccination coverage (40-50%):Galicia
RV vaccine introduction
Martinón-Torres F, et al. Human Vaccine & Immuno 2012
45%RV-AGE
49%All cause
AGE
@fedemartinon, GENVIP 2016
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Vaccine effectiveness to prevent any rotavirus AGE
Vaccine effectiveness to prevent hospital admision
91.5%(CI 95%:83.7%-95.6%)
Complete vacc: 92.8% (84.7-96.6%)Partial vacc: 84.0% (45.5-95.3%)
95.6%(CI 95%: 85.6-98.6%)
Complete vacc: 98.3% (87.4-100%)Partial vacc: 89.4% (53.9-97.5%)
– October 2008-June 2009– 682 children below 5 yo with AGE prospectively collected– 18 C.S. y 10 hospitals from Galicia and Asturias– In all cases, rotavirus antigen detection was performed (Test Vikia®)– Case-control design VE= 1-OR
@fedemartinon, GENVIP 2016
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29 %
49 %49 %
22%*
28 %
0
10
20
30
40
50
60
70
80
90
100
0
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400
600
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1200
2003-2004 2004-2005 2005-2006 2006-2007 2007-2008 2008-2009 2009-2010 2010-2011 2011-2012
Rotav
rius v
accin
ateion
cove
rage (%
)
Rotav
irus a
cute
gastr
oente
ritis h
ospit
alizati
on ra
te (/1
00.00
0)
Period (from July to June)
<12 months12-23 months24-35 months36-47 months48-59 monthsRV Vaccination coverage
(*)22%is the mean RVvaccine coverage for that period.However, for 5months within that period,nonew batches ofvaccine werereleased onto the market,andthe coverage estimated for those months was 0-5%.
Martinón-Torres F et al. Human Vaccine 2013
Reverseevidence ofrotavirusvaccines effectiveness
@fedemartinon, GENVIP 2016
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@fedemartinon, GENVIP 2016
¿Qué pasa si NO ves
rotavirus porque NO lo sospechas?
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OtrasformasclínicasdescritasdeenfermedadporRotavirus
@fedemartinon, GENVIP 2016
Ø Encefalopatia aguda
Ø Convulsiones
Ø Pancreatitis
Ø Coagulación intravascular diseminada
Ø Cerebelitis
Ø SIRS
Ø Megacolon tóxico
Giordano S et al. New Microbiol 2013;36(1):97-101.Thompson MJ et al. Pediatr Neurol 2012;46(1):48-50.Nakano I et al. J Clin Microbiol 2011;49(12):4382-5.Bharwani SS et al. BMJ Case Rep 2011Hung CW et al. Acta Paediatr 2009;98(11):1850-2.Limbos MA et al. CID 1996;22(5):834-6.
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@fedemartinon, GENVIP 2016
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Rotavirusinfection:Dowe suspect it?
@fedemartinon, GENVIP 2016
Bernstein et al. J. Inf dis 1991;164:277-284Velazquez FR et al. NEJM 1996;335:1022-28White LJ et al. J. R. Soc. Interface 2008;5:1481-90
Up to 75% of rotavirus infections in children
between 6 and 24 months of age occur
asymptomatically
(this % can be even higher below 6 months of age)
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Sugata K. Pediatrics 2008;122:392-397Blutt SE. J Virol 2006;80(13):6702-5.Fenaux M. J Virol 2006;80(11):5219-32.Fischer TK. J Infect Dis 2005;192(5):913-9.Nakagomi T.Arch Virol 2005;150:1927-31.Azevedo MS J Virol 2005;79(9):5428-36.
● RV Ag in blood in 22/33 samples of RV infected children vs 0/35 in controls (Blutt)
● RV Ag in blood in 30/70 children withRV AGE vs 1/53 in controls (Fischer)
● Viremia without diarrhea (Crawford)
● Extraintestinal presence withoutdiarrhea (macrophages) (Crawford)
@fedemartinon, GENVIP 2016
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@fedemartinon, GENVIP 2016
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@fedemartinon, GENVIP 2016
Very high frequency of rotavirus antigenemia…… but discordance between stool and blood strains!!
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Martinón-Torres, Málaga 2006
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@fedemartinon, GENVIP 2016
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RotavirusandCeliac disease
@fedemartinon, GENVIP 2016
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@fedemartinon, GENVIP 2016
VP6 has epitopes sharing 62-88% similarity with Type 2 human ryanodine receptorsHighly predicted to be B-cell epitopesRecognizable by MG-related HLA
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RevisióndelosdogmasIDs clásicos
@fedemartinon, IIC Oxford 2015
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CONFIDENTIAL – FOR INTERNAL USE ONLY
@fedemartinon, GENVIP 2016
ENFERMEDAD
SISTÉMICA:
- Infecciosa
- Autoinmune
DIARREA
ESPECTRODEENFERMEDADROTAVIRUS
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@fedemartinon, GENVIP 2016
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@fedemartinon, GENVIP 2016
¿Tiene algún impacto la vacuna de
rotavirus frente a formas clínicas NO diarreicas?
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Payne et al. Clin Infect Dis. 2014 Jan;58(2):173-7. doi: 10.1093/cid/cit671
Rotavirusvaccination andseizurereduction
@fedemartinon, IIC 2015
A statistically significant protective association was observed between a full course of rotavirus vaccination vs no vaccination for both first-ever seizures (risk ratio [RR] = 0.82; 95% confidence interval [CI], .73-.91) and all seizures (RR = 0.79; 95% CI, .71-.88).
(186 502 children)
(64 099 children)
Risk ofSeizure Following RotavirusVaccination(first seizure rate per100.000persons/year)
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@fedemartinon, GENVIP 2016
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Pardo Seco J et al. PIDJ 2015 july
VacunaciónfrenteaRVyreduccióndeconvulsiones
@fedemartinon, GENVIP 2016
Convulsiones780.3*
ICD-9-CM codes
18.7% a 45.0% descenso
hospitalizacionespor este motivo tras
introduccion RV
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@fedemartinon, GENVIP 2016
¿Pero POR
QUÉ?
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OMICS APPROACH TO ROTAVIRUS INFECTION/VACCINATION (ROTANEXT PROJECT) Martinón-Torres F, Gómez Rial J, Salas A /ISCIII – FEDER funds grant – 2014-2017 (PI13/02382) + RESCEU
Hypothesis
ROTAVIRUS IMMUNE PROTECTION MIGHT BE ESTABLISHED BY A DUAL MECHANISM
MUCOSAL IMMUNE PROTECTION
Mediated by Intestinal RV-IgASaliva RV-IgA as a good surrogate
ü Critical role for intestinal immunity to RVü Functionally important for clearance of a
primary infectionü Absolutely essential in protection for re-infection
SYSTEMIC IMMUNE PROTECTION
Mediated by Serum IgA (and IgG)
ü Role in systemic rotaviraemiaü Prevent the spread of RV
@fedemartinon, GENVIP 2016
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Which is the key ofthe immunity torotavirus
@fedemartinon, GENVIP 2016 Clarke et al. Mucosal immunology 2015 epub ahead of print
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Naturalinfection with rotavirus
@fedemartinon, GENVIP 2016 Clarke et al. Mucosal immunology 2015 epub ahead of print
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Applying Biology of Systems toRotavirus infection: the transcriptomicsfingerprint
ProyectoROTANEXT:Vacunómica yBiologíadesistemasaplicadasenla
infecciónyvacunaciónporrotavirus
@fedemartinon, GENVIP 2016 Salas A, Gomez-Rial J, Martinón-Torres F. Unpublished data / submitted to Imm & Inf
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Transcriptomics ofrotavirusinfection
@fedemartinon, GENVIP 2016 Salas A, Gomez-Rial J, Martinón-Torres F. Unpublished data / submitted to Imm Inf
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ENFERMEDAD SISTÉMICA
y/o EXTRAINTESTINAL:
- Infecciosas
- Autoimmune
DIARREA ✔✔✔✔
✔ / ??????
ROTAVOLUTION:Nuevoespectroclínicodelainfecciónporrotaviruseimpactoconocidodelasvacunasdisponibles
CUADRO VACUNACLÍNICO IMPACTO
Rivero I, Rial J, Martinón-Torres F. J Inf Dis 2016 in press
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NecesidadesdeINVESTIGACIÓNenelnuevoparadigmadeinfecciónporRV
@fedemartinon, GENVIP 2016
• Desarrollo de tests para deteccion de viremia-antigenemia por RV• Búsqueda de nuevos biomarcadores de manif.extraintestinales de RV• Evaluación de papel de la vacunación por RV frente a las
manifestaciones extraintestinales, agudas o de origen autoinmune• Determinar la frecuencia de sintomas extraintestinales, especialmente
fuera de la edad esperada para la diarrea por rotavirus• Investigar la estacionalidad de los sintomas extraintestinales• Explorar los efectos heterólogos de las vacunas RV y sus mecanismos:
inmunidad heterologa y/o entrenamiento inmune o alteración microbiota• Explorar la patogénesis de la infeccion por rotavirus y la interacción
huesped-rotavirusRivero I, Rial J, Martinón-Torres F. J Inf Dis 2016 en prensa
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@fedemartinon, Toledo 2016
¿Cómo es posible que la vacuna de rotavirus NO esté en el calendario
vacunal español?
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@fedemartinon, Toledo 2016
“ Common barriers that remain include
Ø the perception of a low disease burden
Ø unfavourable cost-effectiveness
Ø potential safety concerns
Since 2006, all of these factors have been further addressed by several
studies … Consequently, and in our opinion, there should be no barriers left
to the implementation of universal rotavirus vaccination in all European
countries.”
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@fedemartinon, GENVIP 2016
Junio 2006
Necesaria actualización eficiente y transparente
Al menos 2.336 nuevos artículos publicados, sólo sobre la vacuna….
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@fedemartinon, Brighton 2016www.tipicosantiago.com
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• Los beneficios reales de la vacunación frente a rotavirus sonmayores que los teóricos•Es necesario profundizar en el concepto de ROTAvolution y explorar los beneficios inesperados de la vacunacion• Hoy por hoy es dificil justificar que la vacuna de rotavirus no forme parte del calendario vacunal infantil español• Debemos trabajar EN SERIO para que la vacuna de rotavirus llegue a todos los niños españoles
MENSAJESPARACASA
TWITTER @fedemartinon, GENVIP 2016
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Translational Pediatrics and Infectious DiseasesGenetics, Vaccines and Infections in Pediatrics Research Group (GENVIP)
Healthcare Research Institute of Santiago (IDIS)www.genvip.org
@fedemartinon